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1. Ventilation Prior to Umbilical Cord Clamping Improves Cardiovascular Stability and Oxygenation in Preterm Lambs After Exposure to Intrauterine Inflammation

Author

Alessandra Lio, Claudia Aurilia, Valerie Zahra, Timothy J. Moss, Domenic A. LaRosa, Stuart B. Hooper, Andrew W. Gill, Martin Kluckow, Ilias Nitsos, Giovanni Vento, and Graeme R. Polglase

Subjects
delayed cord clamping, premature birth, chorioamnionitis, placental transfusion, physiological-based cord clamping, Pediatrics, RJ1-570
Abstract

Background: Delaying umbilical cord clamping until after aeration of the lung (physiological-based cord clamping; PBCC) maintains cardiac output and oxygenation in preterm lambs at birth, however, its efficacy after intrauterine inflammation is not known. Given the high incidence of chorioamnionitis in preterm infants, we investigated whether PBCC conferred any benefits compared to immediate cord clamping (ICC) in preterm lambs exposed antenatally to 7 days of intrauterine inflammation.Methods: Ultrasound guided intraamniotic injection of 20 mg Lipopolysaccharide (from E. coli:055:B5) was administered to pregnant ewes at 0.8 gestation. Seven days later, ewes were anesthetized, preterm fetuses exteriorised via cesarean section, and instrumented for continuous measurement of pulmonary, systemic and cerebral pressures and flows, and systemic, and cerebral oxygenation. Lambs were then randomized to either PBCC, whereupon ventilation was initiated and maintained for 3 min prior to umbilical cord clamping, or ICC where the umbilical cord was cut and ventilation initiated 30 s later. Ventilation was maintained for 30 min.Results: ICC caused a rapid fall in systemic (by 25%) and cerebral (by 11%) oxygen saturation in ICC lambs, concurrent with a rapid increase in carotid arterial pressure and heart rate. The overshoot in carotid arterial pressure was sustained in ICC lambs for the first 20 min of the study. PBCC maintained cardiac output and prevented the fall in cerebral oxygen delivery at birth. PBCC lambs had lower respiratory compliance and higher respiratory requirements throughout the study.Conclusion: PBCC mitigated the adverse effects of ICC on oxygenation and cardiac output, and therefore could be more beneficial in preterm babies exposed to antenatal inflammation as it maintains cardiac output and oxygen delivery. The increased respiratory requirements require further investigation in this sub-group of preterm infants.

Published
2018
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2. Effect of Human Amnion Epithelial Cells on the Acute Inflammatory Response in Fetal Sheep

Author

Alana Westover, Jacqueline M. Melville, Courtney McDonald, Rebecca Lim, Graham Jenkin, Euan M. Wallace, and Timothy J. Moss

Subjects
hAECs, inflammation, fetus, lung, placenta, liver, Physiology, QP1-981
Abstract

Intra-amniotic (IA) lipopolysaccharide (LPS) injection in sheep induces inflammation in the fetus. Human amnion epithelial cells (hAECs) moderate the effect of IA LPS on fetal development, but their influence on the acute inflammatory response to IA LPS is unknown. We aimed to determine the effects of hAECs on the acute fetal inflammatory response to IA LPS. After surgical instrumentation at 116 days' gestation (d) ewes were randomized to 1 of 4 groups at 123 d: IA LPS (10 mg) and intravenous (IV) saline (n = 8), IA LPS and IV hAECs (n = 6), IA saline and IV saline (n = 5) or IA saline and IV hAECs (n = 5). IV injections were administered immediately after IA injections. Serial fetal blood samples were collected. At 125 d, placental, fetal lung and liver samples were collected. IA LPS increased inflammatory cell recruitment in the placenta and lungs, increased IL-1β and IL-8 mRNA levels in the lungs and increased serum amyloid A3 (SAA3) and C-reactive protein (CRP) mRNA levels in the liver. IV hAECs reduced fetal lung inflammatory cell recruitment but did not otherwise alter indices of placental, fetal lung or liver inflammation. The acute fetal inflammatory response to IA LPS is not substantially altered by IV hAEC treatment.

Published
2017
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3. Engaging Australian men in disease prevention – priorities and opportunities from a national survey

Author

Ben J Smith, Timothy J Moss, Bernie Marshall, Nicole Halim, Robert Palmer, and Simon von Saldern

Subjects
Public aspects of medicine, RA1-1270
Abstract

Objective and importance of the study: In Australia, preventable causes of morbidity and mortality are common among men. The National Men’s Health Strategy 2021–2030 highlights the need to successfully engage men in disease prevention; hence, we aimed to examine the prevention priorities, attitudes and information sources reported by Australian men. Study type: Population survey. Methods: Men aged 18 years and over were recruited from the nationally representative Life in Australia panel. Participants completed an online survey that measured the prevention issues of greatest concern, attitudes to prevention behaviours and services, and the health information sources considered most useful. Results: Among 1282 respondents, mental health issues, followed by those pertaining to chronic disease and relationships, were rated of highest concern. Weight management, physical activity, and fruit and vegetable consumption were most often considered as important for personal health. Being 65 years and older and having adequate health literacy were strongly associated with positive attitudes towards prevention practices. More than three-quarters of men rated their doctor as the most useful information source, followed by health websites, internet searching, and their partner. Conclusions: Psychological and social issues are of high concern to men, and their attitudes toward preventive behaviours and services often do not align with public health recommendations. Understanding the topics of greatest concern to men and their preferred sources of information can inform communication and engagement strategies to improve health-related practices among men.

Published
2024
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4. The effect of human amnion epithelial cells on lung development and inflammation in preterm lambs exposed to antenatal inflammation.

Author

Paris Clarice Papagianis, Siavash Ahmadi-Noorbakhsh, Rebecca Lim, Euan Wallace, Graeme Polglase, J Jane Pillow, and Timothy J Moss

Subjects
Medicine, Science
Abstract

BackgroundLung inflammation and impaired alveolarization are hallmarks of bronchopulmonary dysplasia (BPD). We hypothesize that human amnion epithelial cells (hAECs) are anti-inflammatory and reduce lung injury in preterm lambs born after antenatal exposure to inflammation.MethodsPregnant ewes received either intra-amniotic lipopolysaccharide (LPS, from E.coli 055:B5; 4mg) or saline (Sal) on day 126 of gestation. Lambs were delivered by cesarean section at 128 d gestation (term ~150 d). Lambs received intravenous hAECs (LPS/hAECs: n = 7; 30x106 cells) or equivalent volumes of saline (LPS/Sal, n = 10; or Sal/Sal, n = 9) immediately after birth. Respiratory support was gradually de-escalated, aimed at early weaning from mechanical ventilation towards unassisted respiration. Lung tissue was collected 1 week after birth. Lung morphology was assessed and mRNA levels for inflammatory mediators were measured.ResultsRespiratory support required by LPS/hAEC lambs was not different to Sal/Sal or LPS/Sal lambs. Lung tissue:airspace ratio was lower in the LPS/Sal compared to Sal/Sal lambs (PConclusionsPostnatal administration of a single dose of hAECs stimulates a pulmonary immune response without changing ventilator requirements in preterm lambs born after intrauterine inflammation.

Published
2021
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5. Intrauterine inflammation exacerbates maladaptive remodeling of the immature myocardium after preterm birth in lambs

Author

Amanda Vrselja, J. Jane Pillow, Jonathan G. Bensley, Stacey J. Ellery, Siavash Ahmadi-Noorbakhsh, Timothy J. Moss, and M. Jane Black

Subjects
Pediatrics, Perinatology and Child Health
Abstract

Background Antenatal conditions that are linked with preterm birth, such as intrauterine inflammation, can influence fetal cardiac development thereby rendering the heart more vulnerable to the effects of prematurity. We aimed to investigate the effect of intrauterine inflammation, consequent to lipopolysaccharide exposure, on postnatal cardiac growth and maturation in preterm lambs. Methods Preterm lambs (~129 days gestational age) exposed antenatally to lipopolysaccharide or saline were managed according to contemporary neonatal care and studied at postnatal day 7. Age-matched fetal controls were studied at ~136 days gestational age. Cardiac tissue was sampled for molecular analyses and assessment of cardiac structure and cardiomyocyte maturation. Results Lambs delivered preterm showed distinct ventricular differences in cardiomyocyte growth and maturation trajectories as well as remodeling of the left ventricular myocardium compared to fetal controls. Antenatal exposure to lipopolysaccharide resulted in further collagen deposition in the left ventricle and a greater presence of immune cells in the preterm heart. Conclusions Adverse impacts of preterm birth on cardiac structure and cardiomyocyte growth kinetics within the first week of postnatal life are exacerbated by intrauterine inflammation. The maladaptive remodeling of the cardiac structure and perturbed cardiomyocyte growth likely contribute to the increased vulnerability to cardiac dysfunction following preterm birth. Impact Preterm birth induces maladaptive cardiac remodeling and adversely impacts cardiomyocyte growth kinetics within the first week of life in sheep. These effects of prematurity on the heart are exacerbated when preterm birth is preceded by exposure to intrauterine inflammation, a common antecedent of preterm birth. Inflammatory injury to the fetal heart coupled with preterm birth consequently alters neonatal cardiac growth and maturation and thus, may potentially influence long-term cardiac function and health.

