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1. uAUG creating variants in the 5’UTR of ENG causing Hereditary Hemorrhagic Telangiectasia

Author: Omar Soukarieh, Emmanuelle Tillet, Carole Proust, Charlène Dupont, Béatrice Jaspard-Vinassa, Florent Soubrier, Aurélie Goyenvalle, Mélanie Eyries, and David-Alexandre Trégouët
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract Hereditary Hemorrhagic Telangiectasia (HHT) is a rare, autosomal dominant, vascular disorder. About 80% of cases are caused by pathogenic variants in ACVRL1 (also known as ALK1) and ENG, with the remaining cases being unexplained. We identified two variants, c.-79C>T and c.-68G>A, in the 5’UTR of ENG in two unrelated patients. They create upstream AUGs at the origin of upstream overlapping open reading frames (uoORFs) ending at the same stop codon. To assess the pathogenicity of these variants, we performed functional assays based on the expression of wild-type and mutant constructs in human cells and evaluated their effect on ALK1 activity in a BMP-response element assay. This assay is mandatory for molecular diagnosis and has been so far only applied to coding ENG variants. These variants were associated with a decrease of protein levels in HeLa and HUVEC cells and a decreased ability to activate ALK1. We applied the same experiments on three additional uoORF-creating variants (c.-142A>T, c.-127C>T and c.-10C>T) located in the 5’UTR of ENG and previously reported in HHT patients. We found that all the analyzed variants alter protein levels and function. Additional experiments relying on an artificial deletion in our mutated constructs show that identified uAUGs could initiate the translation indicating that the associated effect is translation-dependent. Overall, we have identified two 5’UTR ENG variations in HHT patients and shed new light on the role of upstream ORFs on ENG regulation. Our findings contribute to the amelioration of molecular diagnosis in HHT.
Published: 2023
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2. Diagnostic chest X-rays and breast cancer risk among women with a hereditary predisposition to breast cancer unexplained by a BRCA1 or BRCA2 mutation

Author: Maximiliano Ribeiro Guerra, Juliette Coignard, Séverine Eon-Marchais, Marie-Gabrielle Dondon, Dorothée Le Gal, Juana Beauvallet, Noura Mebirouk, Muriel Belotti, Olivier Caron, Marion Gauthier-Villars, Isabelle Coupier, Bruno Buecher, Alain Lortholary, Jean-Pierre Fricker, Paul Gesta, Catherine Noguès, Laurence Faivre, Pascaline Berthet, Elisabeth Luporsi, Capucine Delnatte, Valérie Bonadona, Christine M. Maugard, Pascal Pujol, Christine Lasset, Michel Longy, Yves-Jean Bignon, Claude Adenis-Lavignasse, Laurence Venat-Bouvet, Hélène Dreyfus, Laurence Gladieff, Isabelle Mortemousque, Séverine Audebert-Bellanger, Florent Soubrier, Sophie Giraud, Sophie Lejeune-Dumoulin, Jean-Marc Limacher, Jean Chiesa, Anne Fajac, Anne Floquet, François Eisinger, Julie Tinat, Sandra Fert-Ferrer, Chrystelle Colas, Thierry Frebourg, Francesca Damiola, Laure Barjhoux, Eve Cavaciuti, Sylvie Mazoyer, Anne Tardivon, Fabienne Lesueur, Dominique Stoppa-Lyonnet, and Nadine Andrieu
Subjects: Breast cancer, X-ray exposure, Low dose, High-risk population, DNA repair genes, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Diagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation. Methods We evaluated the effect of chest X-rays from diagnostic medical procedures in a dataset composed of 1552 BC cases identified through French family cancer clinics and 1363 unrelated controls. Participants reported their history of X-ray exposures in a detailed questionnaire and were tested for 113 DNA repair genes. Logistic regression and multinomial logistic regression models were used to assess the association with BC. Results Chest X-ray exposure doubled BC risk. A 3% increased BC risk per additional exposure was observed. Being 20 years old or younger at first exposure or being exposed before first full-term pregnancy did not seem to modify this risk. Birth after 1960 or carrying a rare likely deleterious coding variant in a DNA repair gene other than BRCA1/2 modified the effect of chest X-ray exposure. Conclusion Ever/never chest X-ray exposure increases BC risk 2-fold regardless of age at first exposure and, by up to 5-fold when carrying 3 or more rare variants in a DNA repair gene. Further studies are needed to evaluate other DNA repair genes or variants to identify those which could modify radiation sensitivity. Identification of subpopulations that are more or less susceptible to ionizing radiation is important and potentially clinically relevant.
Published: 2021
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3. Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype

Author: Berivan Tas, Daniele Starnoni, Stanislas Smajda, Alexandre J. Vivanti, Catherine Adamsbaum, Mélanie Eyries, Judith Melki, Marcel Tawk, Augustin Ozanne, Nicole Revencu, Florent Soubrier, Selima Siala, Miikka Vikkula, Kumaran Deiva, and Guillaume Saliou
Subjects: vein of Galen aneurysmal malformation, cerebral arteriovenous fistula, arteriovenous shunt (AVS), Rendu-Osler-Weber disease, RASA1 mutation, EPHB4 mutation, Pediatrics, RJ1-570
Abstract: ObjectiveTo study the genotypes and phenotypes of cerebral arteriovenous fistulas that drain or do not drain through the vein of Galen, and true vein of Galen aneurysmal malformations, in order to determine whether genotyping could help improve classification of these malformations and their management.MethodsWe carried out a retrospective review of genetic and phenotypic data in databases of four centers. All children with cerebral arteriovenous fistula or vein of Galen aneurysmal malformations aged below 18 years at onset were included. We recorded the nature of the genetic variant or absence of variant, age at onset, type of malformation, symptoms at onset (hemorrhage, neurological deficit, hydrocephalus, incidental, and heart failure), type of venous drainage and the long-term outcome.ResultsOne hundred and fifteen children were included. Autosomal dominant variants were identified in 39% of patients. The most frequent variant affected was the RASA1 gene (25%) followed by EPHB4 (8%) and the HHT-associated genes (5%). HHT gene variants were only observed in pial arteriovenous fistula not draining into the vein of Galen; on the contrary, EPHB4 variants were only seen in genuine vein of Galen aneurysmal malformation. RASA1 variants were identified in all types of shunts.ConclusionsEPHB4 variants seem specific to the vein of Galen aneurysmal malformation, RASA1 variants are associated with either pial arteriovenous fistulas or with genuine VGAM and HHT gene variants seem specific to pial arteriovenous fistulas. The genetic data helps to classify these malformations and to guide treatment toward lowest risk of post-operative cerebral ischemic-hemorrhagic complications.
Published: 2022
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4. Platelet‐Derived Growth Factor Receptor Type α Activation Drives Pulmonary Vascular Remodeling Via Progenitor Cell Proliferation and Induces Pulmonary Hypertension

Author: Julien Solinc, Jessica Raimbault‐Machado, France Dierick, Lamiaa El Bernoussi, Ly Tu, Raphaël Thuillet, Nathalie Mougenot, Bénédicte Hoareau‐Coudert, Virginie Monceau, Catherine Pavoine, Fabrice Atassi, David Sassoon, Giovanna Marazzi, Richard P. Harvey, Peter Schofield, Daniel Christ, Marc Humbert, Christophe Guignabert, Florent Soubrier, and Sophie Nadaud
Subjects: fibrosis, pulmonary hypertension, platelet‐derived growth factor receptor alpha, stem cells, vascular remodeling, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Platelet‐derived growth factor is a major regulator of the vascular remodeling associated with pulmonary arterial hypertension. We previously showed that protein widely 1 (PW1+) vascular progenitor cells participate in early vessel neomuscularization during experimental pulmonary hypertension (PH) and we addressed the role of the platelet‐derived growth factor receptor type α (PDGFRα) pathway in progenitor cell‐dependent vascular remodeling and in PH development. Methods and Results Remodeled pulmonary arteries from patients with idiopathic pulmonary arterial hypertension showed an increased number of perivascular and vascular PW1+ cells expressing PDGFRα. PW1nLacZ reporter mice were used to follow the fate of pulmonary PW1+ progenitor cells in a model of chronic hypoxia–induced PH development. Under chronic hypoxia, PDGFRα inhibition prevented the increase in PW1+ progenitor cell proliferation and differentiation into vascular smooth muscle cells and reduced pulmonary vessel neomuscularization, but did not prevent an increased right ventricular systolic pressure or the development of right ventricular hypertrophy. Conversely, constitutive PDGFRα activation led to neomuscularization via PW1+ progenitor cell differentiation into new smooth muscle cells and to PH development in male mice without fibrosis. In vitro, PW1+ progenitor cell proliferation, but not differentiation, was dependent on PDGFRα activity. Conclusions These results demonstrate a major role of PDGFRα signaling in progenitor cell–dependent lung vessel neomuscularization and vascular remodeling contributing to PH development, including in idiopathic pulmonary arterial hypertension patients. Our findings suggest that PDGFRα blockers may offer a therapeutic add‐on strategy to combine with current pulmonary arterial hypertension treatments to reduce vascular remodeling. Furthermore, our study highlights constitutive PDGFRα activation as a novel experimental PH model.
Published: 2022
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5. The Platelet-Derived Growth Factor Pathway in Pulmonary Arterial Hypertension: Still an Interesting Target?

Author: Julien Solinc, Jonathan Ribot, Florent Soubrier, Catherine Pavoine, France Dierick, and Sophie Nadaud
Subjects: PDGF, PDGFR, smooth muscle cells, fibroblast, pulmonary arterial hypertension, vascular remodeling, Science
Abstract: The lack of curative options for pulmonary arterial hypertension drives important research to understand the mechanisms underlying this devastating disease. Among the main identified pathways, the platelet-derived growth factor (PDGF) pathway was established to control vascular remodeling and anti-PDGF receptor (PDGFR) drugs were shown to reverse the disease in experimental models. Four different isoforms of PDGF are produced by various cell types in the lung. PDGFs control vascular cells migration, proliferation and survival through binding to their receptors PDGFRα and β. They elicit multiple intracellular signaling pathways which have been particularly studied in pulmonary smooth muscle cells. Activation of the PDGF pathway has been demonstrated both in patients and in pulmonary hypertension (PH) experimental models. Tyrosine kinase inhibitors (TKI) are numerous but without real specificity and Imatinib, one of the most specific, resulted in beneficial effects. However, adverse events and treatment discontinuation discouraged to pursue this therapy. Novel therapeutic strategies are currently under experimental evaluation. For TKI, they include intratracheal drug administration, low dosage or nanoparticles delivery. Specific anti-PDGF and anti-PDGFR molecules can also be designed such as new TKI, soluble receptors, aptamers or oligonucleotides.
Published: 2022
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6. Higher prevalence of splenic artery aneurysms in hereditary hemorrhagic telangiectasia: Vascular implications and risk factors.

Author: Jacques Sellier, Carma Karam, Alain Beauchet, Axel Dallongeville, Stephen Binsse, Sandra Blivet, Isabelle Bourgault-Villada, Philippe Charron, Thierry Chinet, Mélanie Eyries, Carole Fagnou, Jérome Lesniak, Gilles Lesur, Jérome Lucas, Agnès Nicod-Tran, Augustin Ozanne, Aurélien Palmyre, Florent Soubrier, Mostafa El Hajjam, and Pascal Lacombe
Subjects: Medicine, Science
Abstract: BACKGROUND:Splenic artery aneurysm (SAA) is a rare but potentially fatal condition. Rupture results in 25% mortality up to 75% in pregnant women with 95% fetal mortality. Brief reports suggest an increased risk of developing SAA in patients with HHT. METHODS:We analyzed enhanced multidetector CT data in 186 HHT patients matched (gender and ± 5 year old) with 186 controls. We screened for SAA and recorded diameter of splenic and hepatic arteries and hepatic, pancreatic and splenic parenchymal involvements. We determined by univariate and multivariate analysis, the relationship with age, sex, genetic status, cardiovascular risk factors (CVRF) and visceral involvement. RESULTS:SAA concerned 24.7% of HHT patients and 5.4% of controls, p
Published: 2020
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7. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Author: Stefan Gräf, Matthias Haimel, Marta Bleda, Charaka Hadinnapola, Laura Southgate, Wei Li, Joshua Hodgson, Bin Liu, Richard M. Salmon, Mark Southwood, Rajiv D. Machado, Jennifer M. Martin, Carmen M. Treacy, Katherine Yates, Louise C. Daugherty, Olga Shamardina, Deborah Whitehorn, Simon Holden, Micheala Aldred, Harm J. Bogaard, Colin Church, Gerry Coghlan, Robin Condliffe, Paul A. Corris, Cesare Danesino, Mélanie Eyries, Henning Gall, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Arjan C. Houweling, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Robert V. MacKenzie Ross, Shahin Moledina, David Montani, Michael Newnham, Andrea Olschewski, Horst Olschewski, Andrew J. Peacock, Joanna Pepke-Zaba, Inga Prokopenko, Christopher J. Rhodes, Laura Scelsi, Werner Seeger, Florent Soubrier, Dan F. Stein, Jay Suntharalingam, Emilia M. Swietlik, Mark R. Toshner, David A. van Heel, Anton Vonk Noordegraaf, Quinten Waisfisz, John Wharton, Stephen J. Wort, Willem H. Ouwehand, Nicole Soranzo, Allan Lawrie, Paul D. Upton, Martin R. Wilkins, Richard C. Trembath, and Nicholas W. Morrell
Subjects: Science
Abstract: Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2, ATP13A3, AQP1 and SOX17.
Published: 2018
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8. Progenitor/Stem Cells in Vascular Remodeling during Pulmonary Arterial Hypertension

Author: France Dierick, Julien Solinc, Juliette Bignard, Florent Soubrier, and Sophie Nadaud
Subjects: pulmonary arterial hypertension, vascular remodeling, progenitor cells, stem cells, endothelial cells, smooth muscle cells, Cytology, QH573-671
Abstract: Pulmonary arterial hypertension (PAH) is characterized by an important occlusive vascular remodeling with the production of new endothelial cells, smooth muscle cells, myofibroblasts, and fibroblasts. Identifying the cellular processes leading to vascular proliferation and dysfunction is a major goal in order to decipher the mechanisms leading to PAH development. In addition to in situ proliferation of vascular cells, studies from the past 20 years have unveiled the role of circulating and resident vascular in pulmonary vascular remodeling. This review aims at summarizing the current knowledge on the different progenitor and stem cells that have been shown to participate in pulmonary vascular lesions and on the pathways regulating their recruitment during PAH. Finally, this review also addresses the therapeutic potential of circulating endothelial progenitor cells and mesenchymal stem cells.
Published: 2021
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9. Whole-genome sequencing of patients with rare diseases in a national health system.

