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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.

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.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Kim JH,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 Mende

doi

10.1016/j.ajhg.2016.06.029

subject

Has Abstract

pub_date

2016-09-01 00:00:00

pages

711-719

issue

3

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(16)30267-1

journal_volume

99

pub_type

杂志文章

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