Published
2022
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6. Delineating the expanding phenotype associated with SCAPER gene mutation

Author

Anthony G. Robson, Claire G. Salter, James Fasham, Gaurav V. Harlalka, Olivia Wenger, Amelia Lane, F. Lucy Raymond, Sarah Hull, Rui Chen, Emma L. Baple, Lynn Schema, Gavin Arno, Mingchu Xu, Anthony T. Moore, Andrew R. Webster, Siying Lin, Michael E. Cheetham, Timothy J. Moss, Keren J. Carss, Jay E. Self, and Andrew H. Crosby

Subjects
0303 health sciences, Philosophy, Brachydactyly, 030305 genetics & heredity, Intellectual disability, Gene mutation, Research Letters, 3. Good health, Retinitis pigmentosa, 03 medical and health sciences, Research Letter, Genetics, Theology, SCAPER, CCNA2–CDK2, Genetics (clinical), 030304 developmental biology
Abstract

Author(s): Fasham, James; Arno, Gavin; Lin, Siying; Xu, Mingchu; Carss, Keren J; Hull, Sarah; Lane, Amelia; Robson, Anthony G; Wenger, Olivia; Self, Jay E; Harlalka, Gaurav V; Salter, Claire G; Schema, Lynn; Moss, Timothy J; Cheetham, Michael E; Moore, Anthony T; Raymond, F Lucy; Chen, Rui; Baple, Emma L; Webster, Andrew R; Crosby, Andrew H; NIHR Bioresource Rare Diseases Consortium

Published
2019
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7. Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Author

Gijs W. E. Santen, Damara Ortiz, Elisabeth M. Lodder, Francesca Clementina Radio, Michael V. Airola, Monique C. Haak, Dominic S Zimmerman, Quinn Gunst, Peter de Knijff, Katherine H. Kim, Viktor Stránecký, Stanislav Kmoch, Hiba Mustafa, Dmitriy Niyazov, H. Alex Brown, Najim Lahrouchi, Jamille Y. Robinson, Rick H. de Leeuw, Anne Sophie Denommé-Pichon, Sara Cherny, George A. Tanteles, Mariam Hababa, Joey V. Barnett, Doris Škorić-Milosavljević, Annemiek C. Dutman, Timothy J. Moss, Daniel M. de Laughter, Connie R. Bezzina, Zeev Perles, Fleur V.Y. Tjong, Matthew Ambrose, Forrest Z. Bowling, Arend D. J. ten Harkel, Katelijne Bouman, Barry Wolf, Monia Magliozzi, Asaf Ta-Shma, Lenka Piherová, Aho Ilgun, Sabrina C. Burn, Orly Elpeleg, Michael A. Frohman, Alex V. Postma, Maurice J.B. van den Hoff, Christian M. Salazar, Johanna C. Herkert, Christine Francannet, Jennifer Jacober, Andreas Rousounides, Leander Beekman, Barbara J.M. Mulder, Viktor Tomek, Bruel Ange-Line, Aphrodite Aristidou-Kallika, S. A. Clur, Gwendolyn T. R. Manten, Cardiology, ACS - Heart failure & arrhythmias, Human Genetics, Medical Biology, ACS - Pulmonary hypertension & thrombosis, ACS - Amsterdam Cardiovascular Sciences, ARD - Amsterdam Reproduction and Development, Graduate School, APH - Aging & Later Life, APH - Personalized Medicine, Paediatric Cardiology, and APH - Amsterdam Public Health

Subjects
Heart Defects, Congenital, Male, 0301 basic medicine, Heart disease, Heart Valve Diseases, Cardiomyopathy, HEART-DISEASE, PHOSPHOLIPASE-D DEFINES, 03 medical and health sciences, 0302 clinical medicine, DESIGN, Loss of Function Mutation, Phospholipase D, Humans, Medicine, Missense mutation, CRYSTAL-STRUCTURE, Allele frequency, Alleles, Loss function, Genetics, business.industry, GROWTH-FACTOR-BETA, MUTATIONS, INDUCTION, FACTOR-ALPHA, General Medicine, medicine.disease, Phenotype, Ashkenazi jews, TRANSFORMATION, 030104 developmental biology, D1, 030220 oncology & carcinogenesis, Heart failure, Female, business, Research Article
Abstract

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.1668F is a founder variant among Ashkenazi Jews (allele frequency of -.2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.

Published
2021

8. The cerebral haemodynamic response to somatosensory stimulation in preterm newborn lambs is reduced following intrauterine inflammation and dopamine infusion

Author

Ishmael M. Inocencio, Nhi T. Tran, Manon Wiersma, Katja Stoecker, Shinji Nakamura, Timothy J. Moss, David W. Walker, and Flora Y. Wong

Subjects
Inflammation, Lipopolysaccharides, Sheep, Dopamine, Hemodynamics, Infant, Newborn, Chorioamnionitis, Animals, Newborn, Developmental Neuroscience, Neurology, Pregnancy, Animals, Humans, Premature Birth, Female, Hypoxia, Infant, Premature
Abstract

Neurovascular coupling leads to an increase in local cerebral blood flow and oxygenation in response to increased neural activity. Reduced cerebral functional responses may predispose to tissue hypoxia when neural activity is increased. Intrauterine inflammation, identified clinically as chorioamnionitis, is a major contributor to the neuropathology arising after preterm birth. The impact of chorioamnionitis on the preterm cerebral functional haemodynamic response is unknown. Previously, we have reported that somatosensory stimulation produces predominantly positive cerebral haemodynamic responses (i.e., increased cerebral oxygenation) in preterm lambs, which are reduced with dopamine treatment. As preterm infants born after chorioamnionitis often suffer from hypotension and are treated with dopamine, we aimed to investigate how chorioamnionitis with and without dopamine treatment affect the cerebral haemodynamic response in preterm lambs.At 119 days of gestation, intrauterine inflammation was induced by intra-amniotic injection of lipopolysaccharide (LPS) in pregnant ewes. At 126-7 days of gestation (term is ~147 days), these LPS-exposed lambs were delivered and mechanically ventilated. The cerebral functional response was assessed by near infrared spectroscopy as changes in cerebral oxy- and deoxyhaemoglobin (ΔoxyHb, ΔdeoxyHb), following left median nerve stimulation of 1.8, 4.8 and 7.8 s durations without dopamine; and 4.8 and 7.8 s stimulations with intravenous dopamine infusion.Stimulation for 1.8, 4.8 and 7.8 s durations led to negative functional responses (decreased ΔoxyHb) in 5 (62.5%), 5 (62.5%) and 4 (50%) of 8 preterm lambs respectively, while other lambs showed positive responses (increased ∆oxyHb). Dopamine infusion increased baseline tissue oxygenation index (TOI), oxyHb and total Hb. In lambs with a positive functional response, dopamine decreased the evoked ΔoxyHb response, increasing the overall incidence of negative cerebral haemodynamic responses.Somatosensory stimulation produced mostly negative responses with decreased cerebral oxygenation in preterm lambs exposed to intrauterine inflammation, contrasting with our previous findings of predominantly positive responses in non-inflamed, control, preterm lambs. Dopamine increased baseline cerebral oxygenation, but further increased the incidence of negative functional responses. Impaired neurovascular coupling leading to intermittent localised tissue hypoxia may therefore contribute to the neuropathy in infants with chorioamnionitis, with the risk of injury exacerbated with dopamine treatment.

