title: De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.
abstract: The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Ambry Genetics, Aliso Viejo, CA 92656, USA.
authors.forename: Deepali N
authors.initials: DN
authors.lastname: Shinde
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
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authors.affiliation: Department of Biological Sciences, California State University, Chico, Chico, CA 95929, USA.
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authors.affiliation: Department of Biological Sciences, California State University, Chico, Chico, CA 95929, USA.
authors.forename: Gregory R
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authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
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authors.initials: DGM
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authors.affiliation: Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA.
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authors.lastname: Petrovski
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors.forename: Joshua K
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authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors.forename: Eun Young
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authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
authors.forename: Joris A
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authors.affiliation: Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
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authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
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authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
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authors.initials: TM
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authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
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authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
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authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
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authors.affiliation: Department of Biological Sciences, California State University, Chico, Chico, CA 95929, USA.
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authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: lisenka.vissers@radboudumc.nl.
authors.forename: Lisenka E L M
authors.initials: LELM
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authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA. Electronic address: eahn@health.southalabama.edu.
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mesh_terms: D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D002658:Developmental Disabilities / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005124:Eye Abnormalities / Q000235:genetics; D005260:Female; D020043:Genes, Essential / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics; D006257:Head / Q000002:abnormalities; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics / Q000378:metabolism; D015778:Minor Histocompatibility Antigens / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D013131:Spine / Q000002:abnormalities; D013577:Syndrome; D015027:Zebrafish / Q000002:abnormalities / Q000196:embryology / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; C088203:SON protein, human