De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome
| Autor: | Ssang-Taek Lim, Helger G. Yntema, Tara Funari, Alexander P.A. Stegmann, Daniel G. MacArthur, Jung-Hyun Kim, Bert B.A. de Vries, Alyson Krokosky, Joost Nicolai, Sha Tang, Serge Romana, Megan T. Cho, Joris A. Veltman, Berivan Baskin, Vandana Shashi, Clesson Turner, Deepali N. Shinde, Maja Hempel, Franco Laccone, Lisenka E.L.M. Vissers, Richard M. Myers, Grazia M.S. Mancini, Daniëlle G.M. Bosch, Eun-Young Erin Ahn, Tamison Jewett, Ganka Douglas, Margot R.F. Reijnders, Eun Young Park, Axel Neu, Dong-Er Zhang, Joshua K. Stone, Davor Lessel, Connie T.R.M. Stumpel, Helga Rehder, Christopher T. Gordon, Luis Rohena, Laurie B. Owen, Dima El-Khechen, Jana Behunova, Tim M. Strom, Julie Vogt, Andrea H. Seeley, Kirsty McWalter, Nuria C. Bramswig, Margje Sinnema, Marlène Rio, Natalie Hauser, Rebecca L. Belmonte, Servi J. C. Stevens, Kristin Lindstrom, Han G. Brunner, Fanny Kortüm, Kelly Schoch, Amber Begtrup, Kristine K. Bachman, Paula A. Bubulya, Stephanie L. Santoro, Jos M. T. Draaisma, Dagmar Wieczorek, Xu Yao, David L. Stachura, Slavé Petrovski, Gregory R. Wilson, David Traver |
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| Přispěvatelé: | Clinical Genetics, Genetica & Celbiologie, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Pat Cytologie (9), MUMC+: DA Klinische Genetica (5) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Developmental Disabilities Medizin Haploinsufficiency Bioinformatics Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] 0302 clinical medicine Intellectual disability FLNA Genetics(clinical) Eye Abnormalities Zebrafish Genetics (clinical) Genetics Gene knockdown Genes Essential biology Brain Syndrome Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] Pedigree DNA-Binding Proteins RNA splicing Female Heterozygote RNA Splicing Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18] Minor Histocompatibility Antigens 03 medical and health sciences Metabolic Diseases Intellectual Disability Report medicine Animals Humans RNA Messenger Gene Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] RNA medicine.disease biology.organism_classification Spine 030104 developmental biology Mutation Head 030217 neurology & neurosurgery |
| Zdroj: | American Journal of Human Genetics, 99, 711-9 American Journal of Human Genetics, 99, 3, pp. 711-9 Am. J. Hum. Genet. 99, 711-719 (2016) American Journal of Human Genetics, 99(3), 711-719. Cell Press |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2016.06.029 |
| Popis: | Contains fulltext : 167701.pdf (Publisher’s version ) (Open Access) 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. |
| Databáze: | OpenAIRE |
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