Published
2022
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9. Patient Decisions to Receive Secondary Pharmacogenomic Findings and Development of a Multidisciplinary Practice Model to Integrate Results Into Patient Care

Author

Timothy J. Moss, Amy Shealy, J. Kevin Hicks, Allison Schreiber, Ryan Noss, Marvin R. Natowicz, Charis Eng, Angelika Erwin, Marissa Coleridge, and Rocio Moran

Subjects
0301 basic medicine, medicine.medical_specialty, business.industry, General Neuroscience, Genetic counseling, General Medicine, Bioinformatics, 030226 pharmacology & pharmacy, General Biochemistry, Genetics and Molecular Biology, Patient care, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Pharmacotherapy, Multidisciplinary approach, Family medicine, Pharmacogenomics, medicine, Dosing, General Pharmacology, Toxicology and Pharmaceutics, business, Pharmacogenetics, Exome sequencing
Abstract

Whole exome sequencing (WES) has the potential of identifying secondary findings that are predictive of poor pharmacotherapy outcomes. The purpose of this study was to investigate patients’ wishes regarding the reporting of secondary pharmacogenomic findings. WES results (n = 106 patients) were retrospectively reviewed to determine the number of patients electing to receive secondary pharmacogenomic results. Phenotypes were assigned based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. The percent of patients with a predicted phenotype associated with a gene-based CPIC dosing recommendation was determined. Ninety-nine patients (93.4%) elected to receive secondary pharmacogenomic findings. For each gene–drug pair analyzed, the number of patients with an actionable phenotype ranged from two (2%) to 43 patients (43.4%). Combining all gene–drug pairs, 84 unique patients (84.8%) had an actionable phenotype. A prospective multidisciplinary practice model was developed for integrating secondary pharmacogenomic findings into clinical practice. Our model highlights a unique collaboration between physician-geneticists, pharmacists, and genetic counselors.

Published
2017
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10. Umbilical cord blood versus mesenchymal stem cells for inflammation-induced preterm brain injury in fetal sheep

Author

Madison C B, Paton, Beth J, Allison, Michael C, Fahey, Jingang, Li, Amy E, Sutherland, Yen, Pham, Ilias, Nitsos, Robert J, Bischof, Timothy J, Moss, Graeme R, Polglase, Graham, Jenkin, Suzanne L, Miller, and Courtney A, McDonald

Subjects
Inflammation, Lipopolysaccharides, Male, Sheep, Cell Death, Apoptosis, Mesenchymal Stem Cells, Fetal Blood, White Matter, Neuroprotection, Disease Models, Animal, Oligodendroglia, Animals, Newborn, Astrocytes, Brain Injuries, Leukocytes, Mononuclear, Animals, Humans, Female, Gliosis
Abstract

Chorioamnionitis and fetal inflammation are principal causes of neuropathology detected after birth, particularly in very preterm infants. Preclinical studies show that umbilical cord blood (UCB) cells are neuroprotective, but it is uncertain if allogeneic UCB cells are a feasible early intervention for preterm infants. In contrast, mesenchymal stem cells (MSCs) are more readily accessible and show strong anti-inflammatory benefits. We aimed to compare the neuroprotective benefits of UCB versus MSCs in a large animal model of inflammation-induced preterm brain injury. We hypothesized that MSCs would afford greater neuroprotection.Chronically instrumented fetal sheep at 0.65 gestation received intravenous lipopolysaccharide (150 ng; 055:B5, n = 8) over 3 consecutive days; or saline for controls (n = 8). Cell-treated animals received 10Lipopolysaccharide induced neuroinflammation and apoptosis, and reduced the number of mature oligodendrocytes. MSCs reduced astrogliosis, but UCB did not have the same effect. UCB significantly decreased cerebral apoptosis and protected mature myelinating oligodendrocytes, but MSCs did not.UCB appears to better protect white matter development in the preterm brain in response to inflammation-induced brain injury in fetal sheep.

