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

Publication ,  Journal Article
Kim, J-H; Shinde, DN; Reijnders, MRF; Hauser, NS; Belmonte, RL; Wilson, GR; Bosch, DGM; Bubulya, PA; Shashi, V; Petrovski, S; Stone, JK ...
Published in: Am J Hum Genet
September 1, 2016

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.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

September 1, 2016

Volume

99

Issue

3

Start / End Page

711 / 719

Location

United States

Related Subject Headings

  • Zebrafish
  • Syndrome
  • Spine
  • RNA, Messenger
  • RNA Splicing
  • Pedigree
  • Mutation
  • Minor Histocompatibility Antigens
  • Metabolic Diseases
  • Male
 

Citation

APA
Chicago
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Kim, J.-H., Shinde, D. N., Reijnders, M. R. F., Hauser, N. S., Belmonte, R. L., Wilson, G. R., … Ahn, E.-Y. (2016). De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome. Am J Hum Genet, 99(3), 711–719. https://doi.org/10.1016/j.ajhg.2016.06.029
Kim, Jung-Hyun, Deepali N. Shinde, Margot R. F. Reijnders, Natalie S. Hauser, Rebecca L. Belmonte, Gregory R. Wilson, Daniëlle G. M. Bosch, et al. “De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.Am J Hum Genet 99, no. 3 (September 1, 2016): 711–19. https://doi.org/10.1016/j.ajhg.2016.06.029.
Kim J-H, Shinde DN, Reijnders MRF, Hauser NS, Belmonte RL, Wilson GR, et al. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome. Am J Hum Genet. 2016 Sep 1;99(3):711–9.
Kim, Jung-Hyun, et al. “De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.Am J Hum Genet, vol. 99, no. 3, Sept. 2016, pp. 711–19. Pubmed, doi:10.1016/j.ajhg.2016.06.029.
Kim J-H, Shinde DN, Reijnders MRF, Hauser NS, Belmonte RL, Wilson GR, Bosch DGM, Bubulya PA, Shashi V, Petrovski S, Stone JK, Park EY, Veltman JA, Sinnema M, Stumpel CTRM, Draaisma JM, Nicolai J, University of Washington Center for Mendelian Genomics, Yntema HG, Lindstrom K, de Vries BBA, Jewett T, Santoro SL, Vogt J, Deciphering Developmental Disorders Study, 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-YE. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome. Am J Hum Genet. 2016 Sep 1;99(3):711–719.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

September 1, 2016

Volume

99

Issue

3

Start / End Page

711 / 719

Location

United States

Related Subject Headings

  • Zebrafish
  • Syndrome
  • Spine
  • RNA, Messenger
  • RNA Splicing
  • Pedigree
  • Mutation
  • Minor Histocompatibility Antigens
  • Metabolic Diseases
  • Male