De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.

TitleDe Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.
Publication TypeJournal Article
Year of Publication2016
AuthorsKim, J-H, Shinde, DN, Reijnders, MRF, Hauser, NS, Belmonte, RL, Wilson, GR, Bosch, DGM, Bubulya, PA, Shashi, V, Petrovski, S, Stone, JK, Park, EYoung, Veltman, JA, Sinnema, M, Stumpel, CTRM, Draaisma, JM, Nicolai, J, Yntema, HG, Lindstrom, K, de Vries, BBA, Jewett, T, Santoro, SL, Vogt, J, Bachman, KK, Seeley, AH, Krokosky, A, Turner, C, Rohena, L, Hempel, M, Kortüm, F, Lessel, D, Neu, A, Strom, TM, Wieczorek, D, Bramswig, N, Laccone, FA, Behunova, J, Rehder, H, Gordon, CT, Rio, M, Romana, S, Tang, S, El-Khechen, D, Cho, MT, McWalter, K, Douglas, G, Baskin, B, Begtrup, A, Funari, T, Schoch, K, Stegmann, APA, Stevens, SJC, Zhang, D-E, Traver, D, Yao, X, MacArthur, DG, Brunner, HG, Mancini, GM, Myers, RM, Owen, LB, Lim, S-T, Stachura, DL, Vissers, LELM, Ahn, E-YErin
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics, Deciphering Developmental Disorders Study
JournalAm J Hum Genet
Date Published2016 09 01
KeywordsAnimals, Brain, Developmental Disabilities, DNA-Binding Proteins, Eye Abnormalities, Female, Genes, Essential, Haploinsufficiency, Head, Heterozygote, Humans, Intellectual Disability, Male, Metabolic Diseases, Minor Histocompatibility Antigens, Mutation, Pedigree, RNA Splicing, RNA, Messenger, Spine, Syndrome, Zebrafish

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID27545680
PubMed Central IDPMC5011044
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
R21 CA185818 / CA / NCI NIH HHS / United States
R15 GM084407 / GM / NIGMS NIH HHS / United States
R01 CA190688 / CA / NCI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States