Published
2018

11. Quantifying the effects of 16p11.2 copy number variants on brain structure: A multisite genetic-first study

Author

Sandra Martin-Brevet, Borja Rodríguez-Herreros, Jared A. Nielsen, Clara Moreau, Claudia Modenato, Anne M. Maillard, Aurélie Pain, Sonia Richetin, Aia E. Jønch, Abid Y. Qureshi, Nicole R. Zürcher, Philippe Conus, Wendy K. Chung, Elliott H. Sherr, John E. Spiro, Ferath Kherif, Jacques S. Beckmann, Nouchine Hadjikhani, Alexandre Reymond, Randy L. Buckner, Bogdan Draganski, Sébastien Jacquemont, Marie-Claude Addor, Joris Andrieux, Benoît Arveiler, Geneviève Baujat, Frédérique Sloan-Béna, Marco Belfiore, Dominique Bonneau, Sonia Bouquillon, Odile Boute, Alfredo Brusco, Tiffany Busa, Jean-Hubert Caberg, Dominique Campion, Vanessa Colombert, Marie-Pierre Cordier, Albert David, François-Guillaume Debray, Marie-Ange Delrue, Martine Doco-Fenzy, Ulrike Dunkhase-Heinl, Patrick Edery, Christina Fagerberg, Laurence Faivre, Francesca Forzano, David Genevieve, Marion Gérard, Daniela Giachino, Agnès Guichet, Olivier Guillin, Delphine Héron, Bertrand Isidor, Aurélia Jacquette, Sylvie Jaillard, Hubert Journel, Boris Keren, Didier Lacombe, Sébastien Lebon, Cédric Le Caignec, Marie-Pierre Lemaître, James Lespinasse, Michèle Mathieu-Dramart, Sandra Mercier, Cyril Mignot, Chantal Missirian, Florence Petit, Kristina Pilekær Sørensen, Lucile Pinson, Ghislaine Plessis, Fabienne Prieur, Caroline Rooryck-Thambo, Massimiliano Rossi, Damien Sanlaville, Britta Schlott Kristiansen, Caroline Schluth-Bolard, Marianne Till, Mieke Van Haelst, Lionel Van Maldergem, Hanalore Alupay, Benjamin Aaronson, Sean Ackerman, Katy Ankenman, Ayesha Anwar, Constance Atwell, Alexandra Bowe, Arthur L. Beaudet, Marta Benedetti, Jessica Berg, Jeffrey Berman, Leandra N. Berry, Audrey L. Bibb, Lisa Blaskey, Jonathan Brennan, Christie M. Brewton, Randy Buckner, Polina Bukshpun, Jordan Burko, Phil Cali, Bettina Cerban, Yishin Chang, Maxwell Cheong, Vivian Chow, Zili Chu, Darina Chudnovskaya, Lauren Cornew, Corby Dale, John Dell, Allison G. Dempsey, Trent Deschamps, Rachel Earl, James Edgar, Jenna Elgin, Jennifer Endre Olson, Yolanda L. Evans, Anne Findlay, Gerald D. Fischbach, Charlie Fisk, Brieana Fregeau, Bill Gaetz, Leah Gaetz, Silvia Garza, Jennifer Gerdts, Orit Glenn, Sarah E. Gobuty, Rachel Golembski, Marion Greenup, Kory Heiken, Katherine Hines, Leighton Hinkley, Frank I. Jackson, Julian Jenkins, Rita J. Jeremy, Kelly Johnson, Stephen M. Kanne, Sudha Kessler, Sarah Y. Khan, Matthew Ku, Emily Kuschner, Anna L. Laakman, Peter Lam, Morgan W. Lasala, Hana Lee, Kevin LaGuerre, Susan Levy, Alyss Lian Cavanagh, Ashlie V. Llorens, Katherine Loftus Campe, Tracy L. Luks, Elysa J. Marco, Stephen Martin, Alastair J. Martin, Gabriela Marzano, Christina Masson, Kathleen E. McGovern, Rebecca McNally Keehn, David T. Miller, Fiona K. Miller, Timothy J. Moss, Rebecca Murray, Srikantan S. Nagarajan, Kerri P. Nowell, Julia Owen, Andrea M. Paal, Alan Packer, Patricia Z. Page, Brianna M. Paul, Alana Peters, Danica Peterson, Annapurna Poduri, Nicholas J. Pojman, Ken Porche, Monica B. Proud, Saba Qasmieh, Melissa B. Ramocki, Beau Reilly, Timothy P.L. Roberts, Dennis Shaw, Tuhin Sinha, Bethanny Smith-Packard, Anne Snow Gallagher, Vivek Swarnakar, Tony Thieu, Christina Triantafallou, Roger Vaughan, Mari Wakahiro, Arianne Wallace, Tracey Ward, Julia Wenegrat, Anne Wolken, 16p11.2 European Consortium, Simons Variation in Individuals Project (VIP) Consortium, CSIR-Institute of Microbial Technology [Chandigarh] (IMTech), Council of Scientific and Industrial Research [India] (CSIR), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Human Genetics, Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), The Wellcome Trust Sanger Institute [Cambridge], Department of Psychiatry [Boston], Massachusetts General Hospital [Boston], Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Humaine, Développement et Cancer, Université Bordeaux Segalen - Bordeaux 2, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Guglielmo Marconi University [Roma], Laboratoire de biomécanique (LBM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Systèmes de Référence Temps Espace (SYRTE), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Medical Sciences, Università degli studi di Torino (UNITO), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Liège (CHU-Liège), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Department of Clinical Genetics, Vejle Hospital, Institute of Child Health, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Institut de Myologie, 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), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, CHU Bordeaux [Bordeaux], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department of Genomics of Common Disease, Imperial College London, Regional Hospital, Department of Psychiatry and Behavioral Sciences! (UW psychiatry), University of Washington [Seattle], University of California, San Francisco (UCSF), UCSF, Unité de Recherches Zootechniques (URZ), Institut National de la Recherche Agronomique (INRA), University of California [San Francisco] (UCSF), University of California, UCL Institute of Neurology, Biomagnetic Imaging Laboratory - University of California, SFARI219193, Simons Foundation, 31003A160203, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Roger De Spoelberch, Partridge Foundations, Jeanne et Jean Louis Levesque Foundation, 604102, Seventh Framework Programme, Canada Research Chairs, CRSII33-133044, SNSF Sinergia, 32003B_159780, SNSF National Centre of Competence in Research Synapsy, Foundation Parkinson Switzerland, Foundation Synapsis, Université de Lausanne = University of Lausanne (UNIL), CHU Sainte Justine [Montréal], Harvard University [Cambridge], Odense University Hospital (OUH), Department of radiology (Massachusetts General Hospital), Department of Psychiatry Massachusetts General Hospital (MGH), Columbia University [New York], Simons Foundation, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Gothenburg (GU), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vejle Hospital [Danemark], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Harvard University, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), University of Lausanne (UNIL), Centre de recherche du CHU Sainte-Justine [Montreal], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Human genetics, Institute of Microbial Technology (IMTECH), Intitute of Microbial Technology, Gillberg Neuropsychiatry Centre, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], PSL Research University (PSL)-PSL Research University (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique-Hôpital Chubert, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [APHP], Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Addor, M.C., Andrieux, J., Arveiler, B., Baujat, G., Sloan-Béna, F., Belfiore, M., Bonneau, D., Bouquillon, S., Boute, O., Brusco, A., Busa, T., Caberg, J.H., Campion, D., Colombert, V., Cordier, M.P., David, A., Debray, F.G., Delrue, M.A., Doco-Fenzy, M., Dunkhase-Heinl, U., Edery, P., Fagerberg, C., Faivre, L., Forzano, F., Genevieve, D., Gérard, M., Giachino, D., Guichet, A., Guillin, O., Héron, D., Isidor, B., Jacquette, A., Jaillard, S., Journel, H., Keren, B., Lacombe, D., Lebon, S., Le Caignec, C., Lemaître, M.P., Lespinasse, J., Mathieu-Dramart, M., Mercier, S., Mignot, C., Missirian, C., Petit, F., Pilekær Sørensen, K., Pinson, L., Plessis, G., Prieur, F., Rooryck-Thambo, C., Rossi, M., Sanlaville, D., Schlott Kristiansen, B., Schluth-Bolard, C., Till, M., Van Haelst, M., Van Maldergem, L., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, A.L., Benedetti, M., Berg, J., Berman, J., Berry, L.N., Bibb, A.L., Blaskey, L., Brennan, J., Brewton, C.M., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, A.G., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Olson, J.E., Evans, Y.L., Findlay, A., Fischbach, G.D., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, S.E., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, F.I., Jenkins, J., Jeremy, R.J., Johnson, K., Kanne, S.M., Kessler, S., Khan, S.Y., Ku, M., Kuschner, E., Laakman, A.L., Lam, P., Lasala, M.W., Lee, H., LaGuerre, K., Levy, S., Cavanagh, A.L., Llorens, A.V., Campe, K.L., Luks, T.L., Marco, E.J., Martin, S., Martin, A.J., Marzano, G., Masson, C., McGovern, K.E., McNally Keehn, R., Miller, D.T., Miller, F.K., Moss, T.J., Murray, R., Nagarajan, S.S., Nowell, K.P., Owen, J., Paal, A.M., Packer, A., Page, P.Z., Paul, B.M., Peters, A., Peterson, D., Poduri, A., Pojman, N.J., Porche, K., Proud, M.B., Qasmieh, S., Ramocki, M.B., Reilly, B., Roberts, TPL, Shaw, D., Sinha, T., Smith-Packard, B., Gallagher, A.S., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., and Wolken, A.

Subjects
Adult, Male, 0301 basic medicine, Adolescent, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Autism Spectrum Disorder/diagnostic imaging, Autism Spectrum Disorder/genetics, Brain/pathology, Child, Chromosome Deletion, Chromosome Duplication, Chromosomes, Human, Pair 16/genetics, Cognitive Dysfunction/diagnostic imaging, Cognitive Dysfunction/genetics, Female, Humans, Intellectual Disability/diagnostic imaging, Intellectual Disability/genetics, Language, Magnetic Resonance Imaging, Middle Aged, Neurodevelopmental Disorders/diagnostic imaging, Neurodevelopmental Disorders/genetics, Schizophrenia/diagnostic imaging, Schizophrenia/genetics, Young Adult, 16p11.2, Autism spectrum disorder, Copy number variant, Genetics, Imaging, Neurodevelopmental disorders, Biology, Biological Psychiatry, 03 medical and health sciences, 0302 clinical medicine, Transverse temporal gyrus, Neuroimaging, Intellectual Disability, medicine, Cognitive Dysfunction, Copy-number variation, ComputingMilieux_MISCELLANEOUS, Brain morphometry, Brain, medicine.disease, 16p112, 030104 developmental biology, Schizophrenia, Williams syndrome, Neuroscience, Insula, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery
Abstract

BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure.METHODS: Using voxel- and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV.RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion > control > duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion > control; Cohen's d > 1), the superior and middle temporal gyri (deletion < control; Cohen's d < -1), and the caudate and hippocampus (control > duplication; -0.5 > Cohen's d > -1). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results.CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria.

Published
2018
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12. Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

Author

Sumit Parikh, Charlotte A. Haaxma, Jacy L. Wagnon, James A. Hounshell, Timothy J. Moss, Manoj K. Patel, Bryan S. Barker, Miriam H. Meisler, Amy Shealy, and Ricka D. Messer

Subjects
0301 basic medicine, Genetics, Mutation, Transition (genetics), General Neuroscience, Protein subunit, Sodium channel, Biology, medicine.disease, medicine.disease_cause, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Dravet syndrome, medicine, Missense mutation, Neurology (clinical), Gene, 030217 neurology & neurosurgery, Exome sequencing, Research Articles, Research Article
Abstract

Contains fulltext : 168024.pdf (Publisher’s version ) (Open Access) OBJECTIVE: The early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558) results from de novo missense mutations of SCN8A encoding the voltage-gated sodium channel Nav1.6. More than 20% of patients have recurrent mutations in residues Arg1617 or Arg1872. Our goal was to determine the functional effects of these mutations on channel properties. METHODS: Clinical exome sequencing was carried out on patients with early-onset seizures, developmental delay, and cognitive impairment. Two mutations identified here, p.Arg1872Leu and p.Arg1872Gln, and two previously identified mutations, p.Arg1872Trp and p.Arg1617Gln, were introduced into Nav1.6 cDNA, and effects on electrophysiological properties were characterized in transfected ND7/23 cells. Interactions with FGF14, G-protein subunit Gbetagamma, and sodium channel subunit beta1 were assessed by coimmunoprecipitation. RESULTS: We identified two patients with the novel mutation p.Arg1872Leu and one patient with the recurrent mutation p.Arg1872Gln. The three mutations of Arg1872 and the mutation of Arg1617 all impaired the sodium channel transition from open state to inactivated state, resulting in channel hyperactivity. Other observed abnormalities contributing to elevated channel activity were increased persistent current, increased peak current density, hyperpolarizing shift in voltage dependence of activation, and depolarizing shift in steady-state inactivation. Protein interactions were not affected. INTERPRETATION: Recurrent mutations at Arg1617 and Arg1872 lead to elevated Nav1.6 channel activity by impairing channel inactivation. Channel hyperactivity is the major pathogenic mechanism for gain-of-function mutations of SCN8A. EIEE13 differs mechanistically from Dravet syndrome, which is caused by loss-of-function mutations of SCN1A. This distinction has important consequences for selection of antiepileptic drugs and the development of gene- and mutation-specific treatments.

