AustralieFrV1, Main, Exploration, bibRecord, 003272

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

Identifieur interne : 003272 ( Main/Exploration ); précédent : 003271; suivant : 003273

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

Auteurs : Raman Kumar [Australie] ; Mark A. Corbett [Australie] ; Bregje W. M. Van Bon [Australie, Pays-Bas] ; Joshua A. Woenig [Australie] ; Lloyd Weir [Australie] ; Evelyn Douglas [Australie] ; Kathryn L. Friend [Australie] ; Alison Gardner [Australie] ; Marie Shaw [Australie] ; Lachlan A. Jolly [Australie] ; Chuan Tan [Australie] ; Matthew F. Hunter [Australie] ; Anna Hackett [Australie] ; Michael Field [Australie] ; Elizabeth E. Palmer [Australie] ; Melanie Leffler [Australie] ; Carolyn Rogers [Australie] ; Jackie Boyle [Australie] ; Melanie Bienek [Allemagne] ; Corinna Jensen [Allemagne] ; Griet Van Buggenhout [Belgique] ; Hilde Van Esch [Belgique] ; Katrin Hoffmann [Allemagne] ; Martine Raynaud [France] ; Huiying Zhao [Australie] ; Robin Reed [États-Unis] ; Hao Hu [Allemagne] ; