THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability

Am J Hum Genet. 2015 Aug 6;97(2):302-10. doi: 10.1016/j.ajhg.2015.05.021.

Raman Kumar ¹, Mark A Corbett ¹, Bregje W M van Bon ², Joshua A Woenig ¹, Lloyd Weir ¹, Evelyn Douglas ³, Kathryn L Friend ³, Alison Gardner ¹, Marie Shaw ¹, Lachlan A Jolly ¹, Chuan Tan ¹, Matthew F Hunter ⁴, Anna Hackett ⁵, Michael Field ⁵, Elizabeth E Palmer ⁵, Melanie Leffler ⁵, Carolyn Rogers ⁵, Jackie Boyle ⁵, Melanie Bienek ⁶, Corinna Jensen ⁶, Griet Van Buggenhout ⁷, Hilde Van Esch ⁷, Katrin Hoffmann ⁸, Martine Raynaud ⁹, Huiying Zhao ¹⁰, Robin Reed ¹¹, Hao Hu ⁶, Stefan A Haas ¹², Eric Haan ¹³, Vera M Kalscheuer ⁶, Jozef Gecz ¹⁴

Affiliations

1 School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
2 School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
3 Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.
4 Monash Genetics, Monash Medical Centre, Clayton, VIC 3168, Australia; Department of Paediatrics, Monash University, Clayton, VIC 3168, Australia.
5 Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
6 Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
7 Center for Human Genetics, University Hospitals Leuven, Leuven 3000, Belgium.
8 Institute of Human Genetics, Martin Luther University Halle-Wittenberg, Magdeburger Strasse 2, 06112 Halle (Saale), Germany.
9 INSERM U930, Imaging and Brain, François-Rabelais University, 37000 Tours, France; INSERM U930, Service de Génétique, Centre Hospitalier Régional Universitaire, 37000 Tours, France.
10 QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
11 Department of Cell Biology, Harvard Medical School, Harvard University, Boston, MA 02115, USA.
12 Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
13 School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia; South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.
14 School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia; School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA 5005, Australia. Electronic address: jozef.gecz@adelaide.edu.au.

PMID: 26166480 DOI: 10.1016/j.ajhg.2015.05.021

Abstract

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.

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