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De novo variants in the PABP domain of PABPC1 lead to developmental delay
Authors:Meret Wegler  Xiangbin Jia  Marielle Alders  Arjan Bouman  Jia Chen  Xinyu Duan  Julie L. Lauzon  Inge B. Mathijssen  Heinrich Sticht  Steffen Syrbe  Senwei Tan  Hui Guo  Rami Abou Jamra
Affiliation:1. Institute of Human Genetics, University Medical Center, Leipzig, Germany;2. Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China;3. Department of Human Genetics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands;4. Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands;5. Department of Pediatrics, Daping Hospital, Army Medical University, Chongqing, China;6. Department of Medical Genetics, Cummings School of Medicine, University of Calgary, Alberta Children''s Hospital, Alberta, Canada;7. Institute of Biochemistry, Medical Faculty, Friedrich-Alexander-Universität Erlangen-Nürnberg; Erlangen, Germany;8. Division of Pediatric Epileptology, Centre for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany;1. Kaiser Permanente Center for Health Research, Portland, OR;2. Division of Medical Genetics, Department of Medicine, University of Washington Medical Center, Seattle, WA;3. Treuman Katz Center for Pediatric Bioethics, Seattle Children’s Research Institute, Seattle, WA;4. Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, Portland, OR;5. Genetics, Bioinformatics and Translation, RTI International, Washington, D.C.;6. Division of Bioethics and Palliative Care, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA;1. Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;3. Faculty of Health Sciences, Ben Gurion University of the Negev, Be’er Sheva, Israel;4. Genetic Institute, Soroka University Medical Center, Be’er Sheva, Israel;5. Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;1. Department of Clinical Genomics, Mayo Clinic, Rochester, MN;2. Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium;3. Metabolomics Expertise Center, Center for Cancer Biology, VIB-KU Leuven, Leuven, Belgium;4. Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium;5. Division of Metabolism, Department of Pediatrics Specialties, Bambino Gesù Children’s Research Hospital, Rome, Italy;6. Medical Genetics Unit, Bambino Gesù Children Hospital IRCCS, Rome, Italy;7. Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital IRCCS, Rome, Italy;8. Metabolic Center, University Hospitals Leuven, Leuven, Belgium;9. Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium;10. Department of Medical Genetics, Medical School, University of Pécs, Pecs, Hungary;1. Department of Health and Kinesiology, Texas A&M University, College Station, TX;2. College of Nursing, Texas A&M University, College Station, TX;3. Department of Nutrition, Texas A&M University, College Station, TX;4. School of Public Health, Texas A&M University, College Station, TX;5. Jeb E. Brooks School of Public Policy, Cornell University, Ithaca, NY;6. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;7. College of Nursing, Texas A&M University, McAllen, TX;1. Department of Human Genetics, The University of Chicago, Chicago, IL;2. Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC) and Instituto de Inovação e Investigação em Saúde, University of Porto, Porto, Portugal;3. Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children’s Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA;4. Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada;5. Center for Applied Genomics, The Joseph Stokes Jr Research Institute, The Children''s Hospital of Philadelphia, Philadelphia, PA;6. Mitochondrial Medicine Frontier Program, Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA;7. Department of Pediatrics, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;8. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark;9. Medical Genetics, Helen DeVos Children’s Hospital, Grand Rapids, MI;10. Neurolipid Biology, Instituto de Inovação e Investigação em Saúde, and Instituto de Biologia Molecular e Celular (IBMC), University of Porto, Porto, Portugal;11. Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT;12. The Neuroscience Institute, The University of Chicago, Chicago, IL;1. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands;2. Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, The Netherlands;3. Department of Histo-Embryology and Cytogenetics, Necker-Enfants Malades Hospital, AP-HP, Paris, France;4. National Institute of Health and Medical Research (INSERM), University of Paris, Imagine Institute, Paris, France;5. Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of North Carolina School of Medicine, Chapel Hill, NC;6. Department of Molecular Genetics and Genomics, Rennes University Hospital Center (CHU), Rennes, France;7. Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France;8. Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA;9. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA;10. Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia;11. Paediatric and Reproductive Genetics Unit, Women''s and Children''s Hospital, North Adelaide, South Australia, Australia;12. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia;13. Department of Pediatrics, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX;14. Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children''s Hospital and Research Institute, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy;15. Service de Génétique Médicale, Hôpital de la Timone, APHM, Marseille, France; Department of Medical Genetics, Timone Hospital, APHM, Marseille, France;16. Australian Genomics, Parkville, Victoria, Australia;17. Medical Genetics, University of Siena, Siena, Italy;18. Medical Genetics Lab, Bambino Gesù Children''s Hospital and Research Institute, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy;19. The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada;20. Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;21. Department of Clinical and Molecular Genetics, Vall d''Hebron Barcelona Hospital Campus, Barcelona, Spain;22. Department of Pediatrics, University of Washington, Seattle, WA;23. Center for Integrative Brain Research, Seattle Children''s Research Institute, Seattle, WA;24. Department of Children and Adolescents, University Hospital Rigshospitalet, Copenhagen, Denmark;25. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;26. Aix Marseille University, INSERM, Marseille Medical Genetics, U 1251, Marseille, France;27. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark;28. Pediatrics and Adolescent Medicine, Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark;29. Division of Genetic & Genomic Medicine, Nationwide Children''s Hospital, Columbus, OH;30. Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH;31. Inserm UMR 1231 GAD, Genetics of Developmental Anomalies, F21000 Dijon, France;32. Functional Unit of F?tal Pathology, Pathological Anatomy Department, CHR Orleans, Orleans, France;33. Unit of Fetal Pathology, Antoine Beclere Hospital, AP-HP, Clamart, France;34. Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA;35. Department of Pathology, CHU Charles Nicolle, Rouen, France;36. Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany;37. Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, Hospital La Paz Institute for Health Research, Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain;38. Department of Neuropaediatrics, Charité - Berlin University of Medicine, Berlin, Germany;39. Reference Center for Rare Diseases, « Intellectual Disabilities from rare causes », CHU Dijon Bourgogne, F21000 Dijon, France;40. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands;41. Department of Medical Genetics, University of British Columbia, Children''s and Women''s Hospital, Vancouver, British Columbia, Canada;42. ACRF Cancer Genomics Facility, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia;43. Howard Hughes Medical Institute, University of Washington, Seattle, WA;44. Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;45. Institute for Genomic Medicine, Columbia University Medical Center, New York, NY;46. Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Vagelos Medical Center, New York, NY;47. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;48. Baylor Genetics Laboratories, Houston, TX;49. Department of Obstetrics and Fetal Medicine, Leiden University Medical Center, Leiden, Netherlands
Abstract:PurposeThe study aimed to investigate the role of PABPC1 in developmental delay (DD).MethodsChildren were examined by geneticists and pediatricians. Variants were identified using exome sequencing and standard downstream bioinformatics pipelines. We performed in silico molecular modeling and coimmunoprecipitation to test if the variants affect the interaction between PABPC1 and PAIP2. We performed in utero electroporation of mouse embryo brains to enlighten the function of PABPC1.ResultsWe describe 4 probands with an overlapping phenotype of DD, expressive speech delay, and autistic features and heterozygous de novo variants that cluster in the PABP domain of PABPC1. Further symptoms were seizures and behavioral disorders. Molecular modeling predicted that the variants are pathogenic and would lead to decreased binding affinity to messenger RNA metabolism-related proteins, such as PAIP2. Coimmunoprecipitation confirmed this because it showed a significant weakening of the interaction between mutant PABPC1 and PAIP2. Electroporation of mouse embryo brains showed that Pabpc1 knockdown decreases the proliferation of neural progenitor cells. Wild-type Pabpc1 could rescue this disturbance, whereas 3 of the 4 variants did not.ConclusionPathogenic variants in the PABP domain lead to DD, possibly because of interference with the translation initiation and subsequently an impaired neurogenesis in cortical development.
Keywords:Epilepsy  Exome  Intellectual disability  Neural progenitor cells  Neurodevelopmental disorder
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