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1. Rotor Syndrome Presenting as Dubin-Johnson Syndrome

Author: Mariana Morais, Philippe Couvert, Isabelle Jéru, and Mariana Verdelho Machado
Subjects: conjugated hyperbilirubinemia, dubin-johnson syndrome, abcc2/mrp2, rotor syndrome, slco1b3/oatp1b, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: A 42-year-old man with no relevant past medical history presented with intermittent mild icterus and no signs of chronic liver disease. Laboratory tests were notable for hyperbilirubinemia (total 7.97 mg/dL, direct 5.37 mg/dL), bilirubinuria, no signs of hemolysis, normal liver tests and lipids profile. Abdominal ultrasound was unremarkable. A panel of chronic liver diseases was negative except for increased serum (147.4 μg/dL) and urinary (179 μg/24 h) copper, with normal ceruloplasmin. No other Leipzig criteria for Wilson’s disease were found, including a negative test for ATP7B gene mutations (by exome sequencing). Total urinary coproporphyrin was normal with predominance of isomer I (86% of total urinary coproporphyrin output). Clinical and laboratorial profile was compatible with Dubin-Johnson syndrome; however, exome sequencing and search for deletions in the ABBC2 gene (encoding MRP2) only found a heterozygous potentially pathogenic variant (c.1483A>G – p.Lys495Glu). Additional extended molecular analysis of genes implicated in bilirubin metabolism found a homozygous deletion of a region encompassing exons 4–16 of SLCO1B3 gene (encoding OATP1B3) and all SLCO1B1 exons (encoding OATP1B1), thereby establishing Rotor syndrome diagnosis. Rotor and Dubin-Johnson syndromes are rare autosomal recessive liver diseases characterized by chronic conjugated hyperbilirubinemia, caused by the absence of the hepatic function OATP1B1/B3 (leading to impaired hepatic bilirubin reuptake and storage) and MRP2 transporters (leading to impaired hepatic bilirubin excretion), respectively. We report a case of compound hereditary hyperbilirubinemia with a misleading presentation with special focus on its diagnosis, particularly the advantage of extensive unbiased genetic testing by dedicated laboratories. With this case, we aim to highlight the necessity of establishing a diagnosis, reassuring the patient, and avoiding unnecessary invasive and costly diagnostic procedures.
Published: 2022
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2. Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes

Author: Jérémie Gautheron, Lara Lima, Baris Akinci, Jamila Zammouri, Martine Auclair, Sema Kalkan Ucar, Samim Ozen, Canan Altay, Bridget E. Bax, Ivan Nemazanyy, Véronique Lenoir, Carina Prip-Buus, Cécile Acquaviva-Bourdain, Olivier Lascols, Bruno Fève, Corinne Vigouroux, Esther Noel, and Isabelle Jéru
Subjects: TP, Thymidine phosphorylase, Lipodystrophy, Insulin resistance, Mutation, Adipose stem cell, Medicine
Abstract: Abstract Background Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2′-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. Methods Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. Results All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients’ phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. Conclusions The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology.
Published: 2022
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3. Editorial: Endocrine and metabolic diseases – genetic impact and therapies

Author: Isabelle Jéru, Bruno Fève, and Ralf Jockers
Subjects: endocrinology, metabolic diseases, genetics, gene, therapy, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Published: 2022
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4. The necroptosis-inducing pseudokinase mixed lineage kinase domain-like regulates the adipogenic differentiation of pre-adipocytes

Author: Julie Magusto, Carine Beaupère, Marta B. Afonso, Martine Auclair, Jean-Louis Delaunay, Pierre-Antoine Soret, Gilles Courtois, Tounsia Aït-Slimane, Chantal Housset, Isabelle Jéru, Bruno Fève, Vlad Ratziu, Cecilia M.P. Rodrigues, and Jérémie Gautheron
Subjects: Biological sciences, Molecular biology, Cell biology, Stem cells research, Science
Abstract: Summary: Receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins are key regulators of necroptosis, a highly pro-inflammatory mode of cell death, which has been involved in various human diseases. Necroptotic-independent functions of RIPK3 and MLKL also exist, notably in the adipose tissue but remain poorly defined. Using knock-out (KO) cell models, we investigated the role of RIPK3 and MLKL in adipocyte differentiation. Mlkl-KO abolished white adipocyte differentiation via a strong expression of Wnt10b, a ligand of the Wnt/β-catenin pathway, and a downregulation of genes involved in lipid metabolism. This effect was not recapitulated by the ablation of Ripk3. Conversely, Mlkl and Ripk3 deficiencies did not block beige adipocyte differentiation. These findings indicate that RIPK3 and MLKL have distinct roles in adipogenesis. The absence of MLKL blocks the differentiation of white, but not beige, adipocytes highlighting the therapeutic potential of MLKL inhibition in obesity.
Published: 2022
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5. Molecular and Cellular Bases of Lipodystrophy Syndromes

Author: Jamila Zammouri, Camille Vatier, Emilie Capel, Martine Auclair, Caroline Storey-London, Elise Bismuth, Héléna Mosbah, Bruno Donadille, Sonja Janmaat, Bruno Fève, Isabelle Jéru, and Corinne Vigouroux
Subjects: lipodystrophy, insulin resistance, diabetes, adipose tissue, genetics, senescence, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.
Published: 2022
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6. Adherence with metreleptin therapy and health self-perception in patients with lipodystrophic syndromes

Author: Camille Vatier, Dina Kalbasi, Marie-Christine Vantyghem, Olivier Lascols, Isabelle Jéru, Anne Daguenel, Jean-François Gautier, Marion Buyse, and Corinne Vigouroux
Subjects: Lipodystrophic syndromes, Metreleptin therapy, Health self-perception, Adherence, Social interactions, Medicine
Abstract: Abstract Background Although metreleptin replacement therapy was shown to improve metabolic alterations in lipodystrophic syndromes, patients’ adherence and satisfaction with treatment have never been evaluated. The 20 patients with lipodystrophic syndromes participating in the French compassionate program of metreleptin therapy filled in a self-questionnaire including an Adherence Evaluation Test, the Treatment Satisfaction Questionnaire for Medication (TSQM®-vII), and items about physical appearance. Results 15 patients were women, median age was 32.5 years (IQT 25–75 (16.2;49.5), 18 had diabetes. Adherence with metreleptin (one daily subcutaneous injection) was poor in 25%, excellent in 25% and acceptable in 50% of patients. On a 0-to-100 scale, patients’ satisfaction scores reached 66.7 (52.1;81.2) for effectiveness, 55.6 (44.4;66.7) for ease/comfort of use, and 83.3 (52.1;83.3) for global satisfaction with metreleptin therapy. Self-reported side effects were frequent injection site reactions 100 (79.2;100). Satisfaction scores did not differ in patients with partial (n = 10) or generalized (n = 10) lipodystrophic syndromes, did not correlate with metabolic improvement, but were significantly higher in compliant patients with fewer side effects. Morphological appearance was reported improved under metreleptin therapy in 13 among 17 patients. Conclusions Metreleptin increases health self-perception and decreases morphotype-associated stigmatization in most patients with lipodystrophic syndromes, but poor comfort of use and local side effects weaken adherence.
Published: 2019
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7. Cytokine Signature in Schnitzler Syndrome: Proinflammatory Cytokine Production Associated to Th Suppression

Author: Marie Masson Regnault, Eric Frouin, Isabelle Jéru, Adriana Delwail, Sandrine Charreau, Sébastien Barbarot, Antoine Néel, Agathe Masseau, Xavier Puéchal, Xavier Kyndt, Stephane Gayet, François Lifermann, Bouchra Asli, Xavier Balguerie, Claire Blanchard-Delaunay, François Aubin, Rita Rizzi, Franco Rongioletti, Thierry Boyé, Laurence Gusdorf, Didier Bessis, Franck Morel, Ewa Hainaut, Dan Lipsker, and Jean-Claude Lecron
Subjects: Schnitzler syndrome, inflammasome, IL-1, IL-1 antagonist, cytokines, PBMC (peripheral blood mononuclear cells), Immunologic diseases. Allergy, RC581-607
Abstract: BackgroundSchnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal IgM gammopathy. Overactivation of the interleukin(IL)-1 system is reported, even though the exact pathophysiological pathways remain unknown.ObjectiveTo determine ex vivo cytokine profiles of Peripheral Blood Mononuclear Cells (PBMCs) from SchS patients prior to treatment and after initiation of anti-IL-1 therapy (anakinra). The sera cytokine profile was studied in parallel.MethodsWe collected blood samples from thirty-six untreated or treated SchS. PBMCs were cultured with and without LPS or anti-CD3/CD28. Cytokine levels were evaluated in serum and cell culture supernatants using Luminex technology.ResultsSpontaneous TNFα, IL-6, IL-1β, IL-1α, and IL-1RA release by PBMCs of SchS patients were higher than in controls. LPS-stimulation further induced the secretion of these cytokines. In contrast, after T-cell stimulation, TNFα, IL-10, IFNγ, IL-17A, and IL-4 production decreased in SchS patients compared to healthy controls, but less in treated patients. Whereas IL-1β serum level was not detected in most sera, IL-6, IL-10, and TNFα serum levels were higher in patients with SchS and IFNγ and IL-4 levels were lower. Of note, IL-6 decreased after treatment in SchS (p = 0.04).ConclusionOur data strengthen the hypothesis of myeloid inflammation in SchS, mediated in particular by IL-1β, TNFα, and IL-6, associated with overproduction of the inhibitors IL-1RA and IL-10. In contrast, we observed a loss of Th1, Th2, and Th17 cell functionalities that tends to be reversed by anakinra.
Published: 2020
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8. Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part three