Published
2015

13. Early onset and severe clinical course associated with the m.5540G>A mutation in MT - TW

Author

Jorge L. Granadillo, Timothy J. Moss, Jing Wang, Lee-Jun C. Wong, Richard A. Lewis, Howard Kelfer, Elise G. Austin, and Fernando Scaglia

Subjects
Proband, Mitochondrial DNA, Pediatrics, medicine.medical_specialty, Pathology, Ataxia, Epilepsy, Endocrinology, Ptosis, Genetics, Medicine, lcsh:QH301-705.5, Molecular Biology, lcsh:R5-920, Pigmentary retinopathy, business.industry, MT-TW gene, medicine.disease, MT-TW, Sensorineural hearing loss, lcsh:Biology (General), Mutation (genetic algorithm), medicine.symptom, lcsh:Medicine (General), business
Abstract

We report a patient harboring a de novo m.5540G>A mutation affecting the MT-TW gene coding for the mitochondrial tryptophan-transfer RNA. This patient presented with atonic–myoclonic epilepsy, bilateral sensorineural hearing loss, ataxia, motor regression, ptosis, and pigmentary retinopathy. Our proband had an earlier onset and more severe phenotype than the first reported patient harboring the same mutation. We discuss her clinical presentation and compare it with the only previously published case.

Published
2014
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14. Early childhood presentation of Czech dysplasia

Author

Alan E Schlesinger, Richard A. Gibbs, James T. Lu, Carlos A. Bacino, Philippe M. Campeau, Timothy J. Moss, Brendan Lee, Lindsay C. Burrage, and David S. Liu

Subjects
Pathology, medicine.medical_specialty, Pediatrics, Genetic counseling, Exosomes, Osteochondrodysplasias, Asymptomatic, Article, Pathology and Forensic Medicine, Rare Diseases, Skeletal disorder, medicine, Humans, Age of Onset, Family history, Collagen Type II, Genetics (clinical), Exome sequencing, business.industry, Brachydactyly, General Medicine, Toes, Hand, medicine.disease, Pedigree, Radiography, Child, Preschool, Mutation, Pediatrics, Perinatology and Child Health, Female, Anatomy, medicine.symptom, Age of onset, business, Rare disease
Abstract

Czech dysplasia, metatarsal type is an autosomal dominant skeletal disorder that is characterized by early-onset, progressive arthritis, brachydactyly of the 3rd and 4th toes, and characteristic radiographic findings in patients of normal stature. Patients with Czech dysplasia typically present in late childhood or later. In the present report, whole exome sequencing identified a mutation in COL2A1 (c.823C>T, p.R275C) known to be associated with Czech dysplasia in a 3.5 year old female who had a family history of early-onset arthritis and who was asymptomatic except for prominent knees. The use of whole exome sequencing facilitated diagnosis of this rare disease (less than 15 families in the literature) in the presymptomatic period and thus enabled us to provide early anticipatory guidance and genetic counseling for the family.

Published
2013
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15. Implementation of Clinical Pharmacogenomics within a Large Health System: From Electronic Health Record Decision Support to Consultation Services

Author

Maya Wai, Bret A. Lashner, Jeffrey J. Chalmers, Thomas M. Daly, Marc A. Willner, Scott Knoer, Steven M. Gordon, Angelika Erwin, Sumit Parikh, Kathryn Teng, Charis Eng, J. Kevin Hicks, Timothy J. Moss, Robert White, and David Stowe

Subjects
0301 basic medicine, medicine.medical_specialty, Decision support system, Pharmacist, 030226 pharmacology & pharmacy, Clinical decision support system, 03 medical and health sciences, Patient safety, 0302 clinical medicine, medicine, Electronic Health Records, Humans, Pharmacology (medical), Referral and Consultation, Genetic testing, medicine.diagnostic_test, business.industry, medicine.disease, Decision Support Systems, Clinical, 030104 developmental biology, Pharmacogenetics, Family medicine, Pharmacogenomics, Personalized medicine, Medical emergency, business, Patient education
Abstract

The number of clinically relevant gene-based guidelines and recommendations pertaining to drug prescribing continues to grow. Incorporating gene-drug interaction information into the drug-prescribing process can help optimize pharmacotherapy outcomes and improve patient safety. However, pharmacogenomic implementation barriers exist such as integration of pharmacogenomic results into electronic health records (EHRs), development and deployment of pharmacogenomic decision support tools to EHRs, and feasible models for establishing ambulatory pharmacogenomic clinics. We describe the development of pharmacist-managed pharmacogenomic services within a large health system. The Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B*57:01-abacavir, HLA-B*15:02-carbamazepine, and TPMT-thiopurines (i.e., azathioprine, mercaptopurine, and thioguanine) were systematically integrated into patient care. Sixty-three custom rules and alerts (20 for TPMT-thiopurines, 8 for HLA-B*57:01-abacavir, and 35 for HLA-B*15:02-anticonvulsants) were developed and deployed to the EHR for the purpose of providing point-of-care pharmacogenomic decision support. In addition, a pharmacist and physician-geneticist collaboration established a pharmacogenomics ambulatory clinic. This clinic provides genetic testing when warranted, result interpretation along with pharmacotherapy recommendations, and patient education. Our processes for developing these pharmacogenomic services and solutions for addressing implementation barriers are presented.

Published
2016

16. The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations

Author

Kwame Anyane-Yeboa, Juan M. Pascual, Ganka Douglas, Kristin G. Monaghan, Fuki M. Hisama, Frans P.M. Cremers, Timothy J. Moss, Laurence E. Walsh, Marwan Shinawi, Jill A. Rosenfeld, Elfrida Malkin, Jane Juusola, Keri Ramsey, Parul Jayakar, Fran Kendall, John Mann, Wendy K. Chung, Daniëlle G.M. Bosch, Christian P. Schaaf, Cheri Schoonveld, Dianalee McKnight, Chun-An Chen, Bert B.A. de Vries, Dmitriy Niyazov, Katelyn Payne, F. Nienke Boonstra, Magdalena Walkiewicz, Megan T. Cho, Richard A. Lewis, Frances Elmslie, Vivekanand Veluchamy, Chumei Li, Gabriele Richard, Allison Schreiber, and Francisca Millan

Subjects
Adult, Male, 0301 basic medicine, Nonsynonymous substitution, Adolescent, Autism Spectrum Disorder, Mutation, Missense, Biology, medicine.disease_cause, Corpus callosum, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 03 medical and health sciences, 0302 clinical medicine, Atrophy, medicine, Humans, Missense mutation, Child, Genetic Association Studies, Genetics (clinical), Genetics, Mutation, COUP Transcription Factor I, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Phenotype, Hypotonia, Pedigree, Optic Atrophy, 030104 developmental biology, Autism spectrum disorder, Child, Preschool, Female, medicine.symptom, Gene Deletion, 030217 neurology & neurosurgery
Abstract

Item does not contain fulltext PURPOSE: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy and intellectual disability caused by loss-of-function mutations in NR2F1. We report 20 new individuals with BBSOAS, exploring the spectrum of clinical phenotypes and assessing potential genotype-phenotype correlations. METHODS: Clinical features of individuals with pathogenic NR2F1 variants were evaluated by review of medical records. The functional relevance of coding nonsynonymous NR2F1 variants was assessed with a luciferase assay measuring the impact on transcriptional activity. The effects of two start codon variants on protein expression were evaluated by western blot analysis. RESULTS: We recruited 20 individuals with novel pathogenic NR2F1 variants (seven missense variants, five translation initiation variants, two frameshifting insertions/deletions, one nonframeshifting insertion/deletion, and five whole-gene deletions). All the missense variants were found to impair transcriptional activity. In addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%). CONCLUSION: BBSOAS encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype-phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes.Genet Med 18 11, 1143-1150.

Published
2016

17. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

Author

Laurent Pasquier, Anne V. Snow, David T. Miller, Louise Harewood, Christina Triantafallou, Timothy P.L. Roberts, Leighton B. Hinkley, Zili Chu, Louis Vallée, Alyss Lian Cavanagh, Evica Rajcan-Separovic, Patricia Blanchet, Fiona Miller, Robin P. Goin-Kochel, Beau Reilly, Bettina Cerban, Vanessa Siffredi, Bridget A. Fernandez, Roger Vaughan, Brianna M. Paul, Fanny Morice-Picard, Elisabeth Flori, Dominique Campion, Gérard Didelot, Anne Philippe, Christa Lese Martin, Srikantan S. Nagarajan, Joris Andrieux, Jacques Puechberty, Marie Pierre Cordier, Jill V. Hunter, Ellen van Binsbergen, Catherine Vincent-Delorme, Vivek Swarnakar, Jean Marie Cuisset, Monica Proud, Patrick Callier, Bert B.A. de Vries, Jeffrey I. Berman, Sarah J. Spence, Alexandra Bowe, Wendy K. Chung, Katy Ankenman, Katherine Hines, Sarah E. Gobuty, Philippe Jonveaux, Lisa Blaskey, Alice Goldenberg, Sylvie Jaillard, Alessandra Renieri, Anne M. Maillard, Tracy Luks, Lee Anne Green Snyder, Elliott H. Sherr, Sarah Y. Khan, Fabienne Prieur, Simon A. Zwolinski, Andres Metspalu, Ghislaine Plessis, Jean Chiesa, Rita J. Jeremy, Valérie Malan, Michèle Mathieu-Dramard, Loyse Hippolyte, Bethanny Smith-Packard, Andrea M. Paal, Bénédicte Duban Bedu, Claudine Rieubland, Jordan Burko, Sylvie Joriot, Philippe Conus, Dominique Bonneau, Benoit Arveiler, Nicole de Leeuw, Allison G. Dempsey, John E. Spiro, Julia Wenegrat, Bertrand Isidor, Cédric Le Caignec, Kyle J. Steinman, Bruno Delobel, Ashlie Llorens, Jacques S. Beckmann, Kelly Johnson, Sean Ackerman, Polina Bukshpun, Silvia Garza, Alexandre Reymond, Damien Sanlaville, Ellen Hanson, Martine Doco-Fenzy, Jacques Thonney, Mari Wakahiro, Juliane Hoyer, Jacqueline Vigneron, Katrin Õunap, Arthur L. Beaudet, Mandy Barker, Nicole Visyak, Sonia Bouquillon, W. Andrew Faucett, Raphael Bernier, Sudha Kilaru Kessler, Audrey Lynn Bibb, Dennis Shaw, R. Frank Kooy, Suzanne M E Lewis, Anna L. Laakman, Nicholas J. Pojman, Hubert Journel, Laura Bernardini, Arianne Stevens, Julia P. Owen, Rebecca Mc Nally Keehn, Stéphanie Selmoni, Sébastien Lebon, Aurélien Macé, Bruno Leheup, Saba Qasmieh, Zoltán Kutalik, Anita Rauch, Yiping Shen, Elysa J. Marco, Nathalie Van der Aa, Carina Ferrari, Noam D. Beckmann, Delphine Héron, Jennifer Tjernage, Benjamin Aaronson, Albert David, Marie Pierre Lemaitre, Muriel Holder, Eve Õiglane-Shlik, Anneke T. Vulto-van Silfhout, Flore Zufferey, Constance Atwell, Marta Benedetti, Ellen Grant, Jenna Elgin, Patricia Z. Page, Caroline Rooryck, Randy L. Buckner, Qixuan Chen, Laurence Faivre, Sébastien Jacquemont, Kerri P. Nowell, Florence Fellmann, Disciglio Vittoria, Katharina Magdalena Rötzer, Hana Lee, Alastair J. Martin, Marion Greenup, David H. Ledbetter, Katrin Männik, Morgan W. Lasala, Jennifer Gerdts, Hanalore Alupay, Florence Petit, Elizabeth Aylward, Gerald D. Fischbach, Mafalda Mucciolo, Maxwell Cheong, Gabriela Marzano, Frédérique Béna, Danielle Martinet, Timothy J. Moss, Odile Boute, Jennifer Olson, Marco Belfiore, Christina Fagerberg, Corby L. Dale, Robert M. Witwicki, Yolanda L. Evans, Melissa B. Ramocki, Marie-Claude Addor, Christèle Dubourg, Mariken Ruiter, Tuhin K. Sinha, Mieke M. van Haelst, Alan Packer, Kathleen E. McGovern, Christie M. Brewton, Stephen M. Kanne, Richard I. Fisher, Tracey Ward, Sophie Dupuis-Girod, Pratik Mukherjee, Simons VIP Consortium, 16p11.2 European Consortium, Addor, MC., Arveiler, B., Belfiore, M., Bena, F., Bernardini, L., Blanchet, P., Bonneau, D., Boute, O., Callier, P., Campion, D., Chiesa, J., Cordier, MP., Cuisset, JM., David, A., de Leeuw, N., de Vries, B., Didelot, G., Doco-Fenzy, M., Bedu, BD., Dubourg, C., Dupuis-Girod, S., Fagerberg, CR., Faivre, L., Fellmann, F., Fernandez, BA., Fisher, R., Flori, E., Goldenberg, A., Heron, D., Holder, M., Hoyer, J., Isidor, B., Jaillard, S., Jonveaux, P., Joriot, S., Journel, H., Kooy, F., le Caignec, C., Leheup, B., Lemaitre, MP., Lewis, S., Malan, V., Mathieu-Dramard, M., Metspalu, A., Morice-Picard, F., Mucciolo, M., Oiglane-Shlik, E., Ounap, K., Pasquier, L., Petit, F., Philippe, A., Plessis, G., Prieur, F., Puechberty, J., Rajcan-Separovic, E., Rauch, A., Renieri, A., Rieubland, C., Rooryck, C., Rötzer, KM., Ruiter, M., Sanlaville, D., Selmoni, S., Shen, Y., Siffredi, V., Thonney, J., Vallée, L., van Binsbergen, E., Van der Aa, N., van Haelst MM., Vigneron, J., Vincent-Delorme, C., Vittoria, D., Vulto-van Silfhout AT., Witwicki, RM., Zwolinski, SA., Bowe, A., Beaudet, AL., Brewton, CM., Chu, Z., Dempsey, AG., Evans, YL., Garza, S., Kanne, SM., Laakman, AL., Lasala, MW., Llorens, AV., Marzano, G., Moss, TJ., Nowell, KP., Proud, MB., Chen, Q., Vaughan, R., Berman, J., Blaskey, L., Hines, K., Kessler, S., Khan, SY., Qasmieh, S., Bibb, AL., Paal, AM., Page, PZ., Smith-Packard, B., Buckner, R., Burko, J., Cavanagh, AL., Cerban, B., Snow, AV., Snyder, LG., Keehn, RM., Miller, DT., Miller, FK., Olson, JE., Triantafallou, C., Visyak, N., Atwell, C., Benedetti, M., Fischbach, GD., Greenup, M., Packer, A., Bukshpun, P., Cheong, M., Dale, C., Gobuty, SE., Hinkley, L., Jeremy, RJ., Lee, H., Luks, TL., Marco, EJ., Martin, AJ., McGovern, KE., Nagarajan, SS., Owen, J., Paul, BM., Pojman, NJ., Sinha, T., Swarnakar, V., Wakahiro, M., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Elgin, J., Gerdts, J., Johnson, K., Reilly, B., Shaw, D., Stevens, A., Ward, T., Wenegrat, J., Other departments, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), CHU Pontchaillou [Rennes], Department of Medical Genetics, Université de Lausanne (UNIL), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Texas Children's Hospital [Houston, USA], Department of pediatrics, Primary palliative Care Research Group, Community Health Sciences, General Practice Section, University of Edinburgh, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developmental Brain and Behaviour Unit, University of Southampton, Institute of Molecular and Cell Biology, University of Tartu, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Lausanne = University of Lausanne (UNIL), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of California (UC)-University of California (UC)-Semel Institute, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Kooy, Frank

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Heterozygote, Adolescent, [SDV]Life Sciences [q-bio], Developmental Disabilities, Biology, Body Mass Index, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene Order, Genetics, medicine, Humans, Copy-number variation, Clinical genetics, Obesity, Young adult, Child, Genetics (clinical), 030304 developmental biology, Child Development Disorders, Pervasive/diagnosis, Child Development Disorders, Pervasive/genetics, Chromosome Deletion, Chromosomes, Human, Pair 16, Developmental Disabilities/diagnosis, Developmental Disabilities/genetics, Female, Intelligence Tests, Phenotype, Syndrome, 2. Zero hunger, Psychiatry, 0303 health sciences, Intelligence quotient, Neuropsychology, Complex traits, medicine.disease, Comorbidity, 3. Good health, Autism spectrum disorder, Child Development Disorders, Pervasive, Autism, Medical genetics, Human medicine, Copy-Number Variation, 030217 neurology & neurosurgery
Abstract

Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Published
2012
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19. Connections between epigenetic gene silencing and human disease

Author

Timothy J. Moss and Lori L. Wallrath

Subjects
Chromosomal Proteins, Non-Histone, Health, Toxicology and Mutagenesis, Biology, Models, Biological, Article, Epigenesis, Genetic, Histones, Epigenetics of physical exercise, Histone methylation, Genetics, Animals, Humans, Histone code, DNA (Cytosine-5-)-Methyltransferases, Gene Silencing, Cancer epigenetics, Epigenetics, Molecular Biology, Epigenomics, Models, Genetic, EZH2, Methyltransferases, DNA Methylation, Chromatin, Repressor Proteins, Chromobox Protein Homolog 5, Histone methyltransferase, Mutation
Abstract

Alterations in epigenetic gene regulation are associated with human disease. Here, we discuss connections between DNA methylation and histone methylation, providing examples in which defects in these processes are linked with disease. Mutations in genes encoding DNA methyltransferases and proteins that bind methylated cytosine residues cause changes in gene expression and alterations in the patterns of DNA methylation. These changes are associated with cancer and congenital diseases due to defects in imprinting. Gene silencing is also controlled through histone methylation. Altered levels of methyltransferases that modify lysine 27 of histone H3 (K27H3) and lysine 9 of histone H3 (K9H3) correlate with changes in Rb signaling and disruption of the cell cycle in cancer cells. The K27H3 mark recruits a Polycomb complex that is involved in regulating stem cell pluripotency, silencing of developmentally regulated genes, and controlling cancer progression. The K9H3 methyl mark recruits HP1, a structural protein that plays a role in heterochromatin formation, gene silencing, and viral latency. Cells exhibiting altered levels of HP1 are predicted to show a loss of silencing at genes regulating cancer progression. Gene silencing through K27H3 and K9H3 can involve histone deacetylation and DNA methylation, suggesting cross talk between epigenetic silencing systems through direct interactions among the various players. The reversible nature of these epigenetic modifications offers therapeutic possibilities for a wide spectrum of disease.

Published
2007
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20. De novo mutations in PURA are associated with hypotonia and developmental delay

Author

Kwame Anyane-Yeboa, Jane Juusola, Monica Nardini, Priyanka Ahimaz, Kyle Retterer, Fran Kendall, Mislen Bauer, Wendy K. Chung, Beverly N. Hay, Megan T. Cho, Renkui Bai, Akemi J. Tanaka, Ashley Wilson, and Timothy J. Moss

Subjects
Genetics, Research Report, Candidate gene, Messenger RNA, fungi, Translation (biology), General Medicine, Central hypotonia, Microdeletion syndrome, Biology, generalized tonic seizures, Phenotype, Hypotonia, medicine, medicine.symptom, central hypotonia, severe global developmental delay, De novo mutations, generalized clonic seizures
Abstract

PURA is the leading candidate gene responsible for the developmental phenotype in the 5q31.3 microdeletion syndrome. De novo mutations in PURA were recently reported in 15 individuals with developmental features similar to the 5q31.3 microdeletion syndrome. Here we describe six unrelated children who were identified by clinical whole-exome sequencing (WES) to have novel de novo variants in PURA with a similar phenotype of hypotonia and developmental delay and frequently associated with seizures. The protein Purα (encoded by PURA) is involved in neuronal proliferation, dendrite maturation, and the transport of mRNA to translation sites during neuronal development. Mutations in PURA may alter normal brain development and impair neuronal function, leading to developmental delay and the seizures observed in patients with mutations in PURA.

Published
2015

21. Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome

Author

Fan Xia, Ieva Eglite, Michael F. Wangler, Frank J. Probst, Claudia Gonzaga-Jauregui, James R. Lupski, Austin Larson, Carlos A. Bacino, Timothy J. Moss, Dustin Baldridge, Arthur L. Beaudet, Efrat Lev Lehman, Jeffrey L. Neul, Yaping Yang, Joke Beuten, Richard A. Gibbs, Shalini N. Jhangiani, Tomasz Gambin, Samantha Penney, Donna M. Muzny, Steven L. Werlin, Liene Kornejeva, and Atul R. Chopra

Subjects
Male, Cancer Research, medicine.disease_cause, 0302 clinical medicine, Medicine and Health Sciences, Missense mutation, Exome, Child, Genetics (clinical), Genetics, 0303 health sciences, Mutation, Gastrointestinal Motility Disorders, Genomics, 3. Good health, Child, Preschool, 030220 oncology & carcinogenesis, Pediatric Gastroenterology, Female, Research Article, Adult, Intestinal pseudo-obstruction, Heterozygote, Adolescent, lcsh:QH426-470, Colon, Urinary Bladder, Nonsense mutation, Gastroenterology and Hepatology, Biology, 03 medical and health sciences, medicine, Humans, Abnormalities, Multiple, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Actin, 030304 developmental biology, Clinical Genetics, Intestinal Pseudo-Obstruction, Biology and Life Sciences, Muscle, Smooth, Megacystis, Microcolon, medicine.disease, Actins, lcsh:Genetics
Abstract

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon's initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous ACTG2 missense variants in 15 unrelated subjects, ten being apparent de novo mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent de novo mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that ACTG2 is responsible for a spectrum of smooth muscle disease. ACTG2 encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease., Author Summary In 1976, a radiologist, Walter Berdon described a group of patients with a rare intestinal and bladder disorder in which the smooth muscle of those organs failed to contract. These patients are unable to digest food, require multiple abdominal surgeries and are diagnosed with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). Since the description of MMIHS, the genes that cause it have remained a mystery. We followed and obtained DNA from patients with this disorder over a period of over 14 years and assembled a large group of cases. We used whole-exome sequencing, a powerful tool used to identify disease genes, and found mutations in ACTG2, a visceral actin gene. Actins are components of muscle contractile units, and one Finnish family has been previously found with less severe gastrointestinal problems due to mutations in this gene. In our patients, we find de novo mutations in the majority of cases of MMIHS. However, we also find families with the disease over several generations due to these same mutations. This work provides the first disease gene for MMIHS, and suggests new treatment options.

Published
2014

22. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism

Author

Stephen Sanders, Rui Luo, Patrícia B. S. Celestino-Soper, Frédéric M. Vaz, Ronald J.A. Wanders, Anath C. Lionel, Robin P. Goin-Kochel, Edwin H. Cook, Richard J. Schroer, Arthur L. Beaudet, Roger E. Stevenson, Peter Szatmari, Richard E. Person, Marwan Shinawi, Stephen W. Scherer, Suzanne M. Leal, Kwanghyuk Lee, Ni Huang, Sara Violante, Guiqing Cai, Catalina Betancur, Bekim Sadikovic, Wendy Roberts, Kun Gao, Diane Treadwell-Deering, Daniel H. Geschwind, Chad A. Shaw, Joseph D. Buxbaum, Timothy J. Moss, Bridget A. Fernandez, Elsa Delaby, Emily L. Crawford, Charlene Lo, James S. Sutcliffe, Matthew E. Hurles, Jennifer R. German, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Laboratory Genetic Metabolic Disease, University of Amsterdam [Amsterdam] (UvA)-Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Metabolism and Genetics Group, Universidade de Lisboa (ULISBOA)-Research Institute for Medicines and Pharmaceutical Sciences, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), Department of Neurology, Johns Hopkins University (JHU), Texas Children's Hospital [Houston, USA], Department of psychiatry, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Disciplines of Genetics and Medicine, Memorial University of Newfoundland [St. John's], The Greenwood Genetic Center, Departments of Psychiatry and Genetics, Yale University School of Medicine, Department of Psychiatry, Institute for Juvenile Research-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of pediatrics, The AGRE is a program of Autism Speaks and is supported, in part, by Grant 1U24MH081810 from the National Institute of Mental Health (to Clara M. Lajonchere). Part of this work was supported by Grant SFARI 124827 from the Simons Foundation (to the investigators of the SSC Genetic Consortium) and Grant HD-37283 (to A.L.B) and Grant P30HD-0240640 from the National Institutes of Health. Part of this work was financially supported by the Fundação para a Ciência e Tecnologia, Lisbon, Portugal, by Grant SFRH/BD/38074/2007 (to. S.V.). Part of this work was supported by National Institutes of Health Grants R01 MH061009 and R01 NS049261 (to J.S.S.). Funding for part of this work was provided by the Wellcome Trust under Award 076113 and by Grant 077014/Z/05/Z. Funding for the Paris Autism Research International Sibpair study was provided, in part, by the Institut National de la Santé et de la Recherche Médicale, Fondation de France, Fondation Orange, Fondation pour la Recherche Médicale, Assistance Publique- Hôpitaux de Paris, and the Swedish Science Council., Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Universidade de Lisboa = University of Lisbon (ULISBOA)-Research Institute for Medicines and Pharmaceutical Sciences, University of California (UC)-University of California (UC)-Semel Institute, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Yale School of Medicine [New Haven, Connecticut] (YSM), AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, Betancur, Catalina, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Mazalérat, Charlotte

Subjects
Male, Proband, Penetrance, MESH: Cognition, [SDV.GEN] Life Sciences [q-bio]/Genetics, Mixed Function Oxygenases, Cognition, 0302 clinical medicine, Genes, X-Linked, Risk Factors, MESH: Penetrance, MESH: Risk Factors, Heritability of autism, X chromosome, Genetics, 0303 health sciences, Multidisciplinary, MESH: Carnitine, Exons, Biological Sciences, MESH: Mixed Function Oxygenases, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.drug, MESH: Metabolism, Inborn Errors, TMLHE, MESH: Autistic Disorder, Biology, MESH: Chromosomes, Human, X, 03 medical and health sciences, Carnitine, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Autistic Disorder, 030304 developmental biology, Chromosomes, Human, X, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Siblings, medicine.disease, MESH: Male, MESH: Siblings, MESH: Genes, X-Linked, MESH: Gene Deletion, Carnitine biosynthesis, Autism, MESH: Exons, Gene Deletion, Metabolism, Inborn Errors, 030217 neurology & neurosurgery
Abstract

We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon ( TMLHE ) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6- N -trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6- N -trimethyllysine) and decreased product levels (3-hydroxy-6- N -trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2–4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.

Published
2012
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23. A requirement for dimerization of HP1Hsalpha in suppression of breast cancer invasion

Author

Dawn A. Kirschmann, Lindsay Wright, Laura E. Norwood, Timothy J. Moss, Elisabeth A. Seftor, Sara L. Cook, Naira V. Margaryan, Lori L. Wallrath, and Mary J.C. Hendrix

Subjects
Chromosomal Proteins, Non-Histone, Mutant, Breast Neoplasms, Biology, Biochemistry, Chromodomain, Histone H3, Structure-Activity Relationship, Cell Line, Tumor, medicine, Humans, Neoplasm Invasiveness, Molecular Biology, Regulation of gene expression, Wild type, Cancer, Cell Biology, medicine.disease, Molecular biology, Chromatin, Cell biology, Protein Structure, Tertiary, Gene Expression Regulation, Neoplastic, Chromobox Protein Homolog 5, Heterochromatin protein 1, Female, Dimerization
Abstract

The development and progression of cancer is controlled by gene expression, often regulated through chromatin packaging. Heterochromatin protein 1(Hsalpha) (HP1(Hsalpha)), one of three human HP1 family members, participates in heterochromatin formation and gene regulation. HP1(Hsalpha) possesses an amino-terminal chromodomain, which binds methylated lysine 9 of histone H3 (meK9 H3), and a carboxyl-terminal chromoshadow domain (CSD) that is required for dimerization and interaction with partner proteins. HP1(Hsalpha) is down-regulated in invasive metastatic breast cancer cells compared with poorly invasive nonmetastatic breast cancer cells. Expression of EGFP-HP1(Hsalpha) in highly invasive MDA-MB-231 cells causes a reduction in in vitro invasion, without affecting cell growth. Conversely, knock-down of HP1(Hsalpha) levels in the poorly invasive breast cancer cell line MCF-7 increased invasion, without affecting cell growth. To determine whether functions of the CSD were required for the regulation of invasion, mutant forms of HP1(Hsalpha) were expressed in MDA-MB-231 cells. A W174A mutation that disrupts interactions between HP1(Hsalpha) and PXVXL-containing partner proteins reduced invasion similar to that of the wild type protein. In contrast, an I165E mutation that disrupts dimerization of HP1(Hsalpha) did not decrease invasion. No gross changes in localization and abundance of HP1(Hsbeta), HP1(Hsgamma), and meK9 H3 were observed upon expression of wild type and mutant forms of HP1(Hsalpha) in MDA-MB-231 cells. Taken together, these data demonstrate that modulation of HP1(Hsalpha) alters the invasive potential of breast cancer cells through mechanisms requiring HP1 dimerization, but not interactions with PXVXL-containing proteins.

Published
2006

24. Litter fall beneath Rhizophora stylosa griff., Vaitupu, Tuvalu, South Pacific

Author

Colin D. Woodroffe and Timothy J. Moss

Subjects
Litter fall, Ecology, ved/biology, ved/biology.organism_classification_rank.species, Rhizophoraceae, Plant Science, Rhizophora stylosa, Aquatic Science, Biology, biology.organism_classification, Rhizophora, Stipule, Agronomy, Dry weight, Litter, Mangrove
Abstract

A total dry weight of litter fall of 2423 g was collected beneath a restricted stand of the mangrove, Rhizophora stylosa Griff., 4–6 m tall, on Vaitupu, Tuvalu, over a period of 64 weeks. Leaves comprised 84% of this total, stipules 13% and reproductive parts and twigs 2 and 1%, respectively. The average annual litter fall rate was 777 ± 93 g dry wt./m 2 /year, which is similar to rates observed in mangroves elsewhere. Litter fall rates were lowest in July and August, but seasonal trends were not pronounced. In terms of litter production, inland mangrove stands of low stature on Pacific Islands can be as productive per unit area as mangrove communities in more diverse and more extensive swamplands.

Published
1984
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25. Human amnion epithelial cells modulate the inflammatory response to ventilation in preterm lambs.

Author

Jacqueline M Melville, Courtney A McDonald, Robert J Bischof, Graeme R Polglase, Rebecca Lim, Euan M Wallace, Graham Jenkin, and Timothy J Moss

Subjects
Medicine, Science
Abstract

Ventilation of preterm neonates causes pulmonary inflammation that can contribute to lung injury, propagate systemically and result in long-term disease. Modulation of this initial response may reduce lung injury and its sequelae. We aimed to determine the effect of human amnion epithelial cells (hAECs) on immune activation and lung injury in preterm neonatal lambs. Preterm lambs received intratracheal hAECs (90x106) or vehicle, prior to 2 h of mechanical ventilation. Within 5 min of ventilation onset, lambs also received intravenous hAECs (90x106) or vehicle. Lung histology, bronchoalveolar lavage (BAL) cell phenotypes, and cytokine profiles were examined after 2 h of ventilation, and in unventilated controls. Histological indices of lung injury were higher than control, in vehicle-treated ventilated lambs but not in hAEC-treated ventilated lambs. Ventilation-induced pulmonary leukocyte recruitment was greater in hAEC-treated lambs than in vehicle-treated lambs. Lung IL-1β and IL-6 mRNA expression was higher in vehicle- and hAEC-treated ventilated lambs than in controls but IL-8 mRNA levels were greater than control only in vehicle-treated ventilated lambs. Numbers of CD44+ and CD21+ lymphocytes and macrophages from the lungs were altered in vehicle- and hAEC-treated ventilated lambs. Numbers of CD8+ macrophages were lower in hAEC-treated ventilated lambs than in vehicle-treated ventilated lambs. Indices of systemic inflammation were not different between vehicle- and hAEC-treated lambs. Human amnion epithelial cells modulate the pulmonary inflammatory response to ventilation in preterm lambs, and reduce acute lung injury. Immunomodulatory effects of hAECs reduce lung injury in preterm neonates and may protect against longer-term respiratory disease.

Published
2017
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