Author: Ernest Turro, William J. Astle, Karyn Megy, Stefan Gräf, Daniel Greene, Olga Shamardina, Hana Lango Allen, Alba Sanchis-Juan, Mattia Frontini, Chantal Thys, Jonathan Stephens, Rutendo Mapeta, Oliver S. Burren, Kate Downes, Matthias Haimel, Salih Tuna, Sri V. V. Deevi, Timothy J. Aitman, David L. H. Bennett, Paul Calleja, Keren Carss, Mark J. Caulfield, Patrick F. Chinnery, Peter H. Dixon, Daniel P. Gale, Roger James, Ania Koziell, Michael A. Laffan, Adam P. Levine, Eamonn R. Maher, Hugh S. Markus, Joannella Morales, Nicholas W. Morrell, Andrew D. Mumford, Elizabeth Ormondroyd, Stuart Rankin, Augusto Rendon, Sylvia Richardson, Irene Roberts, Noemi B. A. Roy, Moin A. Saleem, Kenneth G. C. Smith, Hannah Stark, Rhea Y. Y. Tan, Andreas C. Themistocleous, Adrian J. Thrasher, Hugh Watkins, Andrew R. Webster, Martin R. Wilkins, Catherine Williamson, James Whitworth, Sean Humphray, David R. Bentley, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Hana Alachkar, David J. Allsup, Jeff Almeida-King, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, Agnieszka Bierzynska, Tina Biss, Maria A. K. Bitner-Glindzicz, Graeme C. M. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Harm Bogaard, Christian J. Bourne, Sara Boyce, John R. Bradley, Eugene Bragin, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Ruth Casey, Jenny Chambers, John Chambers, Melanie M. Y. Chan, Calvin Cheah, Floria Cheng, Manali Chitre, Martin T. Christian, Colin Church, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Gerry Coghlan, Elizabeth Colby, Trevor R. P. Cole, Janine Collins, Peter W. Collins, Camilla Colombo, Cecilia J. Compton, Robin Condliffe, Stuart A. Cook, H. Terence Cook, Nichola Cooper, Paul A. Corris, Abigail Furnell, Fiona Cunningham, Nicola S. Curry, Antony J. Cutler, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Sofia Douzgou, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Mélanie Eyries, Hiva Fassihi, Remi Favier, Jack Findhammer, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Henning Gall, Vijeya Ganesan, Michael Gattens, Claire Geoghegan, Terence S. A. Gerighty, Ali G. Gharavi, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Barbara Girerd, Nicholas S. Gleadall, Sarah Goddard, David B. Goldstein, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Russell J. Grocock, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, William M. Hague, Rosie Hague, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Simon Holden, Rita Horvath, Henry Houlden, Arjan C. Houweling, Luke S. G. E. Howard, Fengyuan Hu, Gavin Hudson, Joseph Hughes, Aarnoud P. Huissoon, Marc Humbert, Sarah Hunter, Matthew E. Hurles, Melita Irving, Louise Izatt, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Tim Karten, Johannes Karten, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M. Kelly, Wilf Kelsall, Carly Kempster, David G. Kiely, Nathalie Kingston, Robert Klima, Nils Koelling, Myrto Kostadima, Gabor Kovacs, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Fiona Lalloo, Michele Lambert, Allan Lawrie, D. Mark Layton, Nick Lench, Claire Lentaigne, Tracy Lester, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Rajiv D. Machado, Robert V. MacKenzie Ross, Bella Madan, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Kevin J. Marchbank, Stephen Marks, Hanns-Ulrich Marschall, Andrew G. Marshall, Jennifer Martin, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Aoife McMahon, Stuart Meacham, Adam J. Mead, Ignacio Medina Castello, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Shahin Moledina, David Montani, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O'Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Horst Olschewski, Kai Ren Ong, S. Helen Oram, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry 0003, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, John Peden, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, Romina Petersen, Clarissa Pilkington, Kenneth E. S. Poole, Radhika Prathalingam, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Christine Rees, Tara Renton, Christopher J. Rhodes, Andrew S. C. Rice, Alex Richter, Leema Robert, Anthony Rogers, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Nilesh J. Samani, Crina Samarghitean, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, John A. Sayer, Genevieve Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Werner Seeger, Arjune Sen, W. A. Carrock Sewell, Denis Seyres, Neil Shah, Susan E. Shapiro, Adam C. Shaw, Patrick J. Short, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Katie Snape, Nicole Soranzo, Florent Soubrier, Laura Southgate, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Charles A. Steward, Kathleen E. Stirrups, Alex Stuckey, Jay Suntharalingam, Emilia M. Swietlik, Petros Syrris, R. Campbell Tait, Kate Talks, Katie Tate, John M. Taylor, Jenny C. Taylor, James E. Thaventhiran, Ellen Thomas, David Thomas 0004, Moira J. Thomas, Patrick Thomas, Kate Thomson, Glen Threadgold, Tobias Tilly, Marc Tischkowitz, Catherine Titterton, John A. Todd, Cheng-Hock Toh, Bas Tolhuis, Ian P. Tomlinson, Mark Toshner, Matthew Traylor, Carmen Treacy, Paul Treadaway, Richard Trembath, Wojciech Turek, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Maarten Vandekuilen, Anthony M. Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Anton Vonk-Noordegraaf, Annette Wagner, Quinten Waisfisz, Suellen M. Walker, Neil Walker, Klaudia Walter, James S. Ware, Christopher Watt, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, John Wharton, Deborah Whitehorn, Andrew O. M. Wilkie, Brian T. Wilson, Edwin K. S. Wong, Nicholas W. Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Stephen J. Wort, Austen Worth, Michael Wright, Katherine Yates, Patrick F. K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, and Eliska Zlamalova
Published: 2020
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10. T-cell dysregulation and inflammatory process in Gcn2 (Eif2ak4−/−)-deficient rats in basal and stress conditions

Author: Juliette Bignard, Fabrice Atassi, Olivier Claude, Maria-Rosa Ghigna, Nathalie Mougenot, Bahgat Soilih Abdoulkarim, Florence Deknuydt, Aurélie Gestin, Virginie Monceau, David Montani, Sophie Nadaud, Florent Soubrier, and Frédéric Perros
Subjects: Pulmonary and Respiratory Medicine, Physiology, Physiology (medical), Cell Biology
Abstract: Hereditary pulmonary veno-occlusive disease (hPVOD) is a severe form of autosomal recessive pulmonary hypertension and is due to biallelic loss of function of the EIF2AK4 gene (alias GCN2) coding for GCN2. GCN2 is a stress kinase that belongs to the integrated stress response pathway (ISR). Three rat lines carrying biallelic Gcn2 mutation were generated and found phenotypically normal and did not spontaneously develop a PVOD-related disease. We submitted these rats to amino acid deprivation to document the molecular and cellular response of the lungs and to identify phenotypic changes that could be involved in PVOD pathophysiology. Gcn2−/− rat lungs were analyzed under basal conditions and 3 days after a single administration of PEG-asparaginase (ASNase). Lung mRNAs were analyzed by RNAseq and single-cell RNAseq (scRNA-seq), flow cytometry, tissue imaging, and Western blots. The ISR was not activated after ASNase treatment in Gcn2−/− rat lungs, and apoptosis was increased. Several proinflammatory and innate immunity genes were overexpressed, and inflammatory cells infiltration was also observed in the perivascular area. Under basal conditions, scRNA-seq analysis of Gcn2−/− rat lungs revealed increases in two T-cell populations, a LAG3+ T-cell population and a proliferative T-cell population. Following ASNase administration, we observed an increase in calprotectin expression involved in TLR pathway activation and neutrophil infiltration. In conclusion, under basal and asparagine and glutamine deprivation induced by asparaginase administration, Gcn2−/− rats display molecular and cellular signatures in the lungs that may indicate a role for Gcn2 in immune homeostasis and provide further clues to the mechanisms of hPVOD development.
Published: 2023

11. Novel uAUG creating variants in the 5’UTR of ENG causing Hereditary Hemorrhagic Telangiectasia

Author: Omar Soukarieh, Emmanuelle Tillet, Carole Proust, Charlène Dupont, Béatrice Jaspard-Vinassa, Florent Soubrier, Aurélie Goyenvalle, Mélanie Eyries, and David-Alexandre Trégouët
Abstract: Hereditary Hemorrhagic Telangiectasia (HHT) is a rare vascular disorder causing abnormal vessel formation and characterized by autosomal dominant transmission. The associated considerable variability in symptoms and clinical severity complicate the management of the disease. In clinical routine, 3 main genes,ACVRL1(also known asALK1),ENGandSMAD4are screened for pathogenic variants at the origin of HHT. About 80% of HHT cases are caused by pathogenic coding variants inACVRL1andENG. However, at least 15% remain with no molecular explanations in the 3 main genes. We here report the identification of 2 never reported variants, c.-79C>T and c.-68G>A, in the 5’UTR ofENGin 2 unrelated HHT patients. These 2 variants are predicted to create upstream AUGs (uAUGs) in the 5’UTR, which are in frame with a stop codon located within the CoDing Sequence (CDS), thus generating Overlapping upstream Open reading frames (uoORFs). In other cases, uAUGs can lead to fully upstream ORFs (uORFs) when associated with stop codons located within the 5’UTR or to elongated CDS (eCDS) when in frame with the CDS and associated with the main stop codon.In order to assess the pathogenicity of theseENGvariants, we performedin vitrofunctional assays based on the expression of wild-type and mutant constructs in human cells. We found that these 5’UTRENGvariants were associated with a decrease of protein levels in HeLa and HUVEC cells. They were also associated with a decreased ability to activate BMP9-stimulated ALK1 receptor in a BMP-response element (BRE) assay. This assay is a mandatory element before providing a definitive molecular diagnosis and has been so far applied only on codingENGvariants. We applied the same experimental workflow on 3 additional uoORF-creating variants (c.-142A>T, c.-127C>T and c.-10C>T) and one eCDS-creating variant (c.-9G>A) in the 5’UTR ofENGpreviously reported in HHT patients. We found that all the analysed uoORF-creating variants alter endoglin levels and function. A comparison of our experimental results with patients’ clinical characteristics suggests that uoORF-creating variants leading to ENG protein levels ≤ 40%in vitrowould be associated with HHT. Additional experiments relying on an artificial deletion in our mutated constructs show that created uAUGs predicted to create uoORFs are able to initiate the translation indicating that the associated effect is likely caused by an alteration of the translation mechanism.Overall, we here identified two never reported 5’UTRENGvariations in HHT patients and shed new lights on the role of upstream ORFs on ENG regulation. Our findings contribute to the amelioration of molecular diagnosis in HHT.
Published: 2022

12. An emerging phenotype of pulmonary arterial hypertension patients carrying

Author: David, Montani, Benoit, Lechartier, Barbara, Girerd, Mélanie, Eyries, Maria-Rosa, Ghigna, Laurent, Savale, Xavier, Jaïs, Andrei, Seferian, Mitja, Jevnikar, Athénais, Boucly, Marianne, Riou, Julie, Traclet, Ari, Chaouat, Maryline, Levy, Jerome, Le Pavec, Elie, Fadel, Frédéric, Perros, Florent, Soubrier, Martine, Remy-Jardin, Olivier, Sitbon, Damien, Bonnet, and Marc, Humbert
Abstract: The phenotype of pulmonary arterial hypertension (PAH) patients carryingWe report the genetic analysis findings, characteristics and outcomes of patients with heritable PAH carryingTwenty patients and eight unaffected relatives were identified. The median (min-max) age at diagnosis was 17 years (2-53), with a female-to-male ratio of 1.5. At diagnosis, most of the patients (74%) were in functional class III or IV with severe hemodynamic compromise, including a median pulmonary vascular resistance (PVR) of 14.0 (4.2-31.5) Wood units (WU). An associated congenital heart disease (CHD) was found in 7 PAH patients (35%). Patients with CHD-associated PAH were significantly younger at diagnosis than PAH patients without CHD. Four patients (20%) suffered from recurrent haemoptysis requiring repeated arterial embolisations. Thirteen out of 16 patients (81%) of whom imaging was available displayed chest computed tomography abnormalities, including dilated, tortuous pulmonary vessels, ground-glass opacities as well as bronchial and non-bronchial arteries anomalies. After a median follow-up of 47 months (1-591 months), 10 patients underwent lung transplantation and one patient benefited from a heart-lung transplantation due to associated CHD. Histopathologic analysis of lung explants showed a congested lung architecture with severe pulmonary arterial remodelling, subpleural vessel dilation and numerous haemorrhagic foci.PAH due to
Published: 2022

13. Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension

Author: Jules Hernández-Sánchez, David G. Kiely, J. Simon R. Gibbs, Joanna Pepke-Zaba, Christopher J. Rhodes, Brian Y.H. Lam, Luke Howard, Richard C. Trembath, Tae-Hwi Schwantes-An, Mark Toshner, John G Coghlan, Paul A. Corris, Amit Arora, Katie A. Lutz, Emily Knightbridge, Colin Church, Stefan Gräf, James Liley, Ken Batai, Marc Humbert, Ankit A. Desai, Louise Harlow, S. John Wort, Sean Gaine, Martin R. Wilkins, William C. Nichols, Rowena Jones, Sofia S Villar Moreschi, Jason H. Karnes, Rick A. Kittles, Lars Harbaum, Dee Gor, Florent Soubrier, Nicholas W. Morrell, Jay Suntharalingam, and Michael W. Pauciulo
Subjects: Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, Biomedical Research, Disease, chemistry.chemical_compound, Tocilizumab, Internal medicine, medicine, Humans, Familial Primary Pulmonary Hypertension, Adverse effect, Interleukin 6, Associated Pulmonary Arterial Hypertension, Aged, Pulmonary Arterial Hypertension, biology, business.industry, Interleukin-6, Incidence (epidemiology), Middle Aged, medicine.disease, Connective tissue disease, medicine.anatomical_structure, Treatment Outcome, chemistry, Vascular resistance, biology.protein, Female, business
Abstract: BackgroundInflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling.MethodsWe conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg−1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels.ResultsWe recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88).ConclusionAdverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.
Published: 2022

14. Disruption of GCN2 Pathway Aggravates Vascular and Parenchymal Remodeling During Pulmonary Fibrosis

Author: Diana Santos-Ribeiro, Marylène Lecocq, Michèle de Beukelaer, Stijn Verleden, Caroline Bouzin, Jérôme Ambroise, Peter Dorfmuller, Yousef Yakoub, François Huaux, Rozenn Quarck, Harry Karmouty-Quintana, Maria-Rosa Ghigna, Juliette Bignard, Sophie Nadaud, Florent Soubrier, Sandrine Horman, Frederic Perros, Laurent Godinas, Charles Pilette, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, and UCL - (SLuc) Service de pneumologie
Subjects: Pulmonary and Respiratory Medicine, Clinical Biochemistry, Cell Biology, Molecular Biology
Abstract: Pulmonary fibrosis (PF) and pulmonary hypertension (PH) are chronic diseases of the pulmonary parenchyma and circulation, respectively, which may coexist, but underlying mechanisms remain elusive. Mutations in the GCN2 gene (EIF2AK4) were recently associated with pulmonary veno-occlusive disease. This study aims to explore the involvement of the GCN2/eIF2α pathway in the development of PH during PF, in both human disease and in an experimental animal model. Lung tissue from PF patients with or without PH were collected at the time of lung transplantation, and controls were obtained from tumor resection surgery. Experimental lung disease was induced in either male wild-type or EIF2AK4-mutated Sprague-Dawley rats, randomly receiving a single intratracheal instillation of bleomycin or saline. Hemodynamic studies, as well as organ collection were performed 3 weeks post-instillation. Only significant results (p
Published: 2022

15. Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype

Author: Berivan, Tas, Daniele, Starnoni, Stanislas, Smajda, Alexandre J, Vivanti, Catherine, Adamsbaum, Mélanie, Eyries, Judith, Melki, Marcel, Tawk, Augustin, Ozanne, Nicole, Revencu, Florent, Soubrier, Selima, Siala, Miikka, Vikkula, Kumaran, Deiva, Guillaume, Saliou, and UCL - SSS/DDUV/GEHU - Génétique
Subjects: arteriovenous shunt (AVS), vein of Galen aneurysmal malformation, cerebral arteriovenous fistula, cardiovascular system, EPHB4 mutation, Perinatology and Child Health, Rendu-Osler-Weber disease, Pediatrics, RASA1 mutation
Abstract: To study the genotypes and phenotypes of cerebral arteriovenous fistulas that drain or do not drain through the vein of Galen, and true vein of Galen aneurysmal malformations, in order to determine whether genotyping could help improve classification of these malformations and their management. We carried out a retrospective review of genetic and phenotypic data in databases of four centers. All children with cerebral arteriovenous fistula or vein of Galen aneurysmal malformations aged below 18 years at onset were included. We recorded the nature of the genetic variant or absence of variant, age at onset, type of malformation, symptoms at onset (hemorrhage, neurological deficit, hydrocephalus, incidental, and heart failure), type of venous drainage and the long-term outcome. One hundred and fifteen children were included. Autosomal dominant variants were identified in 39% of patients. The most frequent variant affected was the gene (25%) followed by (8%) and the HHT-associated genes (5%). HHT gene variants were only observed in pial arteriovenous fistula not draining into the vein of Galen; on the contrary, variants were only seen in genuine vein of Galen aneurysmal malformation. variants were identified in all types of shunts. variants seem specific to the vein of Galen aneurysmal malformation, variants are associated with either pial arteriovenous fistulas or with genuine VGAM and HHT gene variants seem specific to pial arteriovenous fistulas. The genetic data helps to classify these malformations and to guide treatment toward lowest risk of post-operative cerebral ischemic-hemorrhagic complications.
Published: 2022

16. Diagnostic chest X-rays and breast cancer risk among women with a hereditary predisposition to breast cancer unexplained by a BRCA1 or BRCA2 mutation

Author: Michel Longy, Christine Maugard, Elisabeth Luporsi, Capucine Delnatte, Séverine Eon-Marchais, Marion Gauthier-Villars, Juana Beauvallet, Noura Mebirouk, Muriel Belotti, Alain Lortholary, Sophie Lejeune-Dumoulin, Christine Lasset, Isabelle Mortemousque, Yves-Jean Bignon, François Eisinger, Sylvie Mazoyer, Valérie Bonadona, Jean-Marc Limacher, Anne Tardivon, Paul Gesta, Sandra Fert-Ferrer, Fabienne Lesueur, Dorothée Le Gal, Jean Chiesa, Florent Soubrier, Pascaline Berthet, Laurence Faivre, Bruno Buecher, Nadine Andrieu, Juliette Coignard, Julie Tinat, Thierry Frebourg, Isabelle Coupier, Sophie Giraud, Laure Barjhoux, Catherine Noguès, Séverine Audebert-Bellanger, Claude Adenis-Lavignasse, Chrystelle Colas, Maximiliano Ribeiro Guerra, Laurence Venat-Bouvet, Eve Cavaciuti, Anne Floquet, Pascal Pujol, Francesca Damiola, Anne Fajac, Jean-Pierre Fricker, Hélène Dreyfus, Dominique Stoppa-Lyonnet, Marie-Gabrielle Dondon, Laurence Gladieff, Olivier Caron, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Federal University of Juiz de Fora (UFIJ), Institut Gustave Roussy (IGR), AP-HP. Université Paris Saclay, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Catherine-de-Sienne [Nantes] (CCS), Centre Paul Strauss, CRLCC Paul Strauss, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Hôpital de Mercy, Centre René Gauducheau, CRLCC René Gauducheau, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Bergonié [Bordeaux], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Ramsay Générale de Santé - Hôpital Privé La Louvière, Hôpital Dupuytren [CHU Limoges], Institut Sainte Catherine [Avignon], hôpital couple-enfant [CHU Grenoble Alpes], Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Morvan [Brest], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Groupement Hospitalier Lyon-Est (GHE), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Hôpital pasteur [Colmar], Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU de Bordeaux Pellegrin [Bordeaux], Centre Hospitalier Métropole Savoie [Chambéry], Hôpital René HUGUENIN (Saint-Cloud), CHU Rouen, Normandie Université (NU), Hôpital Edouard Herriot [CHU - HCL], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), MINES ParisTech - École nationale supérieure des mines de Paris, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), COLO, Mouniati, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Adult, Risk, Oncology, medicine.medical_specialty, DNA Repair, DNA repair, [SDV]Life Sciences [q-bio], Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, X-ray exposure, Logistic regression, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Surgical oncology, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Risk factor, RC254-282, High-risk population, Pregnancy, DNA repair genes, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, Middle Aged, medicine.disease, 3. Good health, Radiography, [SDV] Life Sciences [q-bio], Low dose, 030220 oncology & carcinogenesis, Mutation, Female, business, Research Article
Abstract: Background Diagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation. Methods We evaluated the effect of chest X-rays from diagnostic medical procedures in a dataset composed of 1552 BC cases identified through French family cancer clinics and 1363 unrelated controls. Participants reported their history of X-ray exposures in a detailed questionnaire and were tested for 113 DNA repair genes. Logistic regression and multinomial logistic regression models were used to assess the association with BC. Results Chest X-ray exposure doubled BC risk. A 3% increased BC risk per additional exposure was observed. Being 20 years old or younger at first exposure or being exposed before first full-term pregnancy did not seem to modify this risk. Birth after 1960 or carrying a rare likely deleterious coding variant in a DNA repair gene other than BRCA1/2 modified the effect of chest X-ray exposure. Conclusion Ever/never chest X-ray exposure increases BC risk 2-fold regardless of age at first exposure and, by up to 5-fold when carrying 3 or more rare variants in a DNA repair gene. Further studies are needed to evaluate other DNA repair genes or variants to identify those which could modify radiation sensitivity. Identification of subpopulations that are more or less susceptible to ionizing radiation is important and potentially clinically relevant.
Published: 2021

17. Author response for 'A CELSR1 variant in a patient with pulmonary arterial hypertension'

Author: Barbara Girerd, Marc Humbert, Florent Soubrier, David Montani, Laurent Savale, and Mélanie Eyries
Published: 2021

18. Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation

Author: Sven Günther, Laurent Savale, Sébastien Hascoët, Mélanie Eyries, Pierantonio Laveneziana, Florent Soubrier, Gérald Simonneau, Olivier Sitbon, Edmund M.T. Lau, Marc Humbert, Antoine Beurnier, Philippe Hervé, Barbara Girerd, Amir Bouchachi, Florence Parent, Denis Chemla, David Montani, Christophe Guignabert, Laurent Godinas, Xavier Jaïs, Hôpital Bicêtre, Pôle des Cardiopathies Congénitales du Nouveau-Né à L'adulte - Centre Constitutif Cardiopathies Congénitales Complexes M3C, Groupe Hospitalier Paris Saint-Joseph, Hôpital Marie-Lannelongue, Inserm U999, Université Paris-Saclay, Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Département Médico-Universitaire APPROCHES, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Royal Prince Alfred Hospital [Camperdown, Australia] (RPAH), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Pitié-Salpêtrière [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Laveneziana, Pierantonio, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Royal Prince Alfred Hospital [Sydney, Australia], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and HAL-SU, Gestionnaire
Subjects: Male, [SDV]Life Sciences [q-bio], [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Pulmonary function testing, 0302 clinical medicine, Risk Factors, Original Research Articles, Familial Primary Pulmonary Hypertension, Stage (cooking), 0303 health sciences, education.field_of_study, Pulmonary Arterial Hypertension, Incidence (epidemiology), 06 humanities and the arts, 060202 literary studies, Brain natriuretic peptide, 3. Good health, [SDV] Life Sciences [q-bio], 0602 languages and literature, Screening, Female, medicine.symptom, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Hypertension, Pulmonary, Population, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Bone Morphogenetic Protein Receptors, Type II, Asymptomatic, 03 medical and health sciences, Physicians, Internal medicine, Genetics, medicine, Humans, education, 030304 developmental biology, Pulmonary Vascular Disease, Genetic counselling, business.industry, BMPR2, medicine.disease, Pulmonary hypertension, Annual Screening, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030228 respiratory system, Mutation, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business
Abstract: Background Heritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the BMPR2 gene. Based on expert consensus, guidelines recommend annual screening echocardiography in asymptomatic BMPR2 mutation carriers. The main objectives of this study were to evaluate the characteristics of asymptomatic BMPR2 mutation carriers, assess their risk of occurrence of PAH and detect PAH at an early stage in this high-risk population. Methods Asymptomatic BMPR2 mutation carriers underwent screening at baseline and annually for a minimum of 2 years (DELPHI-2 study; ClinicalTrials.gov: NCT01600898). Annual screening included clinical assessment, ECG, pulmonary function tests, 6-min walk distance, cardiopulmonary exercise testing, chest radiography, echocardiography and brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP level. Right heart catheterisation (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline. Results 55 subjects (26 males; median age 37 years) were included. At baseline, no PAH was suspected based on echocardiography and NT-proBNP levels. All subjects accepted RHC at inclusion, which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension (21.8%). At long-term follow-up (118.8 patient-years of follow-up), three additional cases were diagnosed, yielding a PAH incidence of 2.3% per year (0.99% per year in males and 3.5% per year in females). All PAH cases remained at low-risk status on oral therapy at last follow-up. Conclusions Asymptomatic BMPR2 mutation carriers have a significant risk of developing incident PAH. International multicentre studies are needed to confirm that refined multimodal screening programmes with regular follow-up allow early detection of PAH., Asymptomatic BMPR2 mutation carriers have a 2.3% per year risk of developing PAH. DELPHI-2 provides the platform for future international multicentre studies to refine multimodal screening algorithms in BMPR2 mutation carriers. http://bit.ly/3oi2KJ1
Published: 2021

19. Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study

Author: Lieske H. Schrijver, Antonis C. Antoniou, Håkan Olsson, Thea M. Mooij, Marie-José Roos-Blom, Leyla Azarang, Julian Adlard, Munaza Ahmed, Daniel Barrowdale, Rosemarie Davidson, Alan Donaldson, Ros Eeles, D. Gareth Evans, Debra Frost, Alex Henderson, Louise Izatt, Kai-Ren Ong, Valérie Bonadona, Isabelle Coupier, Laurence Faivre, Jean-Pierre Fricker, Paul Gesta, Klaartje van Engelen, Agnes Jager, Fred H. Menko, Marian J.E. Mourits, Christian F. Singer, Yen Y. Tan, Lenka Foretova, Marie Navratilova, Rita K. Schmutzler, Carolina Ellberg, Anne-Marie Gerdes, Trinidad Caldes, Jacques Simard, Edith Olah, Anna Jakubowska, Johanna Rantala, Ana Osorio, John L. Hopper, Kelly-Anne Phillips, Roger L. Milne, Mary Beth Terry, Catherine Noguès, Christoph Engel, Karin Kast, David E. Goldgar, Flora E. van Leeuwen, Douglas F. Easton, Nadine Andrieu, Matti A. Rookus, Lilian Laborde, Pauline Pontois, Emanuelle Breysse, Margot Berline, Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Chrystelle Colas, Olivier Caron, Emmanuelle Mouret-Fourme, Claire Saule, Christine Lasset, Sophie Dussard, Pascaline Berthet, Elisabeth Luporsi, Véronique Mari, Laurence Gladieff, Stéphanie Chieze-Valéro, Jessica Moretta, Hagay Sobol, François Eisinger, Cornel Popovici, Michel Longy, Louise Grivelli, Florent Soubrier, Patrick Benusiglio, Pascal Pujol, Carole Corsini, Marie-Emmanuelle Morin-Meschin, Alain Lortholary, Claude Adenis, Audrey Maillez, Tan Dat Nguyen, Capucine Delnatte, Caroline Abadie, Julie Tinat, Isabelle Tennevet, Christine Maugard, Yves-Jean Bignon, Mathilde Gay Bellile, Clotilde Penet, Hélène Dreyfus, Odile Cohen-Haguenauer, Brigitte Gilbert, Laurence Venat-Bouvet, Dominique Leroux, Clémentine Legrand, Hélène Zattara-Cannoni, Valérie Layet, Elodie Lacaze, Sandra Fert-Ferrer, Odile Bera, Brigitte Gilbert-Dussardier, David Tougeron, Hakima Lallaoui, M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, M.K. Schmidt, D.J. Jenner, J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, I.A. Boere, C.J. van Asperen, P. Devilee, R.B. van der Luijt, T.C.T.E.F. van Cronenburg, M.R. Wevers, A.R. Mensenkamp, M.G.E.M. Ausems, M.J. Koudijs, I. van de Beek, K. van Engelen, J.J.P. Gille, E.B. Gómez García, M.J. Blok, M. de Boer, L.P.V. Berger, A.H. van der Hout, M.J.E. Mourits, G.H. de Bock, S. Siesling, J. Verloop, E.C. van den Broek, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Human genetics, Epidemiology and Data Science, Cancer Center Amsterdam, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Paul Strauss, CRLCC Paul Strauss, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Aix Marseille Université (AMU), Institut Curie [Paris], Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL), Human Genetics, APH - Methodology, APH - Quality of Care, Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, MUMC+: DA KG Lab Centraal Lab (9), Michel-Avella, Amandine, Medical Oncology, and Clinical Genetics
Subjects: endocrine system diseases, [SDV]Life Sciences [q-bio], MESH: Proportional Hazards Models, Cohort Studies, fetal growth restriction, small for gestational age, MESH: BRCA2 Protein, EPITHELIAL OVARIAN-CANCER, Medicine, pharma-ceutical treatment, MESH: Cohort Studies, Original Research, oral contraceptives, risk, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], MESH: Middle Aged, obstetrics, Obstetrics, BRCA1 Protein, Hazard ratio, MESH: Genetic Predisposition to Disease, Obstetrics and Gynecology, Oral/administration & dosage, Contraceptives, pregnancy complica-tions, MESH: Follow-Up Studies, Contraceptives, Oral/administration & dosage, Middle Aged, BRCA2 Protein/genetics, drug therapy, [SDV] Life Sciences [q-bio], Europe, MESH: Ovarian Neoplasms, ovarian cancer, SURVIVAL, Female, epidemiology, Ovarian Neoplasms/epidemiology, pregnancy, MESH: Contraceptives, Oral, preterm delivery, legislative framework, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Cohort study, HORMONAL FACTORS, Adult, preterm labor, medicine.medical_specialty, preterm premature rupture of membranes, MESH: Mutation, Population, REPRODUCTIVE RISK-FACTORS, retrospective, clinical trials with pregnant women, MUTATION CARRIERS, BREAST, Europe/epidemiology, research and development, preeclampsia, Breast cancer, multivariate, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, observational, education, MESH: BRCA1 Protein, Proportional Hazards Models, Retrospective Studies, BRCA2 Protein, MESH: Humans, survival bias, treatment during pregnancy, Proportional hazards model, business.industry, Retrospective cohort study, MESH: Adult, MESH: Retrospective Studies, medicine.disease, BRCA1, BRCA2, drug development, Confidence interval, placental transfer, Gynecology, obstetrical syndromes, Mutation, BRCA1 Protein/genetics, MESH: Europe, business, Ovarian cancer, MESH: Female, Contraceptives, Oral, Follow-Up Studies
Abstract: Contains fulltext : 237895.pdf (Publisher’s version ) (Open Access) BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with 10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; P(trend)=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.
Published: 2021