Author: Riccardo Papa, Alessandro Consolaro, Francesca Minoia, Roberta Caorsi, Gianmichele Magnano, Marco Gattorno, Angelo Ravelli, Paolo Picco, Roberto Pillon, Denise Pires Marafon, Lidia Meli, Claudia Bracaglia, Andrea Taddio, Fabrizio De Benedetti, Enes Turan, Sara Sebnem Kilic, Yasuhiko Itoh, Tomoko Shigemori, Shingo Yamanishi, Hidehiko Nagasaki, Ela Tarakci, Nilay Arman, Devrim Tarakci, Yusuf S. Akgul, Ozgur Kasapcopur, Emily Wilson, Hanna Lythgoe, Eve Smith, Jenny Preston, Michael W. Beresford, Lynn R. Spiegel, Jennifer Stinson, Mark Connelly, Adam Huber, Nadia Luca, Argerie Tsimicalis, Stephanie Luca, Naweed Tajuddin, Roberta Berard, Julie Barsalou, Sarah Campillo, Brian Feldman, Shirley Tse, Paul Dancey, Ciaran Duffy, Nicole Johnson, Patrick McGrath, Natalie Shiff, Lori Tucker, Charles Victor, Chitra Lalloo, Lauren Harris, Joseph Cafazzo, Kristin Houghton, Ronald Laxer, Madeleine Rooney, Roisin Campbell, Catherine Wright, Wineke Armbrust, Otto Lelieveld, Jolanda Tuinstra, Nico Wulffraat, Joyce Bos, Jeanette Cappon, Marion van Rossum, Mariët Hagedoorn, Anna Vermé, Ylva Lampela, Ayse Huri Ozdogan, S. Ugurlu, K. Barut, A. Androvic, O. Kasapçopu, Jody Etheridge, Katie Dobson, Sue Kemp, AnnaCarin Horne, Karin Palmblad, Malin Höglund, Natalia Stepanenko, Svetlana Salugina, Evgeny Fedorov, Irina Nikishina, Maria Kaleda, Kenan Barut, Amra Adrovic, Sezgin Sahin, Laurence Toumoulin, Johnny Frossard, Stephanie Archimbaut, Anne Paitier, Rolande Guastalli, Severine Guillaume Czitrom, Sirirat Charuvanij, Chollada Chaiyadech, Takako Miyamae, Hisashi Yamanaka, Cecile Picard, Guillaume Thouvenin, Caroline Kannengiesser, Jean-Christophe Dubus, Nadia Jeremiah, Frédéric Rieux-Laucat, Bruno Crestani, Véronique Secq, Christelle Ménard, Martine Reynaud-Gaubert, Françoise Thivolet-Bejui, Philippe Reix, Alexandre Belot, Ezgi Deniz Batu, Hafize Emine Sonmez, Abdulsamet Erden, Ekim Z. Taskiran, Omer Karadag, Umut Kalyoncu, İbrahim Oncel, Berkan Kaplan, Zehra Serap Arici, Cagri Mesut Temucin, Haluk Topaloglu, Yelda Bilginer, Mehmet Alikasifoglu, Seza Ozen, Lien Van Eyck, Ellen De Langhe, Isabelle Jéru, Erika Van Nieuwenhove, Vasiliki Lagou, Paul J. Baker, Jocelyn Garcia-Perez, James Dooley, Lien De Somer, Raf Sciot, Pierre-Yves Jeandel, Julia Ruuth-Praz, Bruno Copin, Myrna Medley-Hashim, Andre Megarbane, Sinisa Savic, An Goris, Serge Amselem, Adrian Liston, Seth Masters, Carine Wouters, Nami Okamoto, Yuko Sugita, Kousuke Shabana, Takuji Murata, Hiroshi Tamai, Juliana Ferenczová, Erika Banóova, Pavol Mrážik, Veronika Vargova, Dubravko Bajramovic, Ksenija Stekic Novacki, Kristina Potocki, Marijan Frkovic, Marija Jelusic, Olga Kostareva, Svetlana Arsenyeva, Anna Shapovalenko, Lennart Jans, Nele Herregods, Jacob Jaremko, Rik Joos, Joke Dehoorne, Xenofon Baraliakos, Sofia Ramiro, Julio C. Casasola-Vargas, Désirée van der Heijde, Robert Landewé, Ruben Burgos-Vargas, Shirley M. Tse, Gerd Horneff, Kristina Unnebrink, Jaclyn K. Anderson, Aysenur Paç Kisaarslan, Betül Sözeri, Zübeyde Gündüz, Gökmen Zararsız, Hakan Poyrazoğlu, Ruhan Düşünsel, Kazutaka Ouchi, Shinji Akioka, Hiroshi Kubo, Norio Nakagawa, Hajime Hosoi, Lovro Lamot, Fran Borovecki, Sanja Kapitanovic, Kristina Gotovac, Mandica Vidovic, Mirta Lamot, Edi Paleka Bosak, Miroslav Harjacek, Ricardo A. Russo, María M. Katsicas, Ruben Burgos Vargas, Ana L. Ortiz-Peyegahud, Zhang Pingping, Mou Yikun, Qi Jun, Jiang Yutong, Gu Jieruo, Mikhail M. Kostik, Shilova Ekaterina, Ilia Avrusin, Yuriy Korin, Olga Kopchak, Eugenia Isupova, Irina Chikova, Panova Tatyana, Margarita Dubko, Vera Masalova, Ludmila Snegireva, Tatyana Kornishina, Olga Kalashnikova, Vyacheslav Chasnyk, Tatyana Likhacheva, N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, E. Alexeeva, R. Schneider, I. Kone-Paut, K. Schikler, K. Marzan, N. Wulffraat, S. Padeh, V. Chasnyk, C. Wouters, J. B. Kuemmerle-Deschner, T. Kallinich, B. Lauwerys, E. Haddad, E. Nasonov, M. Trachana, O. Vougiouka, K. Leon, A. Speziale, K. Lheritier, E. Vritzali, A. Martini, D. Lovell, PRINTO/PRCSG, Nienke Ter Haar, Rianne Scholman, Wilco de Jager, Tamar Tak, Pieter Leliefeld, Bas Vastert, Sytze de Roock, Ariane de Ganck, Nadia Ryter, Miha Lavric, Dirk Foell, Renee F. Modica, Kathleen G. Lomax, Pamela Batzel, Armelle Cassanas, Melissa E. Elder, Rina Denisova, Ekaterina Alexeeva, Saniya Valieva, Tatyana Bzarova, Kseniya Isayeva, Tatyana Sleptsova, Olga Lomakina, Alexandra Chomahidze, Margarita Soloshenko, Meyry Shingarova, Elena Kachshenko, Wilco De Jager, Sebastiaan J. Vastert, Gerdien Mijnheer, Berent J. Prakken, Nico M. Wulffraat, Hafize E. Sönmez, Asuman N. Karhan, Ezgi D. Batu, Zehra S. Arıcı, Ersin Gümüş, Hülya Demir, Aysel Yüce, Seza Özen, Jasmina Ahluwalia, Bhavneet Bharti, Sweta Rajpal, Varun Uppal, Alaknanda Walia, Surjit S. Samlok, Narender Kumar, Clarissa C. Valões, Beatriz C. Molinari, Ana Claudia G. Pitta, Natali W. Gormezano, Sylvia C. Farhat, Kátia Kozu, Adriana M. Sallum, Simone Appenzeller, Ana Paula Sakamoto, Maria T. Terreri, Rosa M. Pereira, Claudia S. Magalhães, Cássia Maria Barbosa, Francisco Hugo Gomes, Eloisa Bonfá, Clovis A. Silva, Kubra Ozturk, Zelal Ekinci, Maie Helal, Natalia Cabrera, Jean Christophe Lega, Jocelyne Drai, Rene Ecochard, O. V. Shpitonkova, N. S. Podchernyaeva, Y. O. Kostina, N. G. Dashkova, M. K. Osminina, Gozde Yucel, Ahmet Arvas, Nandini Moorthy, Paraskevi Dimou, Angela Midgley, Matthew Peak, Simon C. Satchell, Rachael D. Wright, Rachel Corkhill, Eve M. Smith, Sagar Bhattad, Amit Rawat, Surjit Singh, Anju Gupta, Deepti Suri, Martin de Boer, Taco Kuijpers, Vignesh Pandiarajan, Sapna Sandal, Sebastian Giraldo, Roy Sanguino, Adriana S. Diaz, Selcuk Uzuner, Gizem Durcan, Ali Guven Kilicoglu, Ayhan Bilgic, Kayhan Bahali, Sinem Durmus, Hafize Uzun, Nur Canpolat, Salim Caliskan, Lale Sever, Tomomi Sato, Fuminori Kimura, Wafaa Suwairi, Reem Abdwani, Abdulaziz Al Rowais, Jubran Al qanatish, Abdulrahman Al Asiri, Ekaterina Gaidar, Mikhail Kostik, Elena Serogodskaya, Tatyana Nikitina, Evgenia Isupova, Elham Sardar, Perrine Dusser, Antoine Rousseau, Marc Labetoulle, Emanuel Barreau, Bahram Bodaghi, Isabelle Kone-Paut, Ivan Foeldvari, Jordi Anton, Rosa Bou, Sheila Angeles-Han, Regitze Bangsgaard, Gabriele Brumm, Tamas Constantin, Clive Edelsten, Jens Klotsche, Kirsten Minden, Elisabetta Miserocchi, Susan Nielsen, Gabriele Simonini, Arnd Heiligenhaus, Juan Manuel Mosquera Angarita, Carmen Garcia de Vicuña, Maria Victoria Hernandez, Alfredo Adan, Victor Llorens, Rosa Alcobendas, Susana Noval, Juan Carlos Lopez Robledillo, Isabel Valls, Mari Carmen Pinedo, Alejandro Fonollosa, Jaime de Inocencio, Pilar Tejada, Beatriz Bravo, Manuel Torribio, María Jesús García de Yebenes, Jordi Antón, Uveitis Working Group of the Spanish Pediatric Rheumatology Society, Lorenza Maria Argolini, Irene Pontikaki, Maria Orietta Borghi, Laura Cesana, Barbara Castiglioni, Maurizio Gattinara, Pierluigi Meroni, Pierre Quartier, Veronique Despert, Sylvaine Poignant, Amandine Baptiste, Caroline Elie, Laurent Kodjikian, Dominique Monnet, Michel Weber, Laura Moal, LuuLy Pham, Emmanuel Barreau, Cherif Titah, Pascal Dureau, Vanessa Cecchin, Maria Elisabetta Zannin, Daniele Ferrari, Francesco Comacchio, Rolando Cimaz, Fernanda Falcini, Antonella Petaccia, Stefania Viola, Luciana Breda, Francesco La Torre, Fabio Vittadello, Giorgia Martini, Francesco Zulian, Caroline Galeotti, Guillaume Sarrabay, Olivier Fogel, Isabelle Touitou, Corinne Miceli-Richard, Isabelle Koné-Paut, Hala Etayari, Hashad Soad, Ihab El Kadry, Habibullah Eatamadi, Kais AlAlgawi, Mustafa Al Maini, Khulood Khawaja, Sophie Van den Berghe, Ilse de Schryver, Ann Raes, Lídia L. C. Teixeira, Ana Duarte, Sandra Sousa, Filipe Vinagre, Maria J. Santos, Nataly S. Shevchenko, Ludmila F. Bogmat, Marina V. Demyanenko, Navdha R. Ramchurn, Mark Friswell, Rebecca A. James, Lucy R. Wedderburn, Reshma Pattani, Clarissa A. Pilkington, Sandrine Compeyrot-Lacassagne, Ana V. Villarreal, Nydia Acevedo, Enrique Faugier, Rocio Maldonado, Dilek Yılmaz, Hilal Bektaş Uysal, Elena Kamenets, Ekaterina Zaharova, Stefka Radenska-Lopovok, Joao Nascimento, Helena Sofia, Carla Zilhão, Rui Almeida, Margarida Guedes, Murat Deveci, Svetlana Rodionovskaya, Vera Vinnikova, Irina Tsymbal, Edyta Olesińska, Jacek Postępski, Agnieszka Mroczkowska-Juchkiewicz, Agnieszka Pawłowska-Kamieniak, Beata Chrapko, Damjana Ključevšek, Nina Emeršič, Nataša Toplak, Tadej Avčin, Faina Rokhlina, Galina Glazyrina, Natalia Kolyadina, Kwangnam Kim, Sinae Eom, Daeyoung Kim, Jungwoo Rhim, Francesca Ricci, Paola Montesano, Barbara Bonafini, Veronica Medeghini, Ilaria Parissenti, Antonella Meini, Marco Cattalini, Paolo Airò, Nataliya Panko, Nataliya Shevchenko, Iryna Lebec, Yevgeniya Zajceva, Sara Rostlund, Marie André, Takuma Hara, Takayuki Kishi, Yumi Tani, Aki Hanaya, Satoru Nagata, Velma Selmanovic, Aida Omercahic-Dizdarevic, Adisa Cengic, Almira Cosickic, Aida Omerčahić Dizdarević, Gemma Lepri, Clara Malattia, Eleonora Bellucci, Marco Matucci-Cerinic, Anton Solovyev, Elena Fedotova, Ana Victoria Villarreal, Talia Diaz, Yuridiana Ramirez, Teresa Giani, Achille Marino, Daniel Hunt, Muthana Al Obaidi, Veli Veli, Charalampia Papadopoulou, Jochen Kammermeier, Anna Poluha, Gangadhara C. Bharmappanavara, Alison Kelly, Lindsay Shaw, Giovanna Ferrara, Michele Luzzati, Mattia Giovannini, Liliana Jurado, Juliana Chamorro, Lorena Sarmiento, Ester Conversano, Maria Francesca Gicchino, Giulia Macchini, Carmela Granato, Assunta Tirelli, Alma N. Olivieri, Marija Perica, Lana Tambić Bukovac, Reza Sinaei, Vadood Javadi Parvaneh, Reza Shiari, Khosro Rahmani, Fatemeh F. Mehregan, Mehrnoush Hassas Yeganeh, Inmaculada Calvo Penadés, Berta López Montesinos, Ma Isabel González Fernández, Adriana Rodríguez Vidal, Anand Prahalad Rao, Ayesha Romana, Jyothi Raghuram, Ankur Kumar, Vishali Gupta, Elif Comak, Gülşah Kaya Aksoy, Aygen Yılmaz, Atike Atalay, Mustafa Koyun, Reha Artan, Sema Akman, Maria I. Kaleda, Irina P. Nikishina, Sergei K. Soloviev, Victor A. Malievsky, Ekaterina V. Nikolaeva, Agnieszka Gazda, Beata Kołodziejczyk, Lidia Rutkowska-Sak, Angela Mauro, Pierluigi Marzuillo, Stefano Guarino, and Angela La Manna
Subjects: Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Published: 2017
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9. Congenital Generalized Lipoatrophy (Berardinelli-Seip Syndrome) Type 1: Description of Novel AGPAT2 Homozygous Variants Showing the Highly Heterogeneous Presentation of the Disease

