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

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

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.

Bibliografische Daten

OriginalspracheEnglisch
ISSN0002-9297
DOIs
StatusVeröffentlicht - 01.09.2016
PubMed 27545680