20. RASA1 phenotype overlaps with hereditary haemorrhagic telangiectasia: two case reports

Author: Florent Soubrier, Augustin Ozanne, Mostafa El Hajjam, Thierry Chinet, Aurélien Palmyre, Mélanie Eyries, Isabelle Bourgault Villada, Robert Carlier, Ahmed Mekki, Hôpital Ambroise Paré [AP-HP], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpital Raymond Poincaré [AP-HP]
Subjects: 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Portocaval shunt, business.industry, [SDV]Life Sciences [q-bio], Mucocutaneous zone, 030105 genetics & heredity, Endoglin, Phenotype, 3. Good health, Cerebral arteriovenous malformations, 03 medical and health sciences, 030104 developmental biology, cardiovascular medicine, Mothers against decapentaplegic homolog 4, otorhinolaryngologic diseases, Genetics, Medicine, Medical genetics, Radiology, business, clinical genetics, Genetics (clinical), Hereditary haemorrhagic telangiectasia
Abstract: Background We report two cases of RASA1-related capillary malformation-arteriovenous malformation (CM-AVM1) syndrome mimicking hereditary haemorrhagic telangiectasia (HHT).Methods and results A 28-year-old man, previously embolised for cerebral arteriovenous malformations (AVMs), presented with epistaxis and typical nasal telangiectasias of HHT. CT scan revealed a large portocaval shunt. The second patient was a 9-year-old girl presenting with cyanosis and several mucocutaneous telangiectasias, similar to those observed in typical cases of HHT. CT scan revealed a huge and complex pulmonary AVM of the right lower lobe and a hepatic AVM within the left lobe. HHT diagnosis was considered possible according to the Curaçao criteria for the two patients, with at least two criteria for each. Genetic tests did not find any mutation in the three classic genes (Endoglin, Activin receptor-like kinase 1 or Mothers against decapentaplegic homolog 4), but identified in both cases an RASA1 mutation, known to cause CM-AVM1 syndrome.Conclusions Pulmonary AVM and portocaval shunt, usually encountered in HHT, have not yet been described in the CM-AVM1 syndrome. RASA1 screening may be considered in case of HHT suspicion, particularly when mutations are not found in the usually affected genes.
Published: 2020

21. TET2

Author: Florent Soubrier, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Inflammation, 0303 health sciences, Diagnostic Tests, Routine, Vascular inflammation, business.industry, [SDV]Life Sciences [q-bio], DNA Methylation, 030204 cardiovascular system & hematology, Bridge (interpersonal), Article, Dioxygenases, DNA-Binding Proteins, 03 medical and health sciences, 0302 clinical medicine, Proto-Oncogene Proteins, Physiology (medical), DNA methylation, Cancer research, Humans, Medicine, Cardiology and Cardiovascular Medicine, business, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: BACKGROUND: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in BMPR2 and 16 other genes. However, these mutations occur in under 25% of idiopathic PAH patients (IPAH) and are rare in PAH associated with connective tissue diseases (APAH). Preclinical studies suggest epigenetic dysregulation, including altered DNA methylation, promotes PAH. Somatic mutations of Tet-methylcytosine-dioxygenase-2 (TET2), a key enzyme in DNA demethylation, occur in cardiovascular disease and are associated with clonal hematopoiesis, inflammation and adverse vascular remodeling. The role of TET2 in PAH is unknown. METHODS: To test for a role of TET2, we utilized a cohort of 2572 cases from the PAH Biobank. Within this cohort, gene-specific rare variant association tests were performed using 1832 unrelated European PAH patients and 7509 non-Finnish European gnomAD subjects as controls. In an independent cohort of 140 patients, we quantified TET2 expression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histologic evidence of PAH in hematopoietic Tet2-knockout mice. RESULTS: We observed an increased burden of rare, predicted deleterious, germline variants in TET2 in PAH patients of European ancestry (9/1832) compared to controls (6/7509; relative risk=6, p=0.00067). Assessing the whole cohort, 0.39% (10/2572) of patients had 12 TET2 mutations (75% predicted germline and 25% somatic). These patients had no mutations in other PAH-related genes. Patients with TET2 mutations were older (71±7 years versus 48±19 years, p86% of PAH patients. Tet2-knockout mice spontaneously developed PAH, adverse pulmonary vascular remodeling and inflammation, with elevated levels of cytokines, including IL-1β. Chronic therapy with an antibody targeting IL-1β blockade regressed PAH. CONCLUSIONS: PAH is the first human disease related to potential TET2 germline mutations. Inherited and acquired abnormalities of TET2 occur in 0.39% of PAH cases. Decreased TET2 expression is ubiquitous and has potential as a PAH biomarker.
Published: 2020

22. A <scp>CELSR1</scp> variant in a patient with pulmonary arterial hypertension

Author: Mélanie Eyries, Florent Soubrier, David Montani, Marc Humbert, Barbara Girerd, and Laurent Savale
Subjects: medicine.medical_specialty, business.industry, Internal medicine, Genetics, medicine, Cardiology, MEDLINE, business, Genetics (clinical)
Published: 2021

23. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

Author: Emilia M. Swietlik, Daniel Greene, Na Zhu, Karyn Megy, Marcella Cogliano, Smitha Rajaram, Divya Pandya, Tobias Tilly, Katie A. Lutz, Carrie C.L. Welch, Michael W. Pauciulo, Laura Southgate, Jennifer M. Martin, Carmen M. Treacy, Christopher J. Penkett, Jonathan C. Stephens, Harm J. Bogaard, Colin Church, Gerry Coghlan, Anna W. Coleman, Robin Condliffe, Christina A. Eichstaedt, Mélanie Eyries, Henning Gall, Stefano Ghio, Barbara Girerd, Ekkehard Grünig, Simon Holden, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Jim Lordan, Rajiv D. Machado, Robert V. MacKenzie Ross, Colm McCabe, Shahin Moledina, David Montani, Horst Olschewski, Joanna Pepke-Zaba, Laura Price, Christopher J. Rhodes, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Anton Vonk Noordegraaf, John Wharton, James M. Wild, Stephen John Wort, Allan Lawrie, Martin R. Wilkins, Richard C. Trembath, Yufeng Shen, Wendy K. Chung, Andrew J. Swift, William C. Nichols, Nicholas W. Morrell, Stefan Gräf, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David J. Allsup, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, David L. Bennett, Agnieszka Bierzynska, Tina Biss, Maria A.K. Bitner-Glindzicz, Graeme C. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Sara Boyce, John R. Bradley, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Oliver S. Burren, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Keren Carss, Ruth Casey, Mark J. Caulfield, Jenny Chambers, John Chambers, Melanie M.Y. Chan, Floria Cheng, Patrick F. Chinnery, Manali Chitre, Martin T. Christian, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Elizabeth Colby, Trevor R.P. Cole, Janine Collins, Peter W. Collins, Cecilia J. Compton, H. Terence Cook, Stuart Cook, Nichola Cooper, Paul A. Corris, Nicola S. Curry, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Sri V.V. Deevi, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Peter H. Dixon, Sofia Douzgou, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Hiva Fassihi, Remi Favier, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Mattia Frontini, Abigail Furnell, Daniel P. Gale, Vijeya Ganesan, Michael Gattens, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, Rosie Hague, William M. Hague, Matthias Haimel, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Rita Horvath, Henry Houlden, Arjan C. Houweling, Fengyuan Hu, Gavin Hudson, Aarnoud P. Huissoon, Matthew Hurles, Melita Irving, Louise Izatt, Roger James, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M Kelly, Wilf Kelsall, Carly Kempster, Nathalie Kingston, Nils Koelling, Myrto Kostadima, Ania Koziell, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Michael A. Laffan, Fiona Lalloo, Michele Lambert, Hana Lango Allen, D. Mark Layton, Claire Lentaigne, Tracy Lester, Adam P. Levine, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Bella Madan, Eamonn R. Maher, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Rutendo Mapeta, Kevin J. Marchbank, Stephen Marks, Hugh S. Markus, Hanns-Ulrich Marschall, Andrew Marshall, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Stuart Meacham, Adam J. Mead, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrew D. Mumford, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O’Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Kai Ren Ong, S. Helen Oram, Elizabeth Ormondroyd, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, Kathelijne Peerlinck, Romina Petersen, Clarissa Pilkington, Kenneth E.S. Poole, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Augusto Rendon, Tara Renton, Andrew S.C. Rice, Alex Richter, Leema Robert, Irene Roberts, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Noemi B.A. Roy, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Moin A. Saleem, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, Genevieve Sayer, John A. Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Arjune Sen, W.A. Carrock Sewell, Denis Seyres, Neil Shah, Olga Shamardina, Susan E. Shapiro, Adam C. Shaw, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Kenneth G.C. Smith, Katie Snape, Nicole Soranzo, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Hannah Stark, Kathleen E. Stirrups, Alex Stuckey, Petros Syrris, R. Campbell Tait, Kate Talks, Rhea Y.Y. Tan, Jenny C. Taylor, John M. Taylor, James E. Thaventhiran, Andreas C. Themistocleous, David Thomas, Ellen Thomas, Moira J. Thomas, Patrick Thomas, Kate Thomson, Adrian J. Thrasher, Chantal Thys, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Ian P. Tomlinson, Matthew Traylor, Paul Treadaway, Salih Tuna, Ernest Turro, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Anthony M Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Annette Wagner, Quinten Waisfisz, Neil Walker, Suellen M. Walker, James S. Ware, Hugh Watkins, Christopher Watt, Andrew R. Webster, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, Deborah Whitehorn, James Whitworth, Andrew O.M. Wilkie, Catherine Williamson, Brian T. Wilson, Edwin K.S. Wong, Nicholas Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Austen Worth, Michael Wright, Katherine Yates, Patrick F.K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, Eliska Zlamalova, Russel Hirsch, R. James White, Marc Simon, David Badesch, Erika Rosenzweig, Charles Burger, Murali Chakinala, Thenappan Thenappan, Greg Elliott, Robert Simms, Harrison Farber, Robert Frantz, Jean Elwing, Nicholas Hill, Dunbar Ivy, James Klinger, Steven Nathan, Ronald Oudiz, Ivan Robbins, Robert Schilz, Terry Fortin, Jeffrey Wilt, Delphine Yung, Eric Austin, Ferhaan Ahmad, Nitin Bhatt, Tim Lahm, Adaani Frost, Zeenat Safdar, Zia Rehman, Robert Walter, Fernando Torres, Sahil Bakshi, Stephen Archer, Rahul Argula, Christopher Barnett, Raymond Benza, Ankit Desai, Veeranna Maddipati, University of Cambridge [UK] (CAM), Columbia University [New York], University of Sheffield [Sheffield], University of Cincinnati (UC), St George's, University of London, Vrije Universiteit Amsterdam [Amsterdam] (VU), Golden Jubilee National Hospital, Glasgow, Royal Free Hospital [London, UK], Heidelberg University Hospital [Heidelberg], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen] (THM), Fondazione IRCCS Policlinico San Matteo, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universität Heidelberg [Heidelberg], Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Imperial College London, Royal Hallamshire Hospital, University of Graz, Freeman Hospital, Royal United Hospitals Bath (RUH), Great Ormond Street Hospital for Children [London] (GOSH), Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom., King‘s College London, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität [Graz, Autriche], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Swietlik, Emilia [0000-0002-4095-8489], Megy, Karyn [0000-0002-2826-3879], Tilly, Tobias [0000-0002-6762-5342], Stephens, Jonathan [0000-0003-2020-9330], Toshner, Mark [0000-0002-3969-6143], Morrell, Nicholas [0000-0001-5700-9792], Graf, Stefan [0000-0002-1315-8873], Apollo - University of Cambridge Repository, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität Graz, HAL-SU, Gestionnaire, British Heart Foundation, and The Academy of Medical Sciences
Subjects: 0301 basic medicine, Candidate gene, Cardiac & Cardiovascular Systems, genetic association studies, 030204 cardiovascular system & hematology, Biology, Bayesian inference, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, pulmonary hypertension, medicine, Family history, Gene, Genetics & Heredity, Genetics, family history, Science & Technology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Kinase insert domain receptor, computed tomography, General Medicine, Original Articles, medicine.disease, Pulmonary hypertension, Phenotype, 3. Good health, 030104 developmental biology, Cardiovascular System & Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, vascular endothelial growth factor receptor
Abstract: Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
Published: 2020

24. Single-cell Study of Two Rat Models of Pulmonary Arterial Hypertension Reveals Connections to Human Pathobiology and Drug Repositioning

Author: Graciel Diamante, Xia Yang, Marc Humbert, Caroline Huynh, Mansoureh Eghbali, May Bhetraratana, Douglas Arneson, David Montani, Emma Said, Richard N. Channick, Christine M. Cunningham, In Sook Ahn, Trixie Le, Jason Hong, Florent Soubrier, Rajan Saggar, Lejla Medzikovic, Gregoire Ruffenach, Soban Umar, Barbara Girerd, David-Alexandre Trégouët, John F. Park, University of California [Los Angeles] (UCLA), University of California, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Pulmonary and Respiratory Medicine, Cell type, Cell, In situ hybridization, Critical Care and Intensive Care Medicine, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, pulmonary hypertension, scRNA-seq, Medicine, 030212 general & internal medicine, Gene, Sugen-hypoxia, drug repurposing, business.industry, RNA, food and beverages, monocrotaline, 3. Good health, Drug repositioning, medicine.anatomical_structure, 030228 respiratory system, Cancer research, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Rationale: The cellular and molecular landscape and translational value of commonly used models of pulmonary arterial hypertension (PAH) are poorly understood. Single-cell transcriptomics can enhance molecular understanding of preclinical models and facilitate their rational use and interpretation.Objectives: To determine and prioritize dysregulated genes, pathways, and cell types in lungs of PAH rat models to assess relevance to human PAH and identify drug repositioning candidates.Methods: Single-cell RNA sequencing was performed on the lungs of monocrotaline (MCT), Sugen-hypoxia (SuHx), and control rats to identify altered genes and cell types, followed by validation using flow-sorted cells, RNA in situ hybridization, and immunofluorescence. Relevance to human PAH was assessed by histology of lungs from patients and via integration with human PAH genetic loci and known disease genes. Candidate drugs were predicted using Connectivity Map.Measurements and Main Results: Distinct changes in genes and pathways in numerous cell types were identified in SuHx and MCT lungs. Widespread upregulation of NF-κB signaling and downregulation of IFN signaling was observed across cell types. SuHx nonclassical monocytes and MCT conventional dendritic cells showed particularly strong NF-κB pathway activation. Genes altered in SuHx nonclassical monocytes were significantly enriched for PAH-associated genes and genetic variants, and candidate drugs predicted to reverse the changes were identified. An open-access online platform was developed to share single-cell data and drug candidates (http://mergeomics.research.idre.ucla.edu/PVDSingleCell/).Conclusions: Our study revealed the distinct and shared dysregulation of genes and pathways in two commonly used PAH models for the first time at single-cell resolution and demonstrated their relevance to human PAH and utility for drug repositioning.
Published: 2020

25. GCN2 regulates BMP signaling: consequence for PVOD pathobiology and therapeutic management

Author: Ignacio Anegon, Mélanie Lambert, Séverine Remy, Marc Humbert, Fabrice Antigny, Florent Soubrier, Olaf Mercier, Elie Fadel, Barbara Girerd, David Montani, Bahgat Soilih, Juliette Bignard, Sophie Nadaud, Grégoire Manaud, Frédéric Perros, Stjin Verleden, Monica Florio, Florence Lecerf, Banghua Sun, Gérald Simmoneau, and Olivier Claude
Subjects: In vivo, business.industry, Transgene, Extracellular, Cancer research, Medicine, Phosphorylation, Chordin, business, medicine.disease, Pulmonary hypertension, Psychological repression, BMPR2
Abstract: Introduction: Pulmonary veno-occlusive disease (PVOD) is an orphan fatal disease. The identification of biallelic inactivating mutations of EIF2AK4 (encoding GCN2) as the major genetic cause of PVOD has clarified the nosology of the disease. On the other hand, BMP/BMPR2 axis is a major axis of pulmonary arterial hypertension pathobiology, a close but better understood form of severe pulmonary hypertension (PH) Objective: To investigate the functional relationship between GCN2 and the BMP/BMPR2 axis. Methods: We investigated GCN2 and the BMP/BMPR2 axis in human and animal models of PVOD, and in cultured human pulmonary microvascular endothelial cells (hPMEC) with interventional experiments (siRNA and pharmacological inhibitors/activators) Results: Pulmonary GCN2 protein expression was decreased in all forms of PVOD. We showed that GCN2 loss-of-function negatively regulates BMP-dependent SMAD1/5/9 signaling in hPMEC. This molecular relationship was confirmed in vivo, in the lungs of a newly created transgenic rat model knock out for Eif2ak4. We found a 4 fold decrease in SMAD1/5/9 phosphorylation in KO rats. We showed this regulation may be mediated through GCN2-dependent repression of chordin, an extracellular antagonist of BMP signaling. GCN2 inhibition induced a dramatic increase in hPMEC proliferation, which is highly relevant of PVOD genesis. BMP9 treatment was able to block this exuberant proliferation Conclusion: GCN2 loss-of-function negatively regulates SMAD1/5/9 phosphorylation. Despite this dampened BMP signaling, exogenous BMP9 was still able to reverse GCN2 inhibition-induced hPMEC proliferation. BMP9 may hence be considered as potential therapeutic options for PVOD
Published: 2020

26. Screening of pulmonary arterial hypertension in BMPR2 mutation carriers

Author: Laurent Godinas, Christophe Guiganbert, David Montani, Gilles Garcia, Edmund M.T. Lau, Laurent Savale, Xavier Jaïs, Gérald Simonneau, Sébastien Hascoët, Amir Bouchachi, Sven Günther, Olivier Sitbon, Marc Humbert, Mélanie Eyries, Philippe Hervé, Florent Soubrier, Florence Parent, Denis Chemla, Pierantonio Laveneziana, and Barbara Girerd
Subjects: medicine.medical_specialty, medicine.drug_class, business.industry, Incidence (epidemiology), medicine.disease, Asymptomatic, Pulmonary hypertension, Annual Screening, BMPR2, Pulmonary function testing, Internal medicine, Mutation (genetic algorithm), Natriuretic peptide, medicine, Cardiology, medicine.symptom, business
Abstract: Introduction: Heritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the BMPR2 gene (encoding Bone Morphogenetic Protein Receptor type II). Despite the lack of clear evidence, asymptomatic BMPR2 mutation carriers are recommended to undergo annual screening echocardiography for early detection of PAH. Objectives: To evaluate the utility of a comprehensive multimodal PAH screening program in asymptomatic adult BMPR2 mutation carriers. Methods: Asymptomatic BMPR2 mutation carriers underwent screening at baseline and annually for a minimum of two years (DELPHI-2 study, NCT01600898). Annual screening included clinical assessment, electrocardiogram, pulmonary function tests, 6-minute walk distance, cardiopulmonary exercise test (CPET), chest x-ray, echocardiography and N-terminal pro-brain natriuretic peptide level. Right heart catheterization (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline. Results: Fifty-five subjects (26 males, median age 37 years) were included. At baseline, no PAH was suspected based on echocardiography and NT pro-BNP levels. All subjects accepted RHC at inclusion which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension of unknown significance (21.8%). At long term follow-up, three additional PAH cases were diagnosed, yielding a PAH incidence of 2.3%/year. All detected cases have remained at low risk status on oral PAH therapy at last follow-up. Conclusion: In adult BMPR2 mutation carriers, a multimodal screening program with regular follow-up allows early detection of PAH.
Published: 2020

27. Comparison of Human and Experimental Pulmonary Veno-Occlusive Disease

Author: Séverine Remy, Juliette Bignard, Audrey Courboulin, Gérald Simonneau, Maria-Rosa Ghigna, Marc Humbert, Ignacio Anegon, Mélanie Lambert, Fabrice Antigny, Monica Florio, Esther J. Nossent, Banghua Sun, Harm Jan Bogaard, Elie Fadel, Aurélie Hautefort, Anton Vonk Noordegraaf, Angèle Boet, Barbara Girerd, Maria-Candida Vinhas, Grégoire Manaud, Sophie Nadaud, Frédéric Perros, Stijn E. Verleden, Olivier Claude, Sébastien J. Dumas, Florent Soubrier, Peter Dorfmüller, Benoit Ranchoux, Florence Lecerf, Olaf Mercier, David Montani, Katrien Grünberg, Centre de Référence de l’Hypertension Pulmonaire Sévère [CHU Le Kremlin Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Vrije Universiteit Amsterdam [Amsterdam] (VU), Centre Chirurgical Marie Lannelongue (CCML), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Amgen Inc. [Thousand Oaks, CA, USA], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de Pneumologie et Réanimation Respiratoire (DHU TORINO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre-Centre de Référence de l'Hypertension Pulmonaire Sévère, University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research, Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval [Québec] (ULaval), This work was funded the French National Research Agency (Agence Nationale de la Recherche, ANR, grant: ANR-13-JSV1-0011-01) and by Pulmonary Vascular Research Institute (PVRI) BMPR2 Research Grant supported by the Dinosaur Trust (to F.P.), and by DHU TORINO (Département Hospitalo-Universitaire Thorax Innovation) and AP-HP. This work was also supported by INSERM, Université Paris-Sud, Université Paris-Saclay and Hôpital Marie Lannelongue. G.M. is 2017 Laureate of Fonds de Recherche en Santé Respiratoire et de la Fondation du Souffle. F.A. receives funding from the Fondation du Souffle et Fonds de Dotation Recherche en Santé Respiratoire, from the Fondation Lefoulon-Delalande and from the Fondation Legs Poix. F.A. also received funding from the National Funding Agency for Research: ANR-18-CE14-0023. M.L. is supported by Therapeutic Innovation Doctoral School (ED569). E.J.N. was supported by an ERS (European Respiratory Society) PAH LongTerm Research Fellowship. S.E.V is supported by a post-doctoral fellowship of FWO (12G8718N) and a grant from KU Leuven (C24/18/073)., ANR-13-JSV1-0011,EMIR,Mécanismes épigénétiques dans l'inflammation et le remodelage vasculaire de l'hypertension pulmonaire(2013), ANR-18-CE14-0023,KAPAH,KCNK3 une nouvelle cible thérapeutique dans l'hypertension artérielle pulmonaire(2018), Le Bihan, Sylvie, Jeunes Chercheuses et Jeunes Chercheurs - Mécanismes épigénétiques dans l'inflammation et le remodelage vasculaire de l'hypertension pulmonaire - - EMIR2013 - ANR-13-JSV1-0011 - JC - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - KCNK3 une nouvelle cible thérapeutique dans l'hypertension artérielle pulmonaire - - KAPAH2018 - ANR-18-CE14-0023 - AAPG2018 - VALID, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Pathology, Centre chirurgical Marie Lannelongue, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Hypertension, Pulmonary, [SDV]Life Sciences [q-bio], SMAD signaling, Clinical Biochemistry, CHOP, Pulmonary Artery, Bone morphogenetic protein, Pulmonary hypertension, 03 medical and health sciences, 0302 clinical medicine, medicine.artery, Medicine, Animals, Humans, Biology, Molecular Biology, Microvessel, Lung, business.industry, Endothelial Cells, BMPR-II, Cell Biology, medicine.disease, 3. Good health, Rats, Heme oxygenase, [SDV] Life Sciences [q-bio], Chemistry, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, 030228 respiratory system, Pulmonary artery, Mutation, Human medicine, Pulmonary Veno-Occlusive Disease, GCN2, business, Transcription Factor CHOP, pulmonary veno-occlusive disease, Signal Transduction
Abstract: Pulmonary veno-occlusive disease (PVOD) occurs in humans either as a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2) or as a sporadic form in older age (sPVOD). The chemotherapeutic agent mitomycin C (MMC) is a potent inducer of PVOD in humans and in rats (MMC-PVOD). Here, we compared human hPVOD and sPVOD, and MMC-PVOD pathophysiology at the histological, cellular, and molecular levels to unravel common altered pathomechanisms. MMC exposure in rats was associated primarily with arterial and microvessel remodeling, and secondarily by venous remodeling, when PVOD became symptomatic. In all forms of PVOD tested, there was convergent GCN2-dependent but eIF2α-independent pulmonary protein overexpression of HO-1 (heme oxygenase 1) and CHOP (CCAAT-enhancer-binding protein [C/EBP] homologous protein), two downstream effectors of GCN2 signaling and endoplasmic reticulum stress. In human PVOD samples, CHOP immunohistochemical staining mainly labeled endothelial cells in remodeled veins and arteries. Strong HO-1 staining was observed only within capillary hemangiomatosis foci, where intense microvascular proliferation occurs. HO-1 and CHOP stainings were not observed in control and pulmonary arterial hypertension lung tissues, supporting the specificity for CHOP and HO-1 involvement in PVOD pathobiology. In vivo loss of GCN2 (EIF2AK4 mutations carriers and Eif2ak4-/- rats) or in vitro GCN2 inhibition in cultured pulmonary artery endothelial cells using pharmacological and siRNA approaches demonstrated that GCN2 loss of function negatively regulates BMP (bone morphogenetic protein)-dependent SMAD1/5/9 signaling. Exogenous BMP9 was still able to reverse GCN2 inhibition-induced proliferation of pulmonary artery endothelial cells. In conclusion, we identified CHOP and HO-1 inhibition, and BMP9, as potential therapeutic options for PVOD. ispartof: AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY vol:63 issue:1 pages:118-131 ispartof: location:United States status: published
Published: 2020

28. Phenotype and outcome of pulmonary arterial hypertension patients carrying a TBX4 mutation

Author: Caroline Ovaert, Damien Bonnet, Gérald Simonneau, Céline Chabanne, Pierre Thoré, Olivier Sitbon, Marc Humbert, Marilyne Lévy, Claire Dauphin, Florent Soubrier, Laurent Savale, E. Boiffard, Xavier Jaïs, Martine Remy-Jardin, Amélie Servettaz, Barbara Girerd, Anne Guillaumot, Ari Chaouat, Frédéric Perros, Maria-Rosa Ghigna, David Montani, Vincent Cottin, Mélanie Eyries, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Pneumologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Centre Chirurgical Marie Lannelongue (CCML), Centre chirurgical Marie Lannelongue, Service d'Oncogénétique et Angiogénétique Moléculaire [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Service de génétique [CHU Pitié-Salpêtrière], Service de cardiologie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Clermont-Ferrand, CHU Pontchaillou [Rennes], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Service de pneumologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Référence des Maladies Pulmonaires Rares [Hôpital Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Immuno-Régulation dans les Maladies Auto-Immunes Inflammatoires et le Cancer - EA 7509 (IRMAIC), Université de Reims Champagne-Ardenne (URCA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Hemodynamics, medicine.disease_cause, Gastroenterology, Vascular remodelling in the embryo, 03 medical and health sciences, 0302 clinical medicine, Diffusing capacity, Internal medicine, Parenchyma, medicine, Lung transplantation, Mutation, business.industry, Phenotype, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, 030228 respiratory system, Vascular resistance, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: IntroductionTBX4 mutation causes small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown.MethodsWe report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French pulmonary hypertension (PH) network.Results20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0–76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2–41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide (DLCO) was decreased in all patients. High-resolution computed tomography (HRCT) showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients had died and two had undergone lung transplantation. One-year, three-year and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic pulmonary arterial hypertension (IPAH) and accumulation of cholesterol crystals within the lung parenchyma.ConclusionPAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.
Published: 2020

29. Familial pulmonary arterial hypertension by KDR heterozygous loss of function

Author: David Montani, Barbara Girerd, Frédéric Perros, Mélanie Eyries, Marc Humbert, Grégoire Manaud, Florent Soubrier, Nicholas W. Morrell, Marianne Riou, Nicolas Favrolt, Laurence Faivre, Stefan Gräf, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de pneumologie [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de Pneumologie Soins Intensifs, Appareillage Respiratoire [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre chirurgical Marie Lannelongue, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), University of Cambridge [UK] (CAM), Addenbrooke's Hospital, Cambridge University NHS Trust, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Chirurgical Marie Lannelongue (CCML), and Perros, Frédéric
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Mutation, business.industry, Interstitial lung disease, medicine.disease, medicine.disease_cause, Major gene, 3. Good health, BMPR2, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030228 respiratory system, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Diffusing capacity, Immunology, Medicine, business, Gene, Loss function, Genetic association
Abstract: Beyond the major gene BMPR2, several new genes predisposing to PAH have been identified during the last decade. Recently, preliminary evidence of the involvement of the KDR gene was found in a large genetic association study.We prospectively analysed the KDR gene by targeted panel sequencing in a series of 311 PAH patients referred to a clinical molecular laboratory for genetic diagnosis of PAH.Two index cases with severe PAH from two different families were found to carry a loss-of-function mutation in the KDR gene. These two index cases were clinically characterised by low diffusing capacity for carbon monoxide adjusted for haemoglobin (DLCOc) and interstitial lung disease. In one family, segregation analysis revealed that variant carriers are either presenting with PAH associated with low DLCOc, or have only decreased DLCOc, whereas non-carrier relatives have normal DLCOc. In the second family, a single affected carrier was alive. His carrier mother was unaffected with normal DLCOc.We provided genetic evidence for considering KDR as a newly identified PAH-causing gene by describing the segregation of KDR mutations with PAH in two families. In our study, KDR mutations are associated with a particular form of PAH characterised by low DLCOc and radiological evidence of parenchymal lung disease including interstitial lung disease and emphysema.
Published: 2020

30. Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension

Author: Christopher J. Rhodes, Allan Lawrie, Robert V. MacKenzie Ross, Mark Toshner, Mélanie Eyries, Werner Seeger, Richard M. Salmon, Stefano Ghio, Laura Scelsi, Stephen J. Wort, Gabor Kovacs, Florent Soubrier, J. Simon R. Gibbs, Richard C. Trembath, Jennifer M. Martin, Nicholas W. Morrell, Matthias Haimel, Gerry Coghlan, Marc Humbert, Jay Suntharalingam, Charaka Hadinnapola, Cesare Danesino, Willem H. Ouwehand, Louise C. Daugherty, Carmen M. Treacy, David G. Kiely, Andrea Olschewski, Joanna Pepke-Zaba, Deborah Whitehorn, Anton Vonk Noordegraaf, Andrew J. Peacock, Robin Condliffe, Horst Olschewski, Paul A. Corris, Joshua Hodgson, Hossein Ardeschir Ghofrani, Arjan C. Houweling, Colin Church, Jingxu Guo, Stefan Gräf, Barbara Girerd, Katherine Yates, Harm Jan Bogaard, Ivana Nikolic, Luke S. Howard, Henning Gall, Laura Southgate, Olga Shamardina, Emilia M. Swietlik, Marta Bleda, Rajiv D. Machado, Inga Prokopenko, John Wharton, James Liley, Simon Holden, Paul B. Yu, Martin R. Wilkins, Shahin Moledina, David Montani, Paul D. Upton, Wei Li, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Swietlik, Emilia [0000-0002-4095-8489], Guo, Jingxu [0000-0002-1568-4842], Shamardina, Olga [0000-0003-4994-2157], Ouwehand, Willem [0000-0002-7744-1790], Toshner, Mark [0000-0002-3969-6143], Li, Wei [0000-0002-1924-3120], Graf, Stefan [0000-0002-1315-8873], Upton, Paul [0000-0003-2716-4921], Morrell, Nicholas [0000-0001-5700-9792], Apollo - University of Cambridge Repository, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, APH - Quality of Care, ACS - Atherosclerosis & ischemic syndromes, and British Heart Foundation
Subjects: Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, Heterozygote, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Respiratory System, Mutation, Missense, GDF2, Critical Care and Intensive Care Medicine, Bone morphogenetic protein, BMP9, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Critical Care Medicine, Sex factors, Internal medicine, General & Internal Medicine, pulmonary arterial hypertension, medicine, Growth Differentiation Factor 2, Humans, In patient, 030212 general & internal medicine, Respiratory system, 11 Medical and Health Sciences, Science & Technology, business.industry, Case-control study, Heterozygote advantage, Middle Aged, 3. Good health, Transport protein, BMP10, Protein Transport, Endocrinology, 030228 respiratory system, Case-Control Studies, Bone Morphogenetic Proteins, Female, business, Life Sciences & Biomedicine
Abstract: International audience; Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.
Published: 2020

31. Phenotype and outcome of PAH patients carrying a TBX4 mutation

Author: Pierre Thoré, Barbara Girerd, Xavier Jaïs, Laurent Savale, Maria Rosa Ghigna, Mélanie Eyries, Marilyne Levy, Caroline Ovaert, Amélie Servettaz, Anne Guillaumot, Claire Dauphin, Céline Chabanne, Emmanuel Boiffard, Vincent Cottin, Frédéric Perros, Gérald Simonneau, Sitbon Olivier, Florent Soubrier, Damien Bonnet, Martine Remy Jardin, Ari Chaouat, Marc Humbert, David Montani, Service de Pneumologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Hypertension artérielle pulmonaire : physiopathologie et innovation thérapeutique [Le Kremlin-Bicêtre], Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Marie Lannelongue Hospital, 92350 Le Plessis-Robinson, France, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Médecine Interne, Immunologie clinique et maladies infectieuses [CHU Reims], Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Service de chirurgie thoracique cardiaque et vasculaire [Rennes] = Thoracic and Cardiovascular Surgery [Rennes], CHU Pontchaillou [Rennes], Service de Cardiologie [La Roche-sur-Yon], Centre Hospitalier Départemental site de la Roche-sur-Yon (CHD de la Roche-sur-Yon), Department of Pneumology [Lyon], Hospices Civils de Lyon (HCL), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de pneumologie [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Centre Chirurgical Marie Lannelongue (CCML), Centre chirurgical Marie Lannelongue, Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Perros, Frédéric, Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Marie-Lannelongue, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), CHU Gabriel Montpied (CHU), Service de chirurgie thoracique cardiaque et vasculaire [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and AP-HP - Hôpital Antoine Béclère [Clamart]
Subjects: [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: International audience; INTRODUCTION:TBX4 mutation cause small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown.METHODS:We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French PH Network.RESULTS:Twenty patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 (0-76) year-old and a female to male ratio of 3. Most of the patients were in NYHA functional class III or IV (70%) with a severe hemodynamic impairment (median pulmonary vascular resistance of 13.6 [6.2-41.8] Wood Units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity for carbon monoxide was decreased in all patients. High-resolution computed tomography showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients died and two underwent lung transplantation. One-, three- and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic PAH, and accumulation of cholesterol crystals within the lung parenchyma.CONCLUSION:PAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.
Published: 2020

32. Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension

Author: Christopher J. Rhodes, Anna Ulrich, William C. Nichols, Tufik R. Assad, Richard C. Trembath, Martin R. Wilkins, Lars Harbaum, Stefan Gräf, Marc Humbert, David-Alexandre Trégouët, John Wharton, Florent Soubrier, Ankit A. Desai, Nicholas W. Morrell, Inga Prokopenko, Emilia M. Swietlik, Evan L. Brittain, Laura Southgate, Timothy E. Thayer, British Heart Foundation, The Academy of Medical Sciences, Imperial College London, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], University of Cambridge [UK] (CAM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Cincinnati Children's Hospital Medical Center, Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), St George's, University of London, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), King‘s College London, University of Surrey (UNIS), Gestionnaire, Hal Sorbonne Université, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Erythrocyte Indices, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Hypertension, Pulmonary, NIHR BioResource – Rare Diseases Consortium, Respiratory System, UK PAH Cohort Study Consortium, Disease, 030204 cardiovascular system & hematology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Gastroenterology, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Internal medicine, medicine, Genetic predisposition, Humans, 030212 general & internal medicine, Respiratory system, 11 Medical and Health Sciences, Pulmonary Vascular Disease, Pulmonary Arterial Hypertension, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Red blood cell distribution width, Original Articles, Odds ratio, Iron deficiency, medicine.disease, and the US PAH Biobank Consortium, 3. Good health, VINTAGE, Case-Control Studies, Mendelian inheritance, symbols, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business, Genome-Wide Association Study, Rare disease
Abstract: Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early-stage iron deficiency or iron deficiency anaemia. This study investigated whether elevated RDW is causally associated with PAH. A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively. We confirmed the observed association between RDW and PAH (OR 1.90, 95% CI 1.80–2.01) in a multicentre case–control study (cases n=642, disease controls n=15 889). The primary MR analysis was adequately powered to detect a causal effect (odds ratio) between 1.25 and 1.52 or greater based on estimates reported in the RDW genome-wide association study or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (ORcausal 1.07, 95% CI 0.92–1.24) or the secondary (ORcausal 1.09, 95% CI 0.77–1.54) MR analysis. The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution, as any improvements observed may not be mechanistically linked to the development of PAH., Mendelian randomisation using genetic data from the largest-to-date PAH cohort does not support red cell distribution width or iron deficiency as a cause of PAH, which is important when interpreting iron replacement trials in this condition http://bit.ly/2PPaa88
Published: 2020

33. Higher prevalence of splenic artery aneurysms in hereditary hemorrhagic telangiectasia: Vascular implications and risk factors

Author: Mostafa El Hajjam, Florent Soubrier, Augustin Ozanne, Gilles Lesur, Alain Beauchet, Philippe Charron, Pascal Lacombe, Aurélien Palmyre, Isabelle Bourgault-Villada, Jerome Lucas, Jérome Lesniak, Axel Dallongeville, Carole Fagnou, J. Sellier, Carma Karam, S. Binsse, Thierry Chinet, Mélanie Eyries, Sandra Blivet, Agnès Nicod-Tran, Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), and Sorbonne Université (SU)
Subjects: Male, 0301 basic medicine, Epidemiology, Physiology, Maternal Health, Blood Pressure, Disease, Cardiovascular Medicine, Splenic artery, Vascular Medicine, Gastroenterology, Diagnostic Radiology, 030218 nuclear medicine & medical imaging, 0302 clinical medicine, Risk Factors, Pregnancy, Blood Flow, hemic and lymphatic diseases, Prevalence, Medicine and Health Sciences, Telangiectasia, Tomography, Multidisciplinary, Radiology and Imaging, Obstetrics and Gynecology, Arteries, Middle Aged, Prognosis, Body Fluids, 3. Good health, Blood, Cardiovascular Diseases, Hypertension, Medicine, Female, Telangiectasia, Hereditary Hemorrhagic, France, Anatomy, medicine.symptom, Aneurysms, Research Article, Adult, medicine.medical_specialty, Imaging Techniques, Science, Neuroimaging, Research and Analysis Methods, 03 medical and health sciences, Hypertensive Disorders in Pregnancy, Diagnostic Medicine, Internal medicine, medicine.artery, Multidetector Computed Tomography, medicine, Humans, Vascular Diseases, Aged, Retrospective Studies, Fetus, Aorta, business.industry, Case-control study, Biology and Life Sciences, Retrospective cohort study, Blood flow, Aneurysm, Computed Axial Tomography, 030104 developmental biology, Case-Control Studies, Medical Risk Factors, Cardiovascular Anatomy, Blood Vessels, Women's Health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Splenic Artery, Follow-Up Studies, Neuroscience
Abstract: International audience; Background: Splenic artery aneurysm (SAA) is a rare but potentially fatal condition. Rupture results in 25% mortality up to 75% in pregnant women with 95% fetal mortality. Brief reports suggest an increased risk of developing SAA in patients with HHT.Methods: We analyzed enhanced multidetector CT data in 186 HHT patients matched (gender and ± 5 year old) with 186 controls. We screened for SAA and recorded diameter of splenic and hepatic arteries and hepatic, pancreatic and splenic parenchymal involvements. We determined by univariate and multivariate analysis, the relationship with age, sex, genetic status, cardiovascular risk factors (CVRF) and visceral involvement.Results: SAA concerned 24.7% of HHT patients and 5.4% of controls, p
Published: 2020

34. Phenotype and outcome of pulmonary arterial hypertension patients carrying a

Author: Pierre, Thoré, Barbara, Girerd, Xavier, Jaïs, Laurent, Savale, Maria-Rosa, Ghigna, Mélanie, Eyries, Marilyne, Levy, Caroline, Ovaert, Amélie, Servettaz, Anne, Guillaumot, Claire, Dauphin, Céline, Chabanne, Emmanuel, Boiffard, Vincent, Cottin, Frédéric, Perros, Gérald, Simonneau, Olivier, Sitbon, Florent, Soubrier, Damien, Bonnet, Martine, Remy-Jardin, Ari, Chaouat, Marc, Humbert, and David, Montani
Subjects: Adult, Male, Bone Diseases, Developmental, Pulmonary Arterial Hypertension, Hip, Adolescent, Infant, Newborn, Infant, Patella, Middle Aged, Survival Rate, Young Adult, Phenotype, Ischium, Child, Preschool, Mutation, Humans, Female, Vascular Resistance, France, Child, T-Box Domain Proteins, Aged, Lung Transplantation, Retrospective Studies
Abstract: We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0-76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2-41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide (PAH due to
Published: 2019

35. Familial pulmonary arterial hypertension by

Author: Mélanie, Eyries, David, Montani, Barbara, Girerd, Nicolas, Favrolt, Marianne, Riou, Laurence, Faivre, Grégoire, Manaud, Frédéric, Perros, Stefan, Gräf, Nicholas W, Morrell, Marc, Humbert, and Florent, Soubrier
Subjects: Mutation, Humans, Familial Primary Pulmonary Hypertension, Genetic Predisposition to Disease, Vascular Endothelial Growth Factor Receptor-2, Genetic Association Studies
Abstract: Beyond the major gene
Published: 2019

36. Characterization of

Author: Joshua, Hodgson, Emilia M, Swietlik, Richard M, Salmon, Charaka, Hadinnapola, Ivana, Nikolic, John, Wharton, Jingxu, Guo, James, Liley, Matthias, Haimel, Marta, Bleda, Laura, Southgate, Rajiv D, Machado, Jennifer M, Martin, Carmen M, Treacy, Katherine, Yates, Louise C, Daugherty, Olga, Shamardina, Deborah, Whitehorn, Simon, Holden, Harm J, Bogaard, Colin, Church, Gerry, Coghlan, Robin, Condliffe, Paul A, Corris, Cesare, Danesino, Mélanie, Eyries, Henning, Gall, Stefano, Ghio, Hossein-Ardeschir, Ghofrani, J Simon R, Gibbs, Barbara, Girerd, Arjan C, Houweling, Luke, Howard, Marc, Humbert, David G, Kiely, Gabor, Kovacs, Allan, Lawrie, Robert V, MacKenzie Ross, Shahin, Moledina, David, Montani, Andrea, Olschewski, Horst, Olschewski, Willem H, Ouwehand, Andrew J, Peacock, Joanna, Pepke-Zaba, Inga, Prokopenko, Christopher J, Rhodes, Laura, Scelsi, Werner, Seeger, Florent, Soubrier, Jay, Suntharalingam, Mark R, Toshner, Richard C, Trembath, Anton, Vonk Noordegraaf, Stephen J, Wort, Martin R, Wilkins, Paul B, Yu, Wei, Li, Stefan, Gräf, Paul D, Upton, and Nicholas W, Morrell
Subjects: Adult, Male, Heterozygote, Pulmonary Arterial Hypertension, DNA Copy Number Variations, Mutation, Missense, Original Articles, Middle Aged, Protein Transport, Sex Factors, Case-Control Studies, Bone Morphogenetic Proteins, Growth Differentiation Factor 2, Humans, Female
Abstract: Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor. Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH. Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260). Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations. Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.
Published: 2019

37. Clinical and genetic findings in children with central nervous system arteriovenous fistulas

Author: Florent Soubrier, Guillaume Saliou, Marie-Christine Waill, Mélanie Eyries, Marta Iacobucci, Florence Coulet, Augustin Ozanne, and Jean-François Knebel
Subjects: Intracranial Arteriovenous Malformations, Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Arteriovenous fistula, Gene mutation, Cohort Studies, Hemangioma, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Modified Rankin Scale, Internal medicine, medicine, Humans, Genetic Testing, Preschool, Child, Genetic testing, medicine.diagnostic_test, business.industry, Infant, Arteriovenous malformation, medicine.disease, Arteriovenous Fistula, Child, Preschool, Female, Mutation, Spinal Cord, 030104 developmental biology, Neurology, Heart failure, Cardiology, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: OBJECTIVE To assess the spectrum of genetic anomalies in a cohort of children presenting at least one cerebral or spinal pial arteriovenous fistula (AVF), and to describe their clinical characteristics. METHODS From 1988 to 2016, all consecutive patients with at least one cerebral or spinal pial AVF were screened for genetic disease. All patients aged
Published: 2017

38. Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Author: Harm Jan Bogaard, Richard C. Trembath, Florent Soubrier, Allan Lawrie, Robin Condliffe, Jennifer M. Martin, Nicholas W. Morrell, Heritable Pah, Nicholas Screaton, Jay Suntharalingam, Robert V. MacKenzie Ross, David G. Kiely, Matthias Haimel, Colin Church, Stefan Gräf, Stephen J. Wort, Paula Rayner-Matthews, Peter Dorfmüller, Andrew Peacock, Marc Humbert, Katherine Yates, Andrew J. Swift, Laura Southgate, Olga Shamardina, Paul A. Corris, Charaka Hadinnapola, Mark Toshner, Rajiv D. Machado, Mark Southwood, Martin R. Wilkins, John Wharton, Shahin Moledina, Simon Holden, Joanna Pepke-Zaba, Anton Vonk Noordegraaf, Gerry Coghlan, Michael Newnham, Carmen M. Treacy, Stephen D. Preston, Jules Hernández-Sánchez, Barbara Girerd, Simon Gibbs, Marta Bleda, David Montani, British Heart Foundation, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, Biochemie, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Hadinnapola, Charaka [0000-0002-7794-3432], Haimel, Matthias [0000-0002-0320-0214], Shamardina, Olga [0000-0003-4994-2157], Toshner, Mark [0000-0002-3969-6143], Graf, Stefan [0000-0002-1315-8873], Morrell, Nicholas [0000-0001-5700-9792], Apollo - University of Cambridge Repository, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care
Subjects: Male, CAPILLARY HEMANGIOMATOSIS, Cardiac & Cardiovascular Systems, Heredity, DNA Mutational Analysis, 030204 cardiovascular system & hematology, Cohort Studies, NIHR BioResource–Rare Diseases Consortium, UK National Cohort Study of Idiopathic and Heritable PAH, 0302 clinical medicine, VENOOCCLUSIVE-DISEASE, Gene Frequency, Risk Factors, pulmonary hypertension, Medicine, Familial Primary Pulmonary Hypertension, genetics, Prospective Studies, Prospective cohort study, 1102 Cardiorespiratory Medicine and Haematology, Middle Aged, Medical research, Protein-Serine-Threonine Kinases, DIFFUSION CAPACITY, 3. Good health, Pedigree, Europe, Phenotype, Predictive value of tests, Pulmonary venoocclusive disease, Female, Pulmonary Veno-Occlusive Disease, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, pulmonary veno-occlusive disease, CT, Adult, medicine.medical_specialty, genetics, human, hypertension, pulmonary, Hypertension, Pulmonary, hypertension, pulmonary, Protein Serine-Threonine Kinases, Pulmonary Artery, Bone Morphogenetic Protein Receptors, Type II, Article, 1117 Public Health and Health Services, 03 medical and health sciences, Young Adult, Predictive Value of Tests, Physiology (medical), Internal medicine, Humans, Arterial Pressure, Genetic Predisposition to Disease, human, Genetic Association Studies, Aged, Retrospective Studies, Science & Technology, pulmonary venoocclusive disease, business.industry, BMPR2, Retrospective cohort study, 1103 Clinical Sciences, medicine.disease, Pulmonary hypertension, Blood pressure, EIF2AK4, 030228 respiratory system, Peripheral Vascular Disease, Cardiovascular System & Hematology, REGISTRY, Physical therapy, Cardiovascular System & Cardiology, prognosis, mutation, business, Tomography, X-Ray Computed
Abstract: Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.
Published: 2017

39. Architecture génétique de l’hypertension pulmonaire : des gènes aux médicaments

Author: David Montani, Florence Coulet, Mélanie Eyries, Marc Humbert, Florent Soubrier, and Barbara Girerd
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, General Medicine
Abstract: RESUME La decouverte de nouveaux genes de susceptibilite a l’hypertension pulmonaire a bouleverse nos connaissances sur la physiopathologie de la maladie. A cote des mutations du gene BMPR2 qui sont, par leurs frequences et leurs effets, les principales mutations responsables des formes heritables de l’hypertension arterielle pulmonaire (HTAP) isolee, des mutations ont ete decrites dans le gene KCNK3 (TASK1) codant pour un canal potassium, le gene SMAD8 codant, comme BMPR2, pour une molecule de signalisation de la voie BMP, le gene CAV1 codant pour la caveoline-1. Les mutations des genes de l’endogline et du recepteur ACVRL1 s’inscrivent dans le cadre de la maladie de Rendu-Osler et la survenue de l’HTAP en aggrave la severite, et les mutations du gene TBX4 sont egalement responsables de formes syndromiques d’HTAP compliquant de facon rare le Small Patella Syndrome. Les mutations du gene EIF2AK4 (GCN2) sont responsables d’une forme rare et severe d’hypertension pulmonaire, la maladie veino-occlusive pulmonaire appelee aussi hemangiomatose capillaire pulmonaire. L’analyse des mecanismes d’action et de regulation de ces genes et des consequences fonctionnelles des mutations conduit a la conception de nouveaux traitements a visee etiologique de l’hypertension pulmonaire.
Published: 2017

40. Non-invasive CT screening for pulmonary arteriovenous malformations in children with confirmed hereditary hemorrhagic telangiectasia: Results from two pediatric centers

Author: Jean-Yves Rioux, Virginie Escabasse, Hubert Ducou Le Pointe, Suzanne Verlhac, Ralph Epaud, Florent Soubrier, Isabelle Hau, Manuela Vasile, Stéphanie Franchi-Abella, Nurcan Soysal, Marie-France Carette, Natascha Remus, Sarah Robert, Aline Tamalet, Céline Delestrain, and Mélanie Eyries
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, High-resolution computed tomography, medicine.diagnostic_test, business.industry, Mucocutaneous zone, Genetic disorder, Arteriovenous malformation, ACVRL1, Endoglin, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Dysplasia, hemic and lymphatic diseases, Pediatrics, Perinatology and Child Health, otorhinolaryngologic diseases, medicine, medicine.symptom, Telangiectasia, business, 030217 neurology & neurosurgery
Abstract: SummaryBackground Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that is caused by mutations in mainly two genes, that is ENG, encoding endoglin (HHT1), or ACVRL1, encoding activin receptor-like kinase 1 (ALK-1/HHT2). HHT is characterized by recurrent epistaxis, mucocutaneous telangiectasia, and vascular visceral dysplasia responsible for visceral arteriovenous malformations (AVM). Aim to report the experience of two university hospitals (Trousseau, Paris, and CHIC, Creteil) with screening children for HHT and pulmonary AVM (PAVM) using high resolution computed tomography (HRCT). Methods parents with confirmed HHT were offered to have their children screened for the mutation identified in their family, and informed consent was obtained. Children carrying the same mutation as their parents underwent HRCT of the chest without contrast. Results between 2008 and 2015, 99 children were screened for HHT mutations. Mutations were identified in 59 patients, that is 24 HHT1 and 35 HHT2. Radiologic and clinical screening was possible in 52 patients (21 HHT-1 and 31 HHT-2). Among those, PAVM was identified in 13 patients (25%; n = 8 HHT1; n = 5 HHT2), and four of them required embolization therapy. Conclusion This study highlights the usefulness of genetic screening in children with known HHT family. It also suggests that a non-invasive protocol such as HRTC is an efficient approach to detect non-symptomatic lesions that are present early on in children carrying the ENG (HHT1), but also the ACVRL1 mutations (HHT2). Pediatr Pulmonol. 2017;52:642–649. © 2017 Wiley Periodicals, Inc.
Published: 2017

41. BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension

Author: Elie Fadel, Olivier Sitbon, Laurent Savale, Marc Humbert, Philippe Hervé, Xavier Jaïs, Maria-Rosa Ghigna, Gérald Simonneau, Barbara Girerd, David Montani, Olaf Mercier, Peter Dorfmüller, Christophe Guignabert, Vincent Thomas de Montpréville, and Florent Soubrier
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, Hemoptysis, Heterozygote, Pathology, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Bronchial Arteries, Vascular Remodeling, 030204 cardiovascular system & hematology, Gene mutation, Bone Morphogenetic Protein Receptors, Type II, Vascular remodelling in the embryo, Muscle hypertrophy, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine.artery, medicine, Humans, Lung transplantation, Familial Primary Pulmonary Hypertension, Child, Lung, business.industry, Middle Aged, BMPR2, medicine.anatomical_structure, 030228 respiratory system, Child, Preschool, Mutation, Female, France, business, Bronchial artery, Lung Transplantation, Artery
Abstract: The impact of bone morphogenetic protein receptor 2 (BMPR2) gene mutations on vascular remodelling in pulmonary arterial hypertension (PAH) is unknown. We sought to identify a histological profile of BMPR2 mutation carriers.Clinical data and lung histology from 44 PAH patients were subjected to systematic analysis and morphometry.Bronchial artery hypertrophy/dilatation and bronchial angiogenesis, as well as muscular remodelling of septal veins were significantly increased in PAH lungs carrying BMPR2 mutations. We found that patients displaying increased bronchial artery remodelling and bronchial microvessel density, irrespective of the mutation status, were more likely to suffer from severe haemoptysis. History of substantial haemoptysis (>50 mL) was significantly more frequent in BMPR2 mutation carriers. 43.5% of BMPR2 mutation carriers, as opposed to 9.5% of noncarriers, displayed singular large fibrovascular lesions, which appear to be closely related to the systemic lung vasculature.Our analysis provides evidence for the involvement of the pulmonary systemic circulation in BMPR2 mutation-related PAH. We show that BMPR2 mutation carriers are more prone to haemoptysis and that haemoptysis is closely correlated to bronchial arterial remodelling and angiogenesis; in turn, pronounced changes in the systemic vasculature correlate with increased pulmonary venous remodelling, creating a distinctive profile in PAH patients harbouring a BMPR2 mutation.
Published: 2016

42. Pulmonary hypertension associated with neurofibromatosis type 1: data from the French Pulmonary Hypertension Registry

Author: Fabrice Bauer, Laurent Bertoletti, Nicolas Favrolt, Laurent Savale, Florent Soubrier, Maria-Rosa Ghigna, Emmanuel Bergot, Etienne-Marie Jutant, Pamela Moceri, Xavier Jaïs, Gérald Simonneau, Pascal Degroote, Xavier Mignard, Pascal Magro, David Montani, Delphine Bourlier, Grégoire Prévot, Cécile Tromeur, Barbara Girerd, Olivier Sitbon, Marc Humbert, Julie Traclet, Pierre-Yves Brillet, Cécile Chabanne, Thibaud Soumagne, and Claire Dauphin
Subjects: medicine.medical_specialty, business.industry, medicine.medical_treatment, Cardiac index, medicine.disease, Pulmonary hypertension, Pulmonary function testing, medicine.anatomical_structure, DLCO, Internal medicine, medicine.artery, Pulmonary artery, Cardiology, Vascular resistance, Medicine, Lung transplantation, Neurofibromatosis, business
Abstract: Introduction: Pulmonary hypertension associated with neurofibromatosis type 1 (PH-NF1) is a rare but severe complication of NF1. The largest study about PH-NF1 described 8 patients and there are few data about outcomes on PH treatment. Methods: We report clinical, functional, radiologic, and hemodynamic characteristics and outcomes of patients with pre-capillary PH-NF1 identified within the French PH Registry. Computed tomography (CT) at PH diagnosis were analysed by a pneumologist and a radiologist. Results: We identified 39 NF1-PH cases, characterized by a female predominance (77%) and a median age at PH diagnosis of 63 [min-max 35-82] y-o. At diagnosis, 90% were in NYHA functional class III or IV. Median 6-min walk distance was 209 [50-460] m. Pulmonary function tests showed normal or mild abnormalities except low DLCO (29 [20-58] %). PH was severe with a mean pulmonary artery pressure of 45 [29-71] mmHg, a cardiac index of 2.3 [1.2-3.6] L/min/m2 and pulmonary vascular resistance of 9.8 [4.6-20.1] WU. CT showed pulmonary cysts (72%), ground glass opacities (67%) and emphysema (49%). 38 patients received PAH-specific therapy. Transplant-free survival rates at 1, 3 and 5 years were 92%, 64% and 44%, respectively. Four patients underwent lung transplantation. Conclusions: PH-NF1 was characterized by female predominance, advanced age, severe hemodynamic impairment and poor prognosis.
Published: 2019

43. Widening the landscape of heritable pulmonary hypertension mutations in pediatric and adult cases

Author: David Montani, Vincent Cottin, Marc Humbert, Martine Reynaud-Gaubert, Claire Dromer, Florence Coulet, Céline Sanfiorenzo, Mélanie Eyries, Florent Soubrier, Barbara Girerd, Ari Chaouat, Marilyne Lévy, Grégoire Prévot, Romain Trésorier, Karine Nguyen, Damien Bonnet, Ali Houeijeh, Arnaud Bourdin, Sophie Nadaud, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre chirurgical Marie Lannelongue, Université Paris-Saclay, Centre National de Référence de l'Hypertension Artérielle Pulmonaire (UPRES - EA2705), Université Paris-Sud - Paris 11 (UP11), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Faculté des Sciences et Technologies [Université de Lorraine] (FST ), Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Department of Pneumology [Lyon], Hospices Civils de Lyon (HCL), Hôpital Pasteur [Nice] (CHU), Service de pneumologie [Toulouse], CHU Toulouse [Toulouse]-Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Assistance Publique - Hôpitaux de Marseille (APHM), CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Centre Chirurgical Marie Lannelongue (CCML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), and MORNET, Dominique
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Adolescent, Disease, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Bone Morphogenetic Protein Receptors, Type II, medicine.disease_cause, Genetic analysis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Growth Differentiation Factor 2, polycyclic compounds, Humans, Medicine, Familial Primary Pulmonary Hypertension, Hemangioma, Capillary, 030212 general & internal medicine, Young adult, Child, Gene, Aged, Aged, 80 and over, Mutation, Lung, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], business.industry, Middle Aged, medicine.disease, Pulmonary hypertension, 3. Good health, BMPR2, medicine.anatomical_structure, 030228 respiratory system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Bone Morphogenetic Proteins, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Pulmonary Veno-Occlusive Disease, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Female, T-Box Domain Proteins, business
Abstract: International audience; Background Heritable forms of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH) diverge by lung histopathological lesions, clinical and para-clinical presentation, their responsible genes, and mode of transmission. Since the identification of the BMPR2 gene in families affected by PAH, mutations in several other genes have been discovered for both forms. The mutation landscape in these new genes is not yet well known.Methods We set up a next-generation sequencing-based targeted sequencing gene panel allowing known genes for PAH and PVOD/PCH to be analysed simultaneously. Genetic analysis was prospectively performed on 263 PAH and PVOD/PCH patients (adult and paediatric cases).Results Pathogenic mutations were identified in 19.5% of sporadic PAH patients (n=180), 54.5% of familial PAH patients and 13.3% of PVOD/PCH patients. BMPR2 was the most frequently mutated gene, followed by TBX4 in both paediatric and adult PAH. BMP9 mutations were identified in 1.2% of adult PAH cases. EIF2AK4 biallelic mutations were restricted to PVOD/PCH. A truncating mutation and a predicted loss-of-function variant were also identified in BMP10 in two severely affected sporadic PAH female patients.Conclusion Our results confirm that mutations are found in genes beyond BMPR2 in heritable PAH, emphasise the role of TBX4 and BMP9, and designate BMP10 as a new PAH gene.
Published: 2019

44. Clinical implications of CTNNA1 germline mutations in asymptomatic carriers

Author: Yann Parc, Isabelle Coupier, Erell Guillerm, Jerôme Bellanger, Aurélie Maran Gonzalez, Magali Svrcek, Jeanne Netter, Jérôme Alexandre Denis, Chrystelle Colas, Mathilde Warcoin, A. Mourregot, Mohamed Zizi, Florent Soubrier, Florence Coulet, Axelle Canard, Mélanie Eyries, Hélène Delhomelle, Véronica Cusin, Patrick R. Benusiglio, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de chirurgie générale et digestive [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut Curie [Paris], Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Sorbonne Université (SU), Institut du Cancer de Montpellier (ICM), Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], CHU Montpellier, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Male, Cancer Research, medicine.medical_treatment, medicine.disease_cause, Gastroenterology, Germline, 0302 clinical medicine, Surgical oncology, Mutation, General Medicine, Middle Aged, Prognosis, 3. Good health, Pedigree, Oncology, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Female, Hereditary diffuse gastric cancer, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Germline mutation, Gastrectomy, Stomach Neoplasms, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Retrospective Studies, Diffuse gastric cancer, CDH1, business.industry, Signet-ring cell, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Hereditary cancer, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Asymptomatic Diseases, CTNNA1, business, Asymptomatic carrier, Carcinoma, Signet Ring Cell, alpha Catenin, Follow-Up Studies
Abstract: International audience; In 2017, we implemented CTNNA1 germline analysis in probands suspected of having hereditary diffuse gastric cancer. Here, we report the results from a retrospective series of 41 cases, including the identification of a new family with a CTNNA1 mutation and the first prophylactic total gastrectomy in an asymptomatic carrier after a normal upper endoscopy. Diffuse gastric cancer foci with loss of catenin alpha-1 expression were seen in the resected tissue, suggesting that CTNNA1 and CDH1 germline mutations behave in a similar manner. Life-changing prophylactic total gastrectomy should therefore also be considered in CTNNA1 mutation carriers.
Published: 2019

45. Loss of Function ABCC8 Mutations in Pulmonary Arterial Hypertension

Author: Michael S. Bohnen, Charaka Hadinnapola, Joanna Pepke-Zaba, Anton Vonk Noordegraaf, David G. Kiely, Stephen J. Wort, Andrew J. Peacock, Alan R. Shuldiner, Claudia Gonzaga-Jauregui, Erika B. Rosenzweig, Frederick E. Dewey, Wendy K. Chung, Kevin J. Sampson, Mélanie Eyries, Paul A. Corris, Robert S. Kass, Lijiang Ma, Allan Lawrie, Yufeng Shen, Colin G. Nichols, Mark Toshner, Katherine Yates, Jeffrey G. Reid, Christophe Guignabert, Matthias Haimel, J. Simon R. Gibbs, Gerry Coghlan, Marc Humbert, John D. Overton, Harm Jan Bogaard, Arjan C. Houweling, Colin Church, Jennifer M. Martin, Robert V. MacKenzie Ross, Stefan Gräf, Barbara Girerd, Martin R. Wilkins, John Wharton, David Montani, Na Zhu, Marta Bleda, Aris Baras, Florent Soubrier, Conor McClenaghan, Nicholas W. Morrell, Usha Krishnan, Hongjian Qi, Jay Suntharalingam, Richard C. Trembath, Carmen M. Treacy, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, and APH - Quality of Care
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, DNA Mutational Analysis, Mutation, Missense, 030204 cardiovascular system & hematology, Sulfonylurea Receptors, ABCC8, Article, 03 medical and health sciences, 0302 clinical medicine, medicine.artery, Internal medicine, medicine, Humans, Exome, Familial Primary Pulmonary Hypertension, Child, Pathological, Loss function, biology, business.industry, General Medicine, medicine.disease, Pulmonary hypertension, 030104 developmental biology, medicine.anatomical_structure, Amino Acid Substitution, Pulmonary artery, biology.protein, Vascular resistance, Cardiology, Female, business
Abstract: Background: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3 , was identified as a genetic cause and pharmacological target. Methods: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis. Results: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)—a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide. Conclusions: Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.
Published: 2018

46. CN2 regulates BMP signaling: Consequence for PVOD pathobiology and therapeutic management

Author: J. Bignard, Sophie Nadaud, Florent Soubrier, Séverine Remy, Grégoire Manaud, V. Stijn, Marc Humbert, Ignacio Anegon, B. Abdoulkarim, Fabrice Antigny, Monica Florio, Maria-Candida Vinhas, O. Claude, Frédéric Perros, David Montani, Olaf Mercier, and S. Banghua
Subjects: business.industry, Transgene, medicine.disease, Pulmonary hypertension, BMPR2, In vivo, medicine.artery, Pulmonary artery, Cancer research, Extracellular, Medicine, Phosphorylation, Chordin, Cardiology and Cardiovascular Medicine, business
Abstract: Introduction Pulmonary veno-occlusive disease (PVOD) occurs in humans as heritable form due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2), or as a sporadic form. The pathobiology of this orphan fatal disease is currently unknown. However, the identification of EIF2AK4 as the major genetic cause of PVOD has clarified the nosology of the disease. On the other hand, BMP/BMPR2 axis is a major axis of pulmonary arterial hypertension pathobiology, a close but better understood form of severe pulmonary hypertension (PH). Objective To investigate the functional relationship between GCN2 and the BMP/BMPR2 axis. Methods We investigated GCN2 and the BMP/BMPR2 axis in human and animal models of PVOD, and in cultured human pulmonary microvascular endothelial cells (hPMEC) with interventional experiments (siRNA and pharmacological inhibitors/activators). Results Pulmonary GCN2 protein expression was decreased in all forms of PVOD. We showed that GCN2 loss-of-function negatively regulates BMP-dependent SMAD1/5/9 signaling in hPMEC. This molecular relationship was confirmed in vivo, in the lungs of a newly created transgenic rat model knock out for Eif2ak4 (Δ152Ex1/Δ152Ex1). We found a 4 fold decrease in SMAD1/5/9 phosphorylation in KO rats. Since those rats don’t have spontaneous PH, the decrease in SMAD1/5/9 phosphorylation is not the mere consequence of high pulmonary artery pressures. We showed this regulation may be mediated through GCN2-dependent repression of chordin, an extracellular antagonist of BMP signaling. GCN2 inhibition induced a dramatic increase in hPMEC proliferation, which is highly relevant of PVOD genesis. BMP9 treatment was able to block this exuberant proliferation. Conclusion GCN2 loss-of-function negatively regulates SMAD1/5/9 phosphorylation. Despite this dampened BMP signaling, exogenous BMP9 was still able to reverse GCN2 inhibition-induced hPMEC proliferation. BMP9 may hence be considered as potential therapeutic options for PVOD.
Published: 2020

47. Modifications du génome des cellules germinales et de l’embryon humains

Author: Anne Fagot-Largeault, Alain Fischer, Raymond Ardaillou, Nathalie Cartier-Lacave, Alfred Spira, Florent Soubrier, Pierre Jouannet, Jacques Milliez, Jean-Louis Mandel, Membres titulaires, Yves Chapuis, Jean-François Mattei, Membres correspondants, Philippe Jeanteur, Jean Yves Le Gall, Yves Le Bouc, Monique Adolphe, Francis Galibert, Marc Delpech, Jean-François Allilaire, Gérard Benoit, and Claudine Bergoignan-Esper
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, General Medicine
Abstract: RESUME Les interventions ayant pour but de modifier le genome de la descendance sont proscrites depuis 1994 en France mais le developpement de methodes comme CRISPR-Cas9 conduit a s’interroger sur leurs utilisations potentielles sur les cellules germinales et l’embryon humains. La seule indication medicale acceptable serait d’eviter la transmission d’une pathologie genique a l’enfant mais les conditions, notamment celles relatives a l’efficacite et a l’innocuite de ces methodes, ne sont pas actuellement reunies pour envisager leur utilisation clinique. De plus il existe d’autres moyens permettant aux couples concernes de realiser leur projet parental. Les questions ethiques suscitees par ces technologies incitent a recommander l’ouverture d’une reflexion pluridisciplinaire qui devrait etre menee dans le cadre d’un debat plus large portant sur l’ensemble des interventions medicales realisees lors de de l’assistance medicale a la procreation, pouvant avoir des consequences sur le genome des enfants a naitre et eventuellement sur celui des generations suivantes. En revanche, les recherches, y compris sur les cellules germinales et l’embryon humains, devraient pouvoir etre menees quand elles sont scientifique- ment et medicalement justifiees.
Published: 2016

48. Pulmonary veno-occlusive disease

Author: David Montani, Laurent Savale, Xavier Jaïs, Barbara Girerd, Olivier Sitbon, Marc Humbert, Elie Fadel, Peter Dorfmüller, Gérald Simonneau, Florent Soubrier, Florence Parent, Frédéric Perros, Gilles Garcia, Edmund M.T. Lau, and Esther J. Nossent
Subjects: Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Pathology, Hypertension, Pulmonary, Definitive Therapy, medicine.medical_treatment, Pulmonary Edema, Pulmonary capillary hemangiomatosis, Disease, Protein Serine-Threonine Kinases, Pulmonary Artery, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Diffusing capacity, Animals, Humans, Medicine, Lung transplantation, Family Health, Inflammation, business.industry, Prognosis, medicine.disease, Pulmonary hypertension, Pedigree, Oxygen, Disease Models, Animal, 030228 respiratory system, Pulmonary venoocclusive disease, Mutation, Cardiology, Pulmonary Veno-Occlusive Disease, Female, Tomography, X-Ray Computed, business, Immunosuppressive Agents, Lung Transplantation
Abstract: Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH) characterised by preferential remodelling of the pulmonary venules. In the current PH classification, PVOD and pulmonary capillary haemangiomatosis (PCH) are considered to be a common entity and represent varied expressions of the same disease. The recent discovery of biallelic mutations in the EIF2AK4 gene as the cause of heritable PVOD/PCH represents a major milestone in our understanding of the molecular pathogenesis of PVOD. Although PVOD and pulmonary arterial hypertension (PAH) share a similar clinical presentation, with features of severe precapillary PH, it is important to differentiate these two conditions as PVOD carries a worse prognosis and life-threatening pulmonary oedema may occur following the initiation of PAH therapy. An accurate diagnosis of PVOD based on noninvasive investigations is possible utilising oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest. No evidence-based medical therapy exists for PVOD at present and lung transplantation remains the preferred definitive therapy for eligible patients.
Published: 2016

49. Resident PW1 + Progenitor Cells Participate in Vascular Remodeling During Pulmonary Arterial Hypertension

Author: France Dierick, Tiphaine Héry, Bénédicte Hoareau-Coudert, Nathalie Mougenot, Virginie Monceau, Caroline Claude, Mihaela Crisan, Vanessa Besson, Peter Dorfmüller, Gilles Marodon, Elie Fadel, Marc Humbert, Elisa Yaniz-Galende, Jean-Sébastien Hulot, Giovanna Marazzi, David Sassoon, Florent Soubrier, Sophie Nadaud, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plateforme Cytométrie Pitié-Salpêtrière (LUMIC-CYPS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Unité Mixte de Service d'Imagerie et de Cytométrie (UMS LUMIC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), PECMV core, Université Pierre et Marie Curie - Paris 6 (UPMC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Anatomie Pathologique [Centre Chirurgical Marie Lannelongue], Centre chirurgical Marie Lannelongue, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Chirurgie Thoracique et Vasculaire [Centre Chirurgical Marie Lannelongue], Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre de Référence de l’Hypertension Pulmonaire Sévère [CHU Le Kremlin Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Chirurgical Marie Lannelongue (CCML), Cell biology, and HAL-UPMC, Gestionnaire
Subjects: Male, 0301 basic medicine, Pathology, medicine.medical_specialty, hypertension, pulmonary, muscle, Physiology, Hypertension, Pulmonary, vascular remodeling, Cellular differentiation, Population, Kruppel-Like Transcription Factors, Mice, Transgenic, Biology, adult stem cells, Muscle, Smooth, Vascular, Mice, 03 medical and health sciences, vascular, medicine, Animals, Humans, Progenitor cell, education, Cells, Cultured, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Lung, hypoxia, Stem Cells, Hypoxia (medical), medicine.disease, Pulmonary hypertension, Rats, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, medicine.symptom, Stem cell, Cardiology and Cardiovascular Medicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, smooth, Adult stem cell
Abstract: Rationale: Pulmonary arterial hypertension is characterized by vascular remodeling and neomuscularization. PW1 + progenitor cells can differentiate into smooth muscle cells (SMCs) in vitro. Objective: To determine the role of pulmonary PW1 + progenitor cells in vascular remodeling characteristic of pulmonary arterial hypertension. Methods and Results: We investigated their contribution during chronic hypoxia–induced vascular remodeling in Pw1 nLacZ+/− mouse expressing β-galactosidase in PW1 + cells and in differentiated cells derived from PW1 + cells. PW1 + progenitor cells are present in the perivascular zone in rodent and human control lungs. Using progenitor markers, 3 distinct myogenic PW1 + cell populations were isolated from the mouse lung of which 2 were significantly increased after 4 days of chronic hypoxia. The number of proliferating pulmonary PW1 + cells and the proportion of β-gal + vascular SMC were increased, indicating a recruitment of PW1 + cells and their differentiation into vascular SMC during early chronic hypoxia–induced neomuscularization. CXCR4 inhibition using AMD3100 prevented PW1 + cells differentiation into SMC but did not inhibit their proliferation. Bone marrow transplantation experiments showed that the newly formed β-gal + SMC were not derived from circulating bone marrow–derived PW1 + progenitor cells, confirming a resident origin of the recruited PW1 + cells. The number of pulmonary PW1 + cells was also increased in rats after monocrotaline injection. In lung from pulmonary arterial hypertension patients, PW1-expressing cells were observed in large numbers in remodeled vascular structures. Conclusions: These results demonstrate the existence of a novel population of resident SMC progenitor cells expressing PW1 and participating in pulmonary hypertension–associated vascular remodeling.
Published: 2016

50. Rapport et recommandations sur la mise en œuvre en France des techniques de séquençage de nouvelle génération

Author: Florent Soubrier, Jean Lunel, Bruno Jarry, F. Galibert, Pierre Tambourin, Jacques P. Caen, Alain Viari, Jean-Yves Le Gall, Mme Alice Dautry, Marc Delpech, Emmanuel Martin, M.M. Laurent Alexandre, M.M. Bruno Jarry, M. Pierre-Étienne Bost, Jean-François Deleuze, M. Raymond Ardaillou, François Sigaux, Patrick Netter, and François Artiguenave
Subjects: business.industry, Big data, Library science, General Medicine, business
Abstract: SUMMARY Next generation sequencing (NGS) technologies, which allow high speed automated DNA sequencing, DNA sequence analysis and comparisons using big data algorithms are being used more and more in medical diagnosis, to provide prognosis information and for choosing a treatment that best fits the patient. The French “Academie nationale de medecine ” (ANM) and “ Academie des technologies “ (NATF) jointly stress the scientific and medical importance of these technologies and call for bringing together strengths of the national computer science industry and the medical community in a public-private consortium in order to build a Demonstrator and Center network filling up the growing gap between France and the most advanced countries in this field with great potential. They underline also common pitfalls which need to be addressed in technic, legal, economic, education and ethics issues, in order to make this complex project a success.
Published: 2016

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