TY - JOUR
T1 - De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome
AU - Kim, Jung-Hyun
AU - Shinde, Deepali N.
AU - Reijnders, Margot R. F.
AU - Hauser, Natalie S.
AU - Belmonte, Rebecca L.
AU - Wilson, Gregory R.
AU - Bosch, Danielle G. M.
AU - Bubulya, Paula A.
AU - Shashi, Vandana
AU - Petrovski, Slave
AU - Stone, Joshua K.
AU - Park, Eun Young
AU - Veltman, Joris
AU - Sinnema, Margje
AU - Stumpel, Constance
AU - Draaisma, Jos M.
AU - Nicolai, Joost
AU - Yntema, Helger G.
AU - Lindstrom, Kristin
AU - de Vries, Bert B. A.
AU - Jewett, Tamison
AU - Santoro, Stephanie L.
AU - Vogt, Julie
AU - Bachman, Kristine K.
AU - Seeley, Andrea H.
AU - Krokosky, Alyson
AU - Turner, Clesson
AU - Rohena, Luis
AU - Hempel, Maja
AU - Kortuem, Fanny
AU - Lessel, Davor
AU - Neu, Axel
AU - Strom, Tim M.
AU - Wieczorek, Dagmar
AU - Bramswig, Nuria
AU - Laccone, Franco A.
AU - Behunova, Jana
AU - Rehder, Helga
AU - Gordon, Christopher T.
AU - Rio, Marlene
AU - Romana, Serge
AU - Tang, Sha
AU - El-Khechen, Dima
AU - Cho, Megan T.
AU - McWalter, Kirsty
AU - Douglas, Ganka
AU - Baskin, Berivan
AU - Begtrup, Amber
AU - Funari, Tara
AU - Schoch, Kelly
AU - Stegmann, Alexander P. A.
AU - Stevens, Servi J. C.
AU - Zhang, Dong-Er
AU - Traver, David
AU - Yao, Xu
AU - MacArthur, Daniel G.
AU - Brunner, Han G.
AU - Mancini, Grazia M.
AU - Myers, Richard M.
AU - Owen, Laurie B.
AU - Lim, Ssang-Taek
AU - Stachura, David L.
AU - Vissers, Lisenka E. L. M.
AU - Ahn, Eun-Young Erin
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
U2 - 10.1016/j.ajhg.2016.06.029
DO - 10.1016/j.ajhg.2016.06.029
M3 - Article
C2 - 27545680
SN - 0002-9297
VL - 99
SP - 711
EP - 719
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -