university website

Kim, J.-H. (Jung-Hyun), Shinde, D.N. (Deepali N.), M.R.F. Reijnders (Margot R.F.), Hauser, N.S. (Natalie S.), Belmonte, R.L. (Rebecca L.), Wilson, G.R. (Gregory R.), Bosch, D.G.M. (Daniëlle G.M.), Bubulya, P.A. (Paula A.), V. Shashi (Vandana), Petrovski, S. (Slavé), et al. Stone, J.K. (Joshua K.), Park, E.Y. (Eun Young), J.A. Veltman (Joris), Sinnema, M. (Margje), C. Stumpel (Connie), J. Draaisma (Jos), J. Nicolai (Joost), H.G. Yntema, Lindstrom, K. (Kristin), B. de Vries (Boukje), Jewett, T. (Tamison), Santoro, S.L. (Stephanie L.), J. Vogt (Julie), Bachman, K.K. (Kristine K.), Seeley, A.H. (Andrea ), Krokosky, A. (Alyson), Turner, C. (Clesson), Rohena, L. (Luis), Hempel, M. (Maja), Kortüm, F. (Fanny), Lessel, D. (Davor), Neu, A. (Axel), T.M. Strom (Tim), D. Wieczorek (Dagmar), Bramswig, N. (Nuria), Laccone, F.A. (Franco A.), Behunova, J. (Jana), Rehder, H. (Helga), Gordon, C.T. (Christopher T.), M. Rio (Marlène), Romana, S. (Serge), Tang, S. (Sha), El-Khechen, D. (Dima), M.T. Cho (Megan T.), McWalter, K. (Kirsty), Douglas, G. (Ganka), Baskin, B. (Berivan), Begtrup, A. (Amber), Funari, T. (Tara), Schoch, K. (Kelly), Stegmann, A.P.A. (Alexander P.A.), S.J. Stevens, Zhang, D.-E. (Dong-Er), Traver, D. (David), Yao, X. (Xu), D.G. MacArthur (Daniel G.), H.G. Brunner, G.M.S. Mancini (Grazia), R.H. Myers (Richard), Owen, L.B. (Laurie B.), Lim, S.-T. (Ssang-Taek), Stachura, D.L. (David L.), L.E.L.M. Vissers and Ahn, E.-Y.E. (Eun-Young Erin)

2016-05-04

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

Publication

Publication

American Journal of Human Genetics

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.

Additional Metadata
Persistent URL doi.org/10.1016/j.ajhg.2016.06.029, hdl.handle.net/1765/95565
Journal American Journal of Human Genetics
Organisation Department of Clinical Genetics
Citation
Kim, J.-H. (Jung-Hyun), Shinde, D.N. (Deepali N.), Reijnders, M. R. F., Hauser, N.S. (Natalie S.), Belmonte, R.L. (Rebecca L.), Wilson, G.R. (Gregory R.), … Ahn, E.-Y.E. (Eun-Young Erin). (2016). De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome. American Journal of Human Genetics. doi:10.1016/j.ajhg.2016.06.029
Free Full Text (Manuscript at PubMed Central)


User Publication Person Organisation Collection
Close