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dc.contributor.authorKumar, R.en
dc.contributor.authorCorbett, M.en
dc.contributor.authorVan Bon, B.en
dc.contributor.authorWoenig, J.en
dc.contributor.authorWeir, L.en
dc.contributor.authorDouglas, E.en
dc.contributor.authorFriend, K.en
dc.contributor.authorGardner, A.en
dc.contributor.authorShaw, M.en
dc.contributor.authorJolly, L.en
dc.contributor.authorTan, C.en
dc.contributor.authorHunter, M.en
dc.contributor.authorHackett, A.en
dc.contributor.authorField, M.en
dc.contributor.authorPalmer, E.en
dc.contributor.authorLeffler, M.en
dc.contributor.authorRogers, C.en
dc.contributor.authorBoyle, J.en
dc.contributor.authorBienek, M.en
dc.contributor.authorJensen, C.en
dc.contributor.authoret al.en
dc.identifier.citationAmerican Journal of Human Genetics, 2015; 97(2):302-310en
dc.description.abstractExport 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.en
dc.description.statementofresponsibilityRaman Kumar, Mark A. Corbett, Bregje W.M. van Bon, Joshua A. Woenig, Lloyd Weir, Evelyn Douglas, Kathryn L. Friend, Alison Gardner, Marie Shaw, Lachlan A. Jolly, Chuan Tan, Matthew F. Hunter, Anna Hackett, Michael Field, Elizabeth E. Palmer, Melanie Leffler, Carolyn Rogers, Jackie Boyle, Melanie Bienek, Corinna Jensen, Griet Van Buggenhout, Hilde Van Esch, Katrin Hoffmann, Martine Raynaud, Huiying Zhao, Robin Reed, Hao Hu, Stefan A. Haas, and Eric Haanen
dc.rights©2015 by The American Society of Human Genetics. All rights reserved.en
dc.subjectChromosomes, Human, Xen
dc.titleTHOC2 mutations implicate mRNA-export pathway in X-linked intellectual disabilityen
dc.typeJournal articleen
pubs.library.collectionPaediatrics publicationsen
dc.identifier.orcidKumar, R. [0000-0001-7976-8386]en
dc.identifier.orcidCorbett, M. [0000-0001-9298-3072]en
dc.identifier.orcidShaw, M. [0000-0002-5060-190X]en
dc.identifier.orcidJolly, L. [0000-0003-4538-2658]en
dc.identifier.orcidHaan, E. [0000-0002-7310-5124]en
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]en
Appears in Collections:Paediatrics publications

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