TY - JOUR
T1 - THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability
AU - Kumar, Raman
AU - Corbett, Mark A.
AU - Van Bon, Bregje W.M.
AU - Woenig, Joshua A.
AU - Weir, Lloyd
AU - Douglas, Evelyn
AU - Friend, Kathryn L.
AU - Gardner, Alison
AU - Shaw, Marie
AU - Jolly, Lachlan A.
AU - Tan, Chuan
AU - Hunter, Matthew F.
AU - Hackett, Anna
AU - Field, Michael
AU - Palmer, Elizabeth E.
AU - Leffler, Melanie
AU - Rogers, Carolyn
AU - Boyle, Jackie
AU - Bienek, Melanie
AU - Jensen, Corinna
AU - Van Buggenhout, Griet
AU - Van Esch, Hilde
AU - Hoffmann, Katrin
AU - Raynaud, Martine
AU - Zhao, Huiying
AU - Reed, Robin
AU - Hu, Hao
AU - Haas, Stefan A.
AU - Haan, Eric
AU - Kalscheuer, Vera M.
AU - Gecz, Jozef
N1 - Funding Information:
This work was supported by the National Health and Medical Research Council (grants 628952 and 1041920 to J.G.), the Channel 7 Children’s Research Foundation (R.K., M.F., and J.G.), the European Commission 7 th Framework Programme project Genetic and Epigenetic Networks in Cognitive Dysfunction (grant 241995 to H.H. and V.M.K.), the MS McLeod Research Fellowship from the Women’s and Children’s Hospital Foundation (to M.A.C.), and the Ter Meulen Fonds stipendium (to B.W.M.v.B). We thank Amanda Springer, Sharon Grosvenor, and Julie Rogerson for their help with the MRX12 family. The authors are also grateful to the families who participated in the study.
PY - 2015/8/6
Y1 - 2015/8/6
N2 - Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.
AB - Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.
UR - http://www.scopus.com/inward/record.url?scp=84938998258&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2015.05.021
DO - 10.1016/j.ajhg.2015.05.021
M3 - Article
C2 - 26166480
AN - SCOPUS:84938998258
VL - 97
SP - 302
EP - 310
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
M1 - 1898
ER -