Author: Giovanni Ceccarini, Silvia Magno, Caterina Pelosini, Federica Ferrari, Maria Rita Sessa, Gaia Scabia, Margherita Maffei, Isabelle Jéru, Olivier Lascols, Corinne Vigouroux, and Ferruccio Santini
Subjects: lipodystrophy, Berardinelli-Seip syndrome, BSCL1, AGPAT2, leptin, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Berardinelli-Seip congenital lipoatrophy (BSCL) is characterized by near total fat atrophy, associated with the progressive development of metabolic complications. BSCL type 1 (BSCL1) is caused by mutations in AGPAT2, encoding 1-acylglycerol-3phosphate-O-acyltransferase β (recently renamed lysophosphatidic acid acyltransferase beta), which catalyzes the transformation of lysophosphatidic acid in phosphatidic acid, the precursor of glycerophospholipids and triglycerides. BSCL1 is an autosomal recessive disease due to AGPAT2 pathogenic variants leading to a depletion of triglycerides inside the adipose organ, and to a defective signaling of key elements involved in proper adipogenesis. We herein investigated the characteristics of two AGPAT2 variants in Caucasian Italian patients with Berardinelli-Seip congenital lipoatrophy. The first patient exhibited a novel homozygous nonsense c.430 C > T AGPAT2 mutation (p.Gln144*) predicting the synthesis of a truncated enzyme of approximately half of the proper size. The second patient harbored a homozygous AGPAT2 missense variant (p.Arg159Cys), never described previously in BSCL1 patients: the segregation of the disease with the mutation in the pedigree of the family and the in silico analysis are compatible with a causative role of the p.Arg159Cys variant. We remark that BSCL1 can be clinically very heterogeneous at presentation and that the associated complications, occurring in the natural history of the disease, reduce life-expectancy. We point to the necessity for medical treatments capable of reducing the risk of cardiovascular death. In BSCL1 patients, the assessment of cardiovascular disease with conventional diagnostic means maybe particularly challenging.
Published: 2020
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10. Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Author: Héléna Mosbah, Camille Vatier, Franck Boccara, Isabelle Jéru, Olivier Lascols, Marie-Christine Vantyghem, Bruno Fève, Bruno Donadille, Elisabeth Sarrazin, Sophie Benabbou, Jocelyn Inamo, Stéphane Ederhy, Ariel Cohen, Barbara Neraud, Pascale Richard, Fabien Picard, Sophie Christin-Maitre, Alban Redheuil, Karim Wahbi, and Corinne Vigouroux
Subjects: lipodystrophy, lmna, cardiovascular disease, Cytology, QH573-671
Abstract: Variants in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and progeroid syndromes. Cardiovascular laminopathic involvement is classically described as cardiomyopathy in striated muscle laminopathies, and arterial wall dysfunction and/or valvulopathy in lipodystrophic and/or progeroid laminopathies. We report unexpected cardiovascular phenotypes in patients with LMNA-associated lipodystrophies, illustrating the complex multitissular pathophysiology of the disease and the need for specific cardiovascular investigations in affected patients. A 33-year-old woman was diagnosed with generalized lipodystrophy and atypical progeroid syndrome due to the newly identified heterozygous LMNA p.(Asp136Val) variant. Her complex cardiovascular phenotype was associated with atherosclerosis, aortic valvular disease and left ventricular hypertrophy with rhythm and conduction defects. A 29-year-old woman presented with a partial lipodystrophy syndrome and a severe coronary atherosclerosis which required a triple coronary artery bypass grafting. She carried the novel heterozygous p.(Arg60Pro) LMNA variant inherited from her mother, affected with partial lipodystrophy and dilated cardiomyopathy. Different lipodystrophy-associated LMNA pathogenic variants could target cardiac vasculature and/or muscle, leading to complex overlapping phenotypes. Unifying pathophysiological hypotheses should be explored in several cell models including adipocytes, cardiomyocytes and vascular cells. Patients with LMNA-associated lipodystrophy should be systematically investigated with 24-h ECG monitoring, echocardiography and non-invasive coronary function testing.
Published: 2020
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11. The risk of familial Mediterranean fever in MEFV heterozygotes: a statistical approach.

Author: Isabelle Jéru, Véronique Hentgen, Emmanuelle Cochet, Philippe Duquesnoy, Gaëlle Le Borgne, Emmanuel Grimprel, Katia Stankovic Stojanovic, Sonia Karabina, Gilles Grateau, and Serge Amselem
Subjects: Medicine, Science
Abstract: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder due to MEFV mutations and one of the most frequent Mediterranean genetic diseases. The observation of many heterozygous patients in whom a second mutated allele was excluded led to the proposal that heterozygosity could be causal. However, heterozygosity might be coincidental in many patients due to the very high rate of mutations in Mediterranean populations.To better delineate the pathogenicity of heterozygosity in order to improve genetic counselling and disease management.Complementary statistical approaches were used: estimation of FMF prevalence at population levels, genotype comparison in siblings from 63 familial forms, and genotype study in 557 patients from four Mediterranean populations.At the population level, we did not observe any contribution of heterozygosity to disease prevalence. In affected siblings of patients carrying two MEFV mutations, 92% carry two mutated alleles, whereas 4% are heterozygous with typical FMF diagnosis. We demonstrated statistically that patients are more likely to be heterozygous than healthy individuals, as shown by the higher ratio heterozygous carriers/non carriers in patients (p
Published: 2013
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12. Involvement of the same TNFR1 residue in mendelian and multifactorial inflammatory disorders.

Author: Isabelle Jéru, Serge Charmion, Emmanuelle Cochet, Bruno Copin, Philippe Duquesnoy, Maria Teresa Mitjavila Garcia, Gaëlle Le Borgne, Pascal Cathebras, Jacques Gaillat, Sonia Karabina, Catherine Dodé, Peter Lohse, Véronique Hentgen, and Serge Amselem
Subjects: Medicine, Science
Abstract: OBJECTIVES: TNFRSF1A is involved in an autosomal dominant autoinflammatory disorder called TNFR-associated periodic syndrome (TRAPS). Most TNFRSF1A mutations are missense changes and, apart from those affecting conserved cysteines, their deleterious effect remains often questionable. This is especially true for the frequent R92Q mutation, which might not be responsible for TRAPS per se but represents a susceptibility factor to multifactorial inflammatory disorders. This study investigates TRAPS pathophysiology in a family exceptional by its size (13 members) and compares the consequences of several mutations affecting arginine 92. METHODS: TNFRSF1A screening was performed by PCR-sequencing. Comparison of the 3-dimensional structure and electrostatic properties of wild-type and mutated TNFR1 proteins was performed by in silico homology modeling. TNFR1 expression was assessed by FACS analysis, western blotting and ELISA in lysates and supernatants of HEK293T cells transiently expressing wild-type and mutated TNFR1. RESULTS: A TNFRSF1A heterozygous missense mutation, R92W (c.361C>T), was shown to perfectly segregate with typical TRAPS manifestations within the family investigated (p
Published: 2013
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13. Involvement of the modifier gene of a human Mendelian disorder in a negative selection process.

Author: Isabelle Jéru, Hasmik Hayrapetyan, Philippe Duquesnoy, Emmanuelle Cochet, Jean-Louis Serre, Josué Feingold, Gilles Grateau, Tamara Sarkisian, Marc Jeanpierre, and Serge Amselem
Subjects: Medicine, Science
Abstract: BACKGROUND:Identification of modifier genes and characterization of their effects represent major challenges in human genetics. SAA1 is one of the few modifiers identified in humans: this gene influences the risk of renal amyloidosis (RA) in patients with familial Mediterranean fever (FMF), a Mendelian autoinflammatory disorder associated with mutations in MEFV. Indeed, the SAA1 alpha homozygous genotype and the p.Met694Val homozygous genotype at the MEFV locus are two main risk factors for RA. METHODOLOGY/PRINCIPAL FINDINGS:HERE, WE INVESTIGATED ARMENIAN FMF PATIENTS AND CONTROLS FROM TWO NEIGHBORING COUNTRIES: Armenia, where RA is frequent (24%), and Karabakh, where RA is rare (2.5%). Sequencing of MEFV revealed similar frequencies of p.Met694Val homozygotes in the two groups of patients. However, a major deficit of SAA1 alpha homozygotes was found among Karabakhian patients (4%) as compared to Armenian patients (24%) (p = 5.10(-5)). Most importantly, we observed deviations from Hardy-Weinberg equilibrium (HWE) in the two groups of patients, and unexpectedly, in opposite directions, whereas, in the two control populations, genotype distributions at this locus were similar and complied with (HWE). CONCLUSIONS/SIGNIFICANCE:The excess of SAA1alpha homozygotes among Armenian patients could be explained by the recruitment of patients with severe phenotypes. In contrast, a population-based study revealed that the deficit of alpha/alpha among Karabakhian patients would result from a negative selection against carriers of this genotype. This study, which provides new insights into the role of SAA1 in the pathophysiology of FMF, represents the first example of deviations from HWE and selection involving the modifier gene of a Mendelian disorder.
Published: 2009
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14. Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip) Cambridge, UK, 7-8 April 2022

Author: Héléna Mosbah, Baris Akinci, David Araújo-Vilar, Juan Carrion Tudela, Giovanni Ceccarini, Philippe Collas, I. Sadaf Farooqi, Antía Fernández-Pombo, Isabelle Jéru, Fredrik Karpe, Kerstin Krause, Margherita Maffei, Konstanze Miehle, Elif Oral, Naca Perez de Tudela, Xavier Prieur, Justin Rochford, Rebecca Sanders, Ferruccio Santini, David B. Savage, Julia von Schnurbein, Robert Semple, Anna Stears, Ekaterina Sorkina, Marie-Christine Vantyghem, Camille Vatier, Antonio Vidal-Puig, Corinne Vigouroux, and Martin Wabitsch
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: Lipodystrophy syndromes are rare diseases with defects in the development or maintenance of adipose tissue, frequently leading to severe metabolic complications. They may be genetic or acquired, with variable clinical forms, and are largely underdiagnosed. The European Consortium of Lipodystrophies, ECLip, is a fully functional non-profit network of European centers of excellence working in the field of lipodystrophies. It provides a favorable environment to promote large Europe-wide and international collaborations to increase the basic scientific understanding and clinical management of these diseases. It works with patient advocacy groups to increase public awareness. The network also promotes a European Patient Registry of lipodystrophies, as a collaborative research platform for consortium members. The annual congress organized gives an update of the findings of network research groups, highlighting clinical and fundamental aspects. The talks presented during the meeting in Cambridge, UK, in 2022 are summarized in these minutes.
Published: 2022

15. Lessons from the impact of COVID-19 on medical educational continuity and practices

Author: Alexandre Hertig, Alain Carrié, Noémie Simon-Tillaux, Marie-Christine Renaud, Isabelle Jéru, and Camille Vatier
Subjects: 020205 medical informatics, Physiology, Distance education, Curriculum Development and Assessment, 02 engineering and technology, Computer-assisted web interviewing, Education, Digital media, Likert scale, 03 medical and health sciences, 0302 clinical medicine, 0202 electrical engineering, electronic engineering, information engineering, ComputingMilieux_COMPUTERSANDEDUCATION, 030212 general & internal medicine, Set (psychology), Curriculum, Multiple choice, Medical education, teachers, business.industry, COVID-19, General Medicine, undergraduate student, Scale (social sciences), digital resources, business, Psychology, remote learning
Abstract: The COVID-19 crisis necessitated abrupt transition to remote learning in medical schools. We aimed to assess the impact of COVID-19 on French undergraduate students and teachers, to identify practice changes, and to evaluate successes and areas for improvement of this remote learning experience. Data from 2 online questionnaires were analyzed with 509 participants among students and 189 among teachers from Sorbonne University. Responses to multiple choice, Likert response scale, and open-ended questions were evaluated. COVID-19 had negative impact on teaching continuity. Sixty-seven percent of students were in a dropout situation, and many suffered from psychological stress, leading to set up of a psychological support unit. Although most teachers (81%) and students (72%) had limited knowledge of digital resources, distance learning was quickly implemented, with a predominant use of Zoom. The analysis of several parameters revealed that students were significantly more satisfied than teachers by remote learning. Nevertheless, both students and teachers agreed to replace classical lectures by digital media and to promote in-person teaching in small interactive groups. This paper shares tips for faculty rapidly establishing remote learning. This comparative study of the students’ and teachers’ points of view underlines that new medical curricula should include more digital contents. We make recommendations regarding general university organization, equipment, and curricular development for long-term implementation of digital resources with reinforced relationships between faculty and students.
Published: 2021

16. Discovery and functional analysis of a novel ALPK1 variant in ROSAH syndrome

Author: Tom Snelling, Leo O. Garnotel, Isabelle Jeru, Maud Tusseau, Laurence Cuisset, Antoinette Perlat, Geoffrey Minard, Thibaut Benquey, Yann Maucourant, Nicola T. Wood, Philip Cohen, and Alban Ziegler
Subjects: ADP-heptose, ALPK1, nucleotide sugar, UDP-mannose, ROSAH, TIFA, Biology (General), QH301-705.5
Abstract: Retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and migraine headache (ROSAH) syndrome is an autosomal dominant disorder and to date is known to be caused by either the Thr237Met or Tyr254Cys variant in the protein kinase ALPK1. Here, we identify a family in which ROSAH syndrome is caused by a novel variant in which Ser277 is changed to Phe. All six patients examined display ocular inflammation and optic nerve elevation, four have retinal degeneration and four are registered blind. In contrast to wild-type ALPK1, which is activated specifically by bacterial ADP-heptose, ALPK1[Ser277Phe] is also activated by the human metabolites UDP-mannose and ADP-ribose and more strongly than the most frequent ROSAH-causing variant (ALPK1[Thr237Met]) but, unlike ALPK1[Thr237Met], ALPK1[Ser277Phe] is also activated by GDP-mannose. These observations can explain why ALPK1 variants causing ROSAH syndrome display constitutive activity in human cells. The side chains of Ser277 and Tyr254 interact in the crystal structure of ALPK1, but mutational analysis established that it is not the loss of this hydrogen bond between Ser277 and Tyr254 that alters the specificity of the ADP-heptose-binding pocket in the Ser277Phe and Tyr254Cys variants. The characterization of ALPK1 variants that cause ROSAH syndrome suggests ways in which drugs that selectively inhibit these disease-causing variants may be developed.
Published: 2024
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17. <scp>RIPK3</scp> dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease

Author: Marta B. Afonso, Tawhidul Islam, Julie Magusto, Ricardo Amorim, Véronique Lenoir, Rui F. Simões, José Teixeira, Liana C. Silva, Dominique Wendum, Isabelle Jéru, Corinne Vigouroux, Rui E. Castro, Paulo J. Oliveira, Carina Prip‐Buus, Vlad Ratziu, Jérémie Gautheron, Cecília M. P. Rodrigues, Prip-Buus, Carina, Universidade de Lisboa, Centre de Recherche Saint-Antoine (CRSA), 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), University of Coimbra [Portugal] (UC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Référence des Maladies Rares - Maladies Inflammatoires des Voies Biliaires et Service d’Hépatologie [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), Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), CHU Saint-Antoine [AP-HP], [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Hepatology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Abstract: International audience; Background and aims: Receptor-interacting protein kinase 3 (RIPK3) mediates NAFLD progression, but its metabolic function is unclear. Here, we aimed to investigate the role of RIPK3 in modulating mitochondria function, coupled with lipid droplet (LD) architecture in NAFLD.Approach and results: Functional studies evaluating mitochondria and LD biology were performed in wild-type (WT) and Ripk3-/- mice fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks and in CRISPR-Cas9 Ripk3-null fat-loaded immortalized hepatocytes. The association between hepatic perilipin (PLIN) 1 and 5, RIPK3, and disease severity was also addressed in a cohort of patients with NAFLD and in PLIN1-associated familial partial lipodystrophy. Ripk3 deficiency rescued impairment in mitochondrial biogenesis, bioenergetics, and function in CDAA diet-fed mice and fat-loaded hepatocytes. Ripk3 deficiency was accompanied by a strong upregulation of antioxidant systems, leading to diminished oxidative stress upon fat loading both in vivo and in vitro. Strikingly, Ripk3-/- hepatocytes displayed smaller size LD in higher numbers than WT cells after incubation with free fatty acids. Ripk3 deficiency upregulated adipocyte and hepatic levels of LD-associated proteins PLIN1 and PLIN5. PLIN1 upregulation controlled LD structure and diminished mitochondrial stress upon free fatty acid overload in Ripk3-/- hepatocytes and was associated with diminished human NAFLD severity. Conversely, a pathogenic PLIN1 frameshift variant was associated with NAFLD and fibrosis, as well as with increased hepatic RIPK3 levels in familial partial lipodystrophy.Conclusions: Ripk3 deficiency restores mitochondria bioenergetics and impacts LD dynamics. RIPK3 inhibition is promising in ameliorating NAFLD.
Published: 2022
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18. Cardiovascular complications of lipodystrophic syndromes – focus on laminopathies

Author: Isabelle Jéru, Marie-Christine Vantyghem, Héléna Mosbah, Karim Wahbi, Camille Vatier, B. Donadille, Corinne Vigouroux, Franck Boccara, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Filière Neuromusculaire (FILNEMUS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), Service de Cardiologie [CHU Saint-Antoine], Laboratoire commun de biologie et génétique moléculaires [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), and Gestionnaire, Hal Sorbonne Université
Subjects: medicine.medical_specialty, Lipodystrophy, Endocrinology, Diabetes and Metabolism, LMNA, MESH: Laminopathies, MESH: Phenotype, Electrocardiography, Endocrinology, MESH: Lipodystrophy, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Humans, Cardiovascular complications, MESH: Syndrome, Intensive care medicine, ComputingMilieux_MISCELLANEOUS, Focus (computing), MESH: Humans, business.industry, Laminopathies, MESH: Cardiovascular Diseases, General Medicine, Syndrome, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Electrocardiography, Phenotype, Cardiovascular Diseases, business
Abstract: International audience
Published: 2021
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19. LIPE-related lipodystrophic syndrome: clinical features and disease modeling using adipose stem cells

Author: Eric Renard, Corinne Vigouroux, Emilie Capel, Caroline Aguilhon, Roberto Motterlini, Camille Sollier, Claire Douillard, Isabelle Jéru, Laura Braud, Camille Vatier, Vasily Smirnov, Olivier Lascols, S. Defoort-Dhellemmes, Jennifer Gorwood, Martine Auclair, Miriam Ladsous, Vigouroux, Corinne, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Département Endocrinologie-Diabétologie-Nutrition [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d’Exploration de la Vision et Neuro-ophtalmologie [CHU Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Faculté de Médecine Henri Warembourg - Université de Lille, Service Endocrinologie, diabétologie, maladies métaboliques et nutrition (LILLE - Endocrino), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Référence des Maladies Héréditaires du Métabolisme [Lille], Hôpital Jeanne de Flandre [Lille]-Clinique de Pédiatrie (Gastro-entérologie, hépatologie et nutrition)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CH de Valenciennes, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), CHU Saint-Antoine [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), Laboratoire commun de biologie et génétique moléculaires [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), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Université Lille 2 - Faculté de Médecine, Service Endocrinologie Diabétologie et Métabolisme (LILLE - Endocrino), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10
Subjects: medicine.medical_specialty, Lipodystrophy, Endocrinology, Diabetes and Metabolism, Lipomatosis, Adipose tissue, 030209 endocrinology & metabolism, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Insulin resistance, Adipocyte, Internal medicine, Diabetes mellitus, Adipocytes, Humans, Medicine, Lipoatrophy, Alleles, Aged, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Models, Genetic, business.industry, Stem Cells, Partial Lipodystrophy, Genetic Variation, Cell Differentiation, Syndrome, General Medicine, Middle Aged, Sterol Esterase, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Phenotype, Adipose Tissue, chemistry, 030220 oncology & carcinogenesis, Lipomatosis, Multiple Symmetrical, Female, business
Abstract: Objective The term Multiple Symmetric Lipomatosis (MSL) describes a heterogeneous group of rare monogenic disorders and multifactorial conditions, characterized by upper-body adipose masses. Biallelic variants in LIPE encoding hormone-sensitive lipase (HSL), a key lipolytic enzyme, were implicated in three families worldwide. We aimed to further delineate LIPE-related clinical features and pathophysiological determinants. Methods A gene panel was used to identify pathogenic variants. The disease features were reviewed at the French lipodystrophy reference center. The immunohistological, ultrastructural, and protein expression characteristics of lipomatous tissue were determined in surgical samples from one patient. The functional impact of variants was investigated by developing a model of adipose stem cells (ASCs) isolated from lipomatous tissue. Results We identified new biallelic LIPE null variants in three unrelated patients referred for MSL and/or partial lipodystrophy. The hallmarks of the disease, appearing in adulthood, included lower-limb lipoatrophy, upper-body and abdominal pseudo-lipomatous masses, diabetes and/or insulin resistance, hypertriglyceridemia, liver steatosis, high blood pressure, and neuromuscular manifestations. Ophthalmological investigations revealed numerous auto-fluorescent drusen-like retinal deposits in all patients. Lipomatous tissue and patient ASCs showed loss of HSL and decreased expression of adipogenic and mature adipocyte markers. LIPE-mutated ASCs displayed impaired adipocyte differentiation, decreased insulin response, defective lipolysis, and mitochondrial dysfunction. Conslusions Biallelic LIPE null variants result in a multisystemic disease requiring multidisciplinary care. Loss of HSL expression impairs adipocyte differentiation, consistent with the lipodystrophy/MSL phenotype and associated metabolic complications. Detailed ophthalmological examination could reveal retinal damage, further pointing to the nervous tissue as an important disease target.
Published: 2021
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20. Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Author: Stéphane Ederhy, Elisabeth Sarrazin, B. Donadille, Olivier Lascols, Fabien Picard, Bruno Fève, Isabelle Jéru, Corinne Vigouroux, Karim Wahbi, Camille Vatier, Ariel Cohen, Héléna Mosbah, Sophie Benabbou, Pascale Richard, Sophie Christin-Maitre, Marie-Christine Vantyghem, B. Neraud, Alban Redheuil, Jocelyn Inamo, Franck Boccara, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU de la Martinique [Fort de France], Hôpital Pierre Zobda-Quitman [CHU de la Martinique], 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], Hôpital Foch [Suresnes], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Filière Neuromusculaire (FILNEMUS), Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], Service de Cardiologie [CHU Saint-Antoine], Laboratoire commun de biologie et génétique moléculaires [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), 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), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Imagerie Biomédicale (LIB), Service de radiologie cardiovasculaire et interventionnelle [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Gestionnaire, Hal Sorbonne Université, and Service de Radiologie cardiovasculaire et interventionnelle [CHU Pitié-Salpêtrière]
Subjects: 0301 basic medicine, medicine.medical_specialty, lipodystrophy, [SDV]Life Sciences [q-bio], Cardiomyopathy, LMNA, 030204 cardiovascular system & hematology, Progeroid syndromes, 03 medical and health sciences, 0302 clinical medicine, lmna, cardiovascular disease, Internal medicine, medicine, lcsh:QH301-705.5, Coronary atherosclerosis, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Generalized lipodystrophy, Partial Lipodystrophy, Dilated cardiomyopathy, General Medicine, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, lcsh:Biology (General), Cardiology, Lipodystrophy, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Variants in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and progeroid syndromes. Cardiovascular laminopathic involvement is classically described as cardiomyopathy in striated muscle laminopathies, and arterial wall dysfunction and/or valvulopathy in lipodystrophic and/or progeroid laminopathies. We report unexpected cardiovascular phenotypes in patients with LMNA-associated lipodystrophies, illustrating the complex multitissular pathophysiology of the disease and the need for specific cardiovascular investigations in affected patients. A 33-year-old woman was diagnosed with generalized lipodystrophy and atypical progeroid syndrome due to the newly identified heterozygous LMNA p.(Asp136Val) variant. Her complex cardiovascular phenotype was associated with atherosclerosis, aortic valvular disease and left ventricular hypertrophy with rhythm and conduction defects. A 29-year-old woman presented with a partial lipodystrophy syndrome and a severe coronary atherosclerosis which required a triple coronary artery bypass grafting. She carried the novel heterozygous p.(Arg60Pro) LMNA variant inherited from her mother, affected with partial lipodystrophy and dilated cardiomyopathy. Different lipodystrophy-associated LMNA pathogenic variants could target cardiac vasculature and/or muscle, leading to complex overlapping phenotypes. Unifying pathophysiological hypotheses should be explored in several cell models including adipocytes, cardiomyocytes and vascular cells. Patients with LMNA-associated lipodystrophy should be systematically investigated with 24-h ECG monitoring, echocardiography and non-invasive coronary function testing.
Published: 2020
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21. European lipodystrophy registry: background and structure

Author: David B. Savage, Alessandra Gambineri, Raoul C.M. Hennekam, Claire Adams, Paolo Sbraccia, Jannik Schaaf, Julia von Schnurbein, David Araújo-Vilar, Camille Vatier, Giovanna Lattanzi, Konstanze Miehle, Baris Akinci, Giuseppe Novelli, Giovanni Ceccarini, Isabelle Jéru, Maria Rosaria D'Apice, Ferruccio Santini, Gabriele Nagel, Elena Vorona, Ekaterina Sorkina, George A. Tanteles, Martin Wabitsch, Corinne Vigouroux, Marie-Christine Vantyghem, Ermelinda Santos Silva, von Schnurbein, Julia [0000-0001-9918-664X], Apollo - University of Cambridge Repository, General Paediatrics, APH - Quality of Care, Von Schnurbein J., Adams C., Akinci B., Ceccarini G., D'Apice M.R., Gambineri A., Hennekam R.C.M., Jeru I., Lattanzi G., Miehle K., Nagel G., Novelli G., Santini F., Santos Silva E., Savage D.B., Sbraccia P., Schaaf J., Sorkina E., Tanteles G., Vantyghem M.-C., Vatier C., Vigouroux C., Vorona E., Araujo-Vilar D., and Wabitsch M.
Subjects: medicine.medical_specialty, Registry, Lipodystrophy, Catabolic state, Pharmacology toxicology, lcsh:Medicine, Adipose tissue, 030209 endocrinology & metabolism, Signs and symptoms, Settore MED/09, Rare diseases, 03 medical and health sciences, 0302 clinical medicine, 0502 economics and business, medicine, Humans, Pharmacology (medical), Registries, ddc:610, Genetics (clinical), Rare endocrinological diseases, User authentication, business.industry, Research, 05 social sciences, lcsh:R, General Medicine, medicine.disease, 3. Good health, Open source, Settore MED/03, Family medicine, General Data Protection Regulation, 050211 marketing, business, Rare disease, Software
Abstract: ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered Background: Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy. Results: The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years. Conclusions: A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry. E.S. has funding for lipodystrophy studies by the Russian Science Foundation,grantNo17–75-30035C.Vi. and C.Va. received funding by the French Ministry of Solidarity andHealth, Assistance-Publique Hôpitaux de Paris, Sorbonne Université, the Insti-tut National de la Santé et de la Recherche Médicale (Inserm), and CardioMe-tabolism and Nutrition University Hospital Institute (ICAN), grant ANR-10-IAHU, FranceD.B.S. is supported by the Wellcome Trust (WT 107064), the MRC MetabolicDisease Unit (MRC_MC_UU_12012/2), and The National Institute for HealthResearch (NIHR) Cambridge Biomedical Research Centre and NIHR RareDisease Translational Research Collaboration.D.A.-V. received funding by the Instituto de Salud Carlos III and the EuropeanRegional Development Fund, FEDER (grant number PI18/01890), by theConsellería de Industria, Xunta de Galicia (grant number ED341b 2017/19),and by Fundación Mutua Madrileña (Call 2015).E.S.-S. work was supported by Applied Molecular Biosciences Unit (UCIBIO),which is financed by national funds from FCT/MCTES (UID/MULTI/04378/2019). info:eu-repo/semantics/publishedVersion
Published: 2020

22. Diagnostic Challenge in PLIN1-Associated Familial Partial Lipodystrophy

Author: Marie-Christine Vantyghem, Martine Auclair, Olivier Lascols, David B. Savage, Camille Vatier, Elise Bismuth, Isabelle Jéru, Sara Barraud, Pascale Cervera, Corinne Vigouroux, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Sorbonne Paris Cité (USPC), Université Pierre et Marie Curie - Paris 6 (UPMC), Pathologie de l'Adipocyte et des Cellules Hepatiques, University of Cambridge [UK] (CAM), and Barraud, Sara
Subjects: 0301 basic medicine, Male, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, DNA Mutational Analysis, Case Report, Bioinformatics, Biochemistry, 0302 clinical medicine, Endocrinology, Hyperinsulinemia, Frameshift Mutation, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, education.field_of_study, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Polycystic ovary, 3. Good health, Lipodystrophy, Familial Partial, Pedigree, Phenotype, Molecular Diagnostic Techniques, Female, Lipodystrophy, Adult, medicine.medical_specialty, Perilipin-1, Population, 030209 endocrinology & metabolism, Frameshift mutation, Diagnosis, Differential, 03 medical and health sciences, Young Adult, Insulin resistance, Diabetes mellitus, Internal medicine, medicine, Humans, Family, education, Aged, business.industry, Biochemistry (medical), Sequence Analysis, DNA, medicine.disease, Familial partial lipodystrophy, 030104 developmental biology, Insulin Resistance, business
Abstract: Context Heterozygous frameshift variants in PLIN1 encoding perilipin-1, a key protein for lipid droplet formation and triglyceride metabolism, have been implicated in familial partial lipodystrophy type 4 (FPLD4), a rare entity with only six families reported worldwide. The pathogenicity of other PLIN1 null variants identified in patients with diabetes and/or hyperinsulinemia was recently questioned because of the absence of lipodystrophy in these individuals and the elevated frequency of PLIN1 null variants in the general population. Objectives To reevaluate the pathogenicity of PLIN1 frameshift variants owing to new data obtained in the largest series of patients with FPLD4. Methods We performed histological and molecular studies for patients referred to our French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity for lipodystrophy and/or insulin resistance and carrying PLIN1 frameshift variants. Results We identified two heterozygous PLIN1 frameshift variants segregating with the phenotype in nine patients from four unrelated families. The FPLD4 stereotypical signs included postpubertal partial lipoatrophy of variable severity, muscular hypertrophy, acromegaloid features, polycystic ovary syndrome and/or hirsutism, metabolic complications (e.g., hypertriglyceridemia, liver steatosis, insulin resistance, diabetes), and disorganized subcutaneous fat lobules with fibrosis and macrophage infiltration. Conclusions These data suggest that some FPLD4-associated PLIN1 variants are deleterious. Thus, the evidence for the pathogenicity of each variant ought to be carefully considered before genetic counseling, especially given the importance of an early diagnosis for optimal disease management. Thus, we recommend detailed familial investigation, adipose tissue-focused examination, and follow-up of metabolic evolution.
Published: 2019
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23. MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue

Author: Corinne Vigouroux, Philippe Froguel, Olivier Lascols, Emmanuel Disse, Sara Barraud, Emilie Capel, Anne Miquel, J.J. Robert, Martine Laville, Héléna Mosbah, Isabelle Jéru, Pierre Gourdy, Brigitte Delemer, Martine Auclair, Florence Tenenbaum, Camille Vatier, Tanya Stojkovic, Amélie Bonnefond, Marie Christine Verpont, Stephan Züchner, Pascale Cervera, Anne-Ségolène Cottereau, Sophie Christin-Maitre, Bruno Fève, Centre de Recherche Saint-Antoine (UMRS893), 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 de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Pathologie de l'Adipocyte et des Cellules Hepatiques, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Endocrinologie - Diabète - Nutrition [Reims], Université de Reims Champagne-Ardenne (URCA)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), 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], Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Reims (CHU Reims), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institute of Cardiometabolism and Nutrition,Institut National de la Sante et de la Recherche MedicaleSorbonne UniversiteAFERO (Association Francaise d’Etude et de Recherche sur l’Obesite)
Subjects: Adult, Male, Leptin, 0301 basic medicine, medicine.medical_specialty, FGF21, Lipodystrophy, Endocrinology, Diabetes and Metabolism, Lipomatosis, Adipose tissue, GTP Phosphohydrolases, Mitochondrial Proteins, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Internal medicine, Genetics, Mitofusin 2, Internal Medicine, medicine, Humans, RNA, Messenger, Lipoatrophy, ComputingMilieux_MISCELLANEOUS, Aged, Nutrition and Dietetics, Adiponectin, business.industry, Thermogenic markers, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Mitochondria, Neuropathy, 3. Good health, 030104 developmental biology, Endocrinology, Adipose Tissue, Dyslipidemia, Positron-Emission Tomography, Lipomatosis, Multiple Symmetrical, Female, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract: Background Multiple symmetric lipomatosis (MSL) is characterized by upper-body lipomatous masses frequently associated with metabolic and neurological signs. MFN2 pathogenic variants were recently implicated in a very rare autosomal recessive form of MSL. MFN2 encodes mitofusin-2, a mitochondrial fusion protein previously involved in Charcot-Marie-Tooth neuropathy. Objective To investigate the clinical, metabolic, tissular, and molecular characteristics of MFN2-associated MSL. Methods We sequenced MFN2 in 66 patients referred for altered fat distribution with one or several lipomas or lipoma-like regions and performed clinical and metabolic investigations in patients with positive genetic testing. Lipomatous tissues were studied in 3 patients. Results Six patients from 5 families carried a homozygous p.Arg707Trp pathogenic variant, representing the largest reported series of MFN2-associated MSL. Patients presented both lipomatous masses and a lipodystrophic syndrome (lipoatrophy, low leptinemia and adiponectinemia, hypertriglyceridemia, insulin resistance and/or diabetes). Charcot-Marie-Tooth neuropathy was of highly variable clinical severity. Lipomatous tissue mainly contained hyperplastic unilocular adipocytes, with few multilocular cells. It displayed numerous mitochondrial alterations (increased number and size, structural defects). As compared to control subcutaneous fat, mRNA and protein expression of leptin and adiponectin was strikingly decreased, whereas the CITED1 and fibroblast growth factor 21 (FGF21) thermogenic markers were strongly overexpressed. Consistently, serum FGF21 was markedly increased, and 18F-FDG-PET-scan revealed increased fat metabolic activity. Conclusion MFN2-related MSL is a novel mitochondrial lipodystrophic syndrome involving both lipomatous masses and lipoatrophy. Its complex neurological and metabolic phenotype justifies careful clinical evaluation and multidisciplinary care. Low leptinemia and adiponectinemia, high serum FGF21, and increased 18F-FDG body fat uptake may be disease markers.
Published: 2018
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24. Clinical Utility Gene Card for: Congenital Generalized Lipodystrophy

Author: Olivier Lascols, Corinne Vigouroux, Camille Vatier, Isabelle Jéru, and David Araújo-Vilar
Subjects: 0301 basic medicine, medicine.medical_specialty, Genotype, BSCL2, Caveolin 1, 030204 cardiovascular system & hematology, Biology, Risk Assessment, Sensitivity and Specificity, Congenital generalized lipodystrophy, 03 medical and health sciences, 0302 clinical medicine, PTRF, Lipodystrophy, Congenital Generalized, Genetic linkage, Molecular genetics, GTP-Binding Protein gamma Subunits, Genetics, medicine, Humans, Genetic Testing, Pathology, Molecular, Genetics (clinical), Cytogenetics, RNA-Binding Proteins, medicine.disease, Human genetics, 030104 developmental biology, Clinical Utility Gene Card, Mutation, Medical genetics, Acyltransferases
Abstract: 1. Name of the disease (synonyms): There are four subclasses of Congenital Generalized Lipodystrophy (CGL), also named Berardinelli–Seip Congenital Lipodystrophy (BSCL): Type 1 CGL (CGL1). Type 2 CGL (CGL2). Type 3 CGL (CGL3). Type 4 CGL (CGL4). 2. OMIM# of the disease: CGL1: #608594. CGL2: #269700. CGL3: #612526. CGL4: #613327. 3. Name of the analysed genes or dna/chromosome segments: CGL1: AGPAT2. CGL2: BSCL2. CGL3: CAV1. CGL4: PTRF. 4. OMIM# of the gene(s): AGPAT2: *603100. BSCL2: *606158. CAV1: *601047. PTRF: *603198. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the four gene(s) in ⊠ diagnostic, □ predictive and ⊠ prenatal settings and for ⊠ risk assessment in relatives.
Published: 2016

25. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation

Author: Dena Lyras, Isabelle Jéru, Kate Schroder, Lien Van Eyck, Emmanuelle Cochet, An Goris, Sinisa Savic, Emanuela Pasciuto, Julia Ruuth-Praz, Laura F. Dagley, Pierre-Yves Jeandel, Carine Wouters, Adrian Liston, Erika Van Nieuwenhove, Serge Amselem, Caroline L. Holley, Paul J. Baker, Raf Sciot, James Dooley, Josselyn E. Garcia-Perez, Sandra E. Nicholson, Bruno Copin, Myrna Medlej-Hashim, Dylan Lawless, Seth L. Masters, Fiona Moghaddas, David A. Parry, Dominic De Nardo, Vasiliki Lagou, André Mégarbané, Lien De Somer, Andrew I. Webb, The Walter and Eliza Hall Institute of Medical Research (WEHI), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Edinburgh, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, University of Queensland [Brisbane], University of Melbourne, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Monash university, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Lebanese University [Beirut] (LU), American University of Beirut Faculty of Medicine and Medical Center (AUB), European Research Council (ERC)Interuniversity Attraction Poles (T-TIME)KU LeuvenFWOAustralian Research Council : FT130100361Institut National de la Sante et de la Recherche Medicale (Inserm)GIS (Groupement d'Interet Scientifique)-Institut des Maladies RaresVictorian State Government Operational Infrastructure Scheme Grant : 1057815 et 1016647Independent Research Institute Infrastructure Support Scheme Grant : 361646National Health and Medical Research Council (NHMRC) of Australia, Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Couvet, Sandrine
Subjects: 0301 basic medicine, Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, Inflammasomes, Neutrophils, [SDV]Life Sciences [q-bio], Interleukin-1beta, Cellular homeostasis, Familial Mediterranean fever, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Pyrin domain, Skin Diseases, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Receptor, 030203 arthritis & rheumatology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Innate immune system, Hereditary Autoinflammatory Diseases, Inflammasome, General Medicine, Pyrin, medicine.disease, MEFV, 3. Good health, Pedigree, [SDV] Life Sciences [q-bio], 030104 developmental biology, HEK293 Cells, Immunology, Mutation, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Inflammasome complex, medicine.drug
Abstract: International audience; Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1β (IL-1β). Mutations in the B30.2/SPRY domain cause pathogen-independent activation of pyrin and are responsible for the autoinflammatory disease familial Mediterranean fever (FMF). We studied a family with a dominantly inherited autoinflammatory disease, distinct from FMF, characterized by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. The disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The mutation results in the loss of a 14-3-3 binding motif at phosphorylated S242, which was not perturbed by FMF mutations in the B30.2/SPRY domain. However, loss of both S242 phosphorylation and 14-3-3 binding was observed for bacterial effectors that activate the pyrin inflammasome, such as Clostridium difficile toxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1β production. Successful therapy targeting IL-1β has been initiated in one patient, resolving pyrin-associated autoinflammation with neutrophilic dermatosis. This disease provides evidence that a guard-like mechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans.
Published: 2016
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26. How should we approach classification of autoinflammatory diseases?

Author: Gilles Grateau, Katia Stankovic Stojanovic, Serge Amselem, Olivier Steichen, Véronique Hentgen, Isabelle Jéru, Groupe de recherche clinique Amylose AA Sorbonne Université (GRC 28 - GRAASU), Sorbonne Université (SU), Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CH Versailles] (CeRéMAIA - Hôpital André Mignot), Centre Hospitalier de Versailles André Mignot (CHV), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Couvet, Sandrine, Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CHU Tenon] (CeréMAIA), 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), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP]
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, Inflammasomes, [SDV]Life Sciences [q-bio], Interleukin-1beta, Family resemblance, [SDV.GEN] Life Sciences [q-bio]/Genetics, Disease, Autoimmune Diseases, Rheumatology, Rheumatic Diseases, Humans, Medicine, Autoinflammatory disease, Inflammation, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Hereditary Autoinflammatory Diseases, Inflammasome, Miscellaneous rheumatic diseases, Immunity, Innate, [SDV] Life Sciences [q-bio], Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunological diseases, business, Neuroscience, Signal Transduction, medicine.drug
Abstract: International audience; The notion of 'autoinflammatory' disease was introduced at the end of the 1990s, and, since then, this concept has rapidly evolved. As a result, multiple definitions of autoinflammatory disease, and classifications of conditions encompassed by these definitions, have been proposed; this succession highlights advances that have been made in understanding of the innate immune system, and especially the roles of IL-1β and the inflammasome in autoinflammtory conditions. However, the definitions and classifications that have been suggested to date face a number of structure and content issues. We therefore propose another, more clinically-oriented, definition: autoinflammatory diseases are diseases with clinical signs of inflammation, associated with elevated levels of acute-phase reactants, which are attributable to dysfunction of the innate immune system, genetically-determined or triggered by an endogenous factor. From this foundation, we propose a clinically-based classification of autoinflammatory diseases, and go on to discuss how immunological diseases as a whole, including autoimmune diseases, can be appropriately located within a continuum only if the classification process is multidimensional. For this purpose, we appeal to the philosophical concepts of family resemblance and signature.
Published: 2013
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27. Familial Mediterranean Fever in Heterozygotes: Are We Able to Accurately Diagnose the Disease in Very Young Children?

Author: Véronique, Hentgen, Gilles, Grateau, Katia, Stankovic-Stojanovic, Serge, Amselem, Isabelle, Jéru, Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CH Versailles] (CeRéMAIA - Hôpital André Mignot), Centre Hospitalier de Versailles André Mignot (CHV), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Couvet, Sandrine
Subjects: Heterozygote, [SDV.GEN]Life Sciences [q-bio]/Genetics, Adolescent, [SDV.IMM] Life Sciences [q-bio]/Immunology, Genetic Carrier Screening, [SDV]Life Sciences [q-bio], Homozygote, [SDV.GEN] Life Sciences [q-bio]/Genetics, Familial Mediterranean Fever, [SDV] Life Sciences [q-bio], Young Adult, Child, Preschool, Mutation, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, Child, Retrospective Studies
Abstract: International audience; Objective: Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disease due to mutations in MEFV. Descriptions of disease manifestations among patients carrying a single mutated MEFV allele are becoming more frequent, although no data are available on the long-term outcome. We undertook this study to assess the accuracy of clinical diagnosis in children carrying a single mutated MEFV allele with symptoms of recurrent autoinflammatory disorder.Methods: We performed a retrospective single-center study of 33 patients with autoinflammatory disorders age
Published: 2013
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28. OR2-002 - The risk of FMF in MEFV heterozygotes

Author: Serge Amselem, Emmanuelle Cochet, Sonia-Athina Karabina, Philippe Duquesnoy, Véronique Hentgen, Isabelle Jéru, G Le Borgne, Emmanuel Grimprel, K Stankovic Stojanovic, Gilles Grateau, Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Physiopathologie des maladies génétiques d'expression pédiatrique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Référence des Maladies AutoInflammatoires, Centre Hospitalier de Versailles André Mignot (CHV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and BMC, Ed.
Subjects: medicine.medical_specialty, Pediatrics, Genetic counseling, Familial Mediterranean fever, Loss of heterozygosity, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Immunology and Allergy, Pediatrics, Perinatology, and Child Health, 030212 general & internal medicine, Allele, ComputingMilieux_MISCELLANEOUS, 030203 arthritis & rheumatology, Genetics, High rate, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Heterozygote advantage, medicine.disease, MEFV, 3. Good health, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Pediatrics, Perinatology and Child Health, Meeting Abstract, business
Abstract: International audience; IntroductionFamilial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder due to MEFV mutations and one of the most frequent Mediterranean genetic diseases. The observation of many heterozygous patients in whom a second mutated allele was excluded led to propose that heterozygosity could be causal; however, this might often be coincidental due to the very high rate ofmutations in Mediterranean populations.ObjectivesTo better delineate the pathogenicity of heterozygosity in order to help genetic counselling and better manage the disease.MethodsComplementary statistical approaches were used: estimation of FMF prevalence at population levels, genotype comparison in siblings from 63 familial forms, and genotype study in 557 patients from four Mediterranean populations.ResultsAt population level, we did not observe any contribution of heterozygosity to the disease prevalence. In affected siblings of patients carrying two MEFV mutations, 92% carry two mutated alleles whereas 4% are heterozygous with typical FMF diagnosis. We also demonstrated statistically that patients are more prone to be heterozygous than healthy individuals, as shown by the higher ratio heterozy-gous carriers/non carriers in patients (p
Published: 2013
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29. Dramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure

Author: Pablo Ureña Torres, Magali Colombat, Isabelle Jéru, Katia Stankovic Stojanovic, Gilles Grateau, Gaëlle Pelle, Julie Peltier, and Yahsou Delmas
Subjects: musculoskeletal diseases, Adult, Male, medicine.medical_specialty, Pathology, Familial Mediterranean fever, Gastroenterology, chemistry.chemical_compound, AA amyloidosis, Internal medicine, medicine, Colchicine, Humans, In patient, Transplantation, Anakinra, business.industry, Amyloidosis, Interleukin, Middle Aged, medicine.disease, Prognosis, Familial Mediterranean Fever, Natural history, Interleukin 1 Receptor Antagonist Protein, Treatment Outcome, chemistry, Nephrology, Kidney Failure, Chronic, Female, business, medicine.drug, Interleukin-1
Abstract: Background. Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder, for which systemic AA amyloidosis is the major complication revealed most of the time by renal abnormalities. Current treatment is daily colchicine that prevents both recurrent inflammatory attacks and amyloidosis deposition in most patients. However, some patients still develop amyloidosis and renal failure. Functional studies suggest that interleukin (IL)-1 is implicated in the inflammatory reaction in FMF and therefore, IL-1 inhibitors could be a new approach to treat FMF. The aim of this series study was to evaluate anakinra in patients with FMF complicated with amyloidosis and renal failure. Methods. We studied a series of adult patients with FMF complicated with amyloidosis and treated with anakinra in one reference centre were reviewed. A search for published patients with FMF associated amyloidosis treated with anakinra was performed by screening PubMed. Results. We report four cases of patients with FMF-associated amyloidosis treated with anakinra and discuss the clinical pertinence of its use in these particular clinical settings. Conclusions. Anakinra has a strong effect on both inflammatory attacks and general status in patients with FMF-associated amyloidosis. It may contribute to changing the prognosis of these patients. Long-term studies are needed to appreciate the effect of anakinra or other IL-1 inhibitors on the natural history of amyloidosis in these patients.
Published: 2012

30. Role of interleukin-1β in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy

Author: Jean-Claude Lecron, Véronique Hentgen, Philippe Duquesnoy, Serge Amselem, Adriana Delwail, Sylvain Normand, Emmanuelle Cochet, Gilles Grateau, Sandrine Marlin, Isabelle Jéru, Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier de Versailles André Mignot (CHV), Laboratoire Inflammation, Tissus épithéliaux et Cytokines (LITEC), Université de Poitiers, CHU Tenon [AP-HP], Centre hospitalier universitaire de Poitiers (CHU Poitiers), the European Union Sixth Framework Programme (EURAMY project grant LSHM-CT-2006-037525), and Couvet, Sandrine
Subjects: Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Interleukin-1beta, Enzyme-Linked Immunosorbent Assay, [SDV.GEN] Life Sciences [q-bio]/Genetics, Peripheral blood mononuclear cell, Rheumatology, In vivo, medicine, Immunology and Allergy, Humans, Pharmacology (medical), Prospective Studies, Anakinra, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Hereditary Autoinflammatory Diseases, Intracellular Signaling Peptides and Proteins, Interleukin, Pathophysiology, [SDV] Life Sciences [q-bio], Interleukin 1 Receptor Antagonist Protein, Cytokine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, business, Ex vivo, medicine.drug, Signal Transduction
Abstract: Objective A new class of autoinflammatory syndromes called NLRP12-associated disorders (NLRP12AD) has been associated with mutations in NLRP12. Conflicting data on the putative role of NLRP12 in interleukin-1β (IL-1β) signaling have been found in in vitro analyses. This prospective study was undertaken to assess the secretion of IL-1β and 3 IL-1β–induced cytokines (IL-1 receptor antagonist [IL-1Ra], IL-6, and tumor necrosis factor α [TNFα]) in patients' peripheral blood mononuclear cells (PBMCs) cultured ex vivo and to evaluate the patients' response to IL-1Ra (anakinra), a major drug used in the treatment of autoinflammatory disorders. Methods Patients' disease manifestations and cytokine measurements were recorded before anakinra treatment was started, during 14 months of therapy, and after discontinuation of anakinra treatment. Results Spontaneous secretion of IL-1β by patients' PBMCs was found to be dramatically increased (80–175 fold) compared to healthy controls. Consistent with these findings, anakinra initially led to a marked clinical improvement and to a rapid near-normalization of IL-1β secretion. However, a progressive clinical relapse occurred secondarily, associated with an increase in TNFα secretion, persistent elevated levels of IL-1Ra and IL-6, and a reactivation of IL-1β secretion. Anakinra was discontinued after 14 months of therapy. Conclusion Our findings provide in vivo evidence of the crucial role of IL-1β in the pathophysiology of NLRP12AD. This is the first time anakinra has been used to treat this disorder. This study provides new insights into the mechanisms underlying resistance to anti–IL-1 therapy observed in a few patients with autoinflammatory syndromes. Our data also point to the potential of ex vivo cytokine measurements as predictors of response to treatment.
Published: 2011
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31. European lipodystrophy registry: background and structure

Author: Julia von Schnurbein, Claire Adams, Baris Akinci, Giovanni Ceccarini, Maria Rosaria D’Apice, Alessandra Gambineri, Raoul C. M. Hennekam, Isabelle Jeru, Giovanna Lattanzi, Konstanze Miehle, Gabriele Nagel, Giuseppe Novelli, Ferruccio Santini, Ermelinda Santos Silva, David B. Savage, Paolo Sbraccia, Jannik Schaaf, Ekaterina Sorkina, George Tanteles, Marie-Christine Vantyghem, Camille Vatier, Corinne Vigouroux, Elena Vorona, David Araújo-Vilar, and Martin Wabitsch
Subjects: Lipodystrophy, Registry, Rare diseases, Adipose tissue, Medicine
Abstract: Abstract Background Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy. Results The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years. Conclusions A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry. Study registration ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered.
Published: 2020
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32. EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence

Author: Jeremie Gautheron, Christophe Morisseau, Wendy K Chung, Jamila Zammouri, Martine Auclair, Genevieve Baujat, Emilie Capel, Celia Moulin, Yuxin Wang, Jun Yang, Bruce D Hammock, Barbara Cerame, Franck Phan, Bruno Fève, Corinne Vigouroux, Fabrizio Andreelli, and Isabelle Jeru
Subjects: diabetes, genetics, epoxide hydrolase, adipocyte, cellular senescence, EPHX1, Medicine, Science, Biology (General), QH301-705.5
Abstract: Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans.
Published: 2021
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33. Interaction of pyrin with 14.3.3 in an Isoform‐specific and phosphorylation‐dependent manner regulates its translocation to the nucleus.

Author: Isabelle Jéru, Stéphanie Papin, Sébastien L'Hoste, Philippe Duquesnoy, Cécile Cazeneuve, Jacques Camonis, and Serge Amselem
Subjects: *LEUCOCYTES, *MONOCYTES, *ALKALINE phosphatase, *AMINO acids, *ARTHRITIS
Abstract: Pyrin, the familial Mediterranean fever gene product, exists in several isoforms of unknown functions. The recombinant full‐length isoform (pyrin.fl) is cytoplasmic, whereas an alternatively spliced isoform lacking exon 2 (pyrin.ΔEx2) concentrates in the nucleus. Native pyrin, mainly consisting of pyrin.fl, is also cytoplasmic in monocytes but is predominantly nuclear in other cell types. To understand pyrin‐dependent biologic pathways and to decipher the mechanisms accounting for such different patterns of subcellular compartmentalization, binding partners and posttranslational modifications of pyrin were assessed.A yeast 2‐hybrid screen was performed with pyrin.fl as the bait. The interaction identified between pyrin.fl and 14.3.3 proteins was confirmed by immunoprecipitation of 35S‐radiolabeled protein complexes; similar experiments were performed with pyrin.ΔEx2, pyrin.fl after alkaline phosphatase treatment, and pyrin.fl mutants in which several exon 2–encoded serine residues were replaced by nonphosphorylatable alanines. The subcellular localization of the different wild‐type and mutated pyrin proteins was assessed by immunofluorescence.Two members of the 14.3.3 protein family were identified as pyrin partners. Whereas pyrin.fl interacted with 14.3.3τ and 14.3.3ε, these interactions did not occur with pyrin.ΔEx2. Pyrin.fl was phosphorylated, and this modification mediated 14.3.3 binding. Serines 208, 209, and 242, within exon 2, acted as critical residues in the interaction between pyrin.fl and 14.3.3. When an S208–S209–S242A pyrin.fl triple mutant or wild‐type pyrin.fl in the presence of an inhibitor of 14.3.3–ligand interactions was used, promotion of nuclear translocation of pyrin was observed.These results disclose the role played by 14.3.3 in the regulation of the subcellular compartmentalization of pyrin in a phosphorylation‐ and isoform‐dependent manner. They also reconcile the observations made in vitro with those made in vivo, while providing a direct link between 14.3.3‐dependent pathways and pyrin. [ABSTRACT FROM AUTHOR]
Published: 2005
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34. FMF in heterozygotes: are we able to accurately diagnose the disease in very young children?

Author: Katia Stankovic Stojanovic, Véronique Hentgen, Gilles Grateau, Isabelle Jéru, and Serge Amselem
Subjects: medicine.medical_specialty, Pediatrics, Young child, business.industry, Heterozygote advantage, Disease, Compound heterozygosity, Rheumatology, Clinical diagnosis, Internal medicine, Poster Presentation, Pediatrics, Perinatology and Child Health, medicine, Immunology and Allergy, Early childhood, Pediatrics, Perinatology, and Child Health, business
Abstract: Results Presenting signs in heterozygous children did not differ from homozygous or compound heterozygous patients. Initial response to colchicine was identical in the two groups. During follow-up heterozygous patients were more likely to have a milder course of the disease. After puberty clinical signs of FMF totally disappeared in 6/11 heterozygous patients. In these 6 patients, colchicine could be withdrawn without recurrence of symptoms or rise of inflammatory markers. If applied after puberty, clinical diagnostic criteria sets were no longer positive in these 6 patients, whereas the same criteria applied retrospectively during early childhood concluded to FMF. Conclusion Our study suggests that the diagnosis of FMF in very young heterozygous children should be cautious. Heterozygous children can present with an FMF-like disease during early childhood that may disappear with age, while others will suffer lifelong from their disease. Only a careful follow-up of FMF heterozygotes allows an accurate diagnosis over time.
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35. OR13-003 - TNFRSF11A molecular defects cause autoinflammatory disorders

Author: Véronique Hentgen, Serge Amselem, S Sheykholeslami, Florence Dastot, Philippe Duquesnoy, Maria Teresa Mitjavila-Garcia, G Le Borgne, Sonia-Athina Karabina, M Mahevas, Isabelle Jéru, Laurence Faivre, Bruno Copin, Emmanuelle Cochet, Sandra Chantot-Bastaraud, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence des Maladies AutoInflammatoires (CeRéMAI), Centre Hospitalier de Versailles André Mignot (CHV), Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Interne, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), BMC, Ed., and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: 030203 arthritis & rheumatology, Pediatrics, medicine.medical_specialty, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, business.industry, Rheumatology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Internal medicine, Meeting Abstract, Pediatrics, Perinatology and Child Health, medicine, Etiology, Immunology and Allergy, Hereditary Recurrent Fevers, 030212 general & internal medicine, Pediatrics, Perinatology, and Child Health, business, Autoinflammatory Disorders, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; IntroductionHereditary recurrent fevers (HRF) are autoinflammatory disorders whose etiology remains unknown in many cases.ObjectivesTo identify a new HRF geneMethodsComparative genomic hybridization (CGH, 385K array) was performed in the proband. TNFRSF11A was screenedby Sanger sequencing in other patients. TNFRS11A expression was quantified by fluorescence-activated cellsorter analysis (FACS). NF-k B activation was assessed using a luciferase assay in HEK293 cells transfected withplasmids encoding wild-type and mutated TNFRSF11A.ResultsArray-CGH analysis performed in a patient with multiple congenital anomalies and a recurrent fever syndromerevealed a de novo heterozygous chromosomal rearrangement encompassing a duplication of TNFRSF11A. Thistransmembrane receptor binds the TNFSF11 cytokine, activates NF-k B signaling, and regulates fever in rodents,consistent with a possible role in HRF. TNFRSF11A screening in other patients with genetically-unexplainedHRF revealed a heterozygous frameshift mutation in a patient and her affected mother. The mutated protein isexpressed at similar levels as the normal receptor on leukocytes. Most importantly, this mutation results in a gainof function on NF-k B signaling, since the mutated protein is more responsive to TNFSF11 stimulation than the wild-type receptor. Since TNFRSF11A (also known as RANK) was previously known for its key role in osteoclastogenesis, the medical history of our patients was reassessed and revealed minor symptoms also found in patients with TNFRSF11A-associated bone disorders.ConclusionThe implication of TNFRSF11A in HRF reveals a key role of this receptor in autoinflammation and opens up newfields of research at the crossroads between bone metabolism and innate immunity.
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36. Rôles biologiques à multiples facettes de l’adiponectine

Author: Charlotte, Cuerq, Gilles, Morineau, Diane, Dufour-Rainfray, Camille, Vatier, Soraya, Fellahi, Corinne, Vigouroux, Annelise, Genoux, Jean-Marc, Lacorte, Rim, Charchour, Bruno, Fève, Jacqueline, Capeau, Christine, Collet, Jean-Philippe, Bastard, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], CHU Saint-Antoine [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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], CHU Pitié-Salpêtrière [AP-HP], CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Henri Mondor, Service de Médecine Nucléaire [Tours], CHU Trousseau [APHP], groupe de travail RIHN Adipokines: Jean-Philippe Bastard, Jacqueline Capeau, Rim Charchour, Christine Collet, Charlotte Cuerq, Diane Dufour-Rainfray, Soraya Fellahi, Annelise Genoux, Jean Guibourdenche, Isabelle Jéru, Jean-Marc Lacorte, Gilles Morineau, Camille Vatier, Corinne Vigouroux, and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP]
Subjects: dementia, leptin, [SDV]Life Sciences [q-bio], Type 2 diabetes, Energy homeostasis, 030207 dermatology & venereal diseases, 0302 clinical medicine, cancer, Neoplasms, Insulin, Abdominal obesity, Type 2/etiology/metabolism/pathology, Metabolic Syndrome, General Medicine, Adiponectin/*physiology, 3. Good health, Neoplasms/etiology/metabolism/pathology, insulin resistance, Adiponectin, medicine.symptom, medicine.medical_specialty, Insulin/metabolism, Adipokine, Fatty Liver/etiology/metabolism, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, Diabetes Mellitus, Animals, Humans, Obesity, Obesity/metabolism/pathology/physiopathology, Metabolic Syndrome/etiology/metabolism/pathology, business.industry, inflammation, Cognition Disorders/etiology/metabolism/pathology, medicine.disease, Fatty Liver, Endocrinology, Diabetes Mellitus, Type 2, Steatohepatitis, Metabolic syndrome, Insulin Resistance, business, Cognition Disorders, Insulin Resistance/physiology, bowel disease, 030217 neurology & neurosurgery
Abstract: International audience; Adiponectin is a major adipokine involved in energy homeostasis that exerts insulin-sensitizing properties. The level of adiponectin is reduced in situations of insulin resistance and is negatively associated with several pathophysiological situations including abdominal obesity, metabolic syndrome, steatosis and non-alcoholic steatohepatitis, type 2 diabetes, some cancers and cognitive diseases. These aspects are discussed in this review.; L’adiponectine est une adipokine majeure de l’homéostasie énergétique qui présente des propriétés insulino-sensibilisatrices. Elle est diminuée dans les états de résistance à l’insuline et est associée négativement à plusieurs situations physiopathologiques dont l’obésité abdominale, le syndrome métabolique, la stéatose et la stéato-hépatite non alcoolique, le diabète de type 2, certains cancers et des maladies cognitives. Ces aspects sont discutés dans cette revue.
Published: 2020
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