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

Kumar, R., Corbett, M. A., van Bon, B. W., Woenig, J. A., Weir, L., Douglas, E., et al. (2015). THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability. The American Journal of Human Genetics, 97(2), 302-310. doi:10.1016/j.ajhg.2015.05.021.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-3ABE-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-60E9-7
Genre: Journal Article

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© 2015 The American Society of Human Genetics
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 Creators:
Kumar, R., Author
Corbett, M. A., Author
van Bon, B. W., Author
Woenig, J. A., Author
Weir, L., Author
Douglas, E., Author
Friend, K. L., Author
Gardner, A., Author
Shaw, M., Author
Jolly, L. A., Author
Tan, C., Author
Hunter, M. F., Author
Hackett, A., Author
Field, M., Author
Palmer, E. E., Author
Leffler, M., Author
Rogers, C., Author
Boyle, J., Author
Bienek, M.1, Author              
Jensen, C.1, Author
Van Buggenhout, G., AuthorVan Esch, H., AuthorHoffmann, K., AuthorRaynaud, M., AuthorZhao, H., AuthorReed, R., AuthorHu, H.1, Author              Haas, S. A.2, Author              Haan, E., AuthorKalscheuer, V. M.3, 4, Author              Gecz, J., Author more..
Affiliations:
1Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              
2Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479640              
3Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              
4Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              

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Free keywords: Active Transport, Cell Nucleus/*genetics Amino Acid Sequence Base Sequence Chromosomes, Human, X/*genetics Humans Mental Retardation, X-Linked/*genetics/pathology *Models, Molecular Molecular Sequence Data Mutation, Missense/*genetics Pedigree RNA, Messenger/*genetics/metabolism RNA-Binding Proteins/chemistry/*genetics Sequence Analysis, DNA Syndrome
 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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Language(s): eng - English
 Dates: 2015-07-092015-08-06
 Publication Status: Published in print
 Pages: 9
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1016/j.ajhg.2015.05.021
ISSN: 1537-6605 (Electronic)0002-9297 (Print)
 Degree: -

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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 97 (2) Sequence Number: - Start / End Page: 302 - 310 Identifier: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1