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

Kim, J.H., Shinde, D.N., Reijnders, M.R., Hauser, N.S., Belmonte, R.L., Wilson, G.R., Bosch, D.G., Bubulya, P.A., Shashi, V., Petrovski, S., Stone, J.K., Park, E.Y., Veltman, J.A., Sinnema, M., Stumpel, C.T., Draaisma, J.M., Nicolai, J., Yntema, H.G., Lindstrom, K., de Vries, B.B., Jewett, T., Santoro, S.L., Vogt, J., Bachman, K.K., Seeley, A.H., Krokosky, A., Turner, C., Rohena, L., Hempel, M., Kortüm, F., Lessel, D., Neu, A., Strom, T.M., Wieczorek, D., Bramswig, N., Laccone, F.A., Behunova, J., Rehder, H., Gordon, C.T., Rio, M., Romana, S., Tang, S., El-Khechen, D., Cho, M.T., McWalter, K., Douglas, G., Baskin, B., Begtrup, A., Funari, T., Schoch, K., Stegmann, A.P., Stevens, S.J., Zhang, D.E., Traver, D., Yao, X., MacArthur, D.G., Brunner, H.G., Mancini, G.M., Myers, R.M., Owen, L.B., Lim, S.T., Stachura, D.L., Vissers, L.E., Ahn, E.E.
American journal of human genetics   99(3): 711-9 (Journal)
Registered Authors
Traver, David
MeSH Terms
  • Animals
  • Brain/abnormalities
  • Brain/embryology*
  • Brain/metabolism*
  • Brain/pathology
  • DNA-Binding Proteins/analysis
  • DNA-Binding Proteins/genetics*
  • DNA-Binding Proteins/metabolism
  • Developmental Disabilities/genetics
  • Developmental Disabilities/pathology
  • Developmental Disabilities/physiopathology
  • Eye Abnormalities/genetics
  • Female
  • Genes, Essential/genetics*
  • Haploinsufficiency/genetics
  • Head/abnormalities
  • Heterozygote
  • Humans
  • Intellectual Disability/genetics*
  • Intellectual Disability/pathology
  • Intellectual Disability/physiopathology
  • Male
  • Metabolic Diseases/genetics
  • Metabolic Diseases/metabolism
  • Minor Histocompatibility Antigens/analysis
  • Minor Histocompatibility Antigens/genetics*
  • Minor Histocompatibility Antigens/metabolism
  • Mutation/genetics*
  • Pedigree
  • RNA Splicing/genetics*
  • RNA, Messenger/analysis
  • Spine/abnormalities
  • Syndrome
  • Zebrafish/abnormalities
  • Zebrafish/embryology
  • Zebrafish/genetics
27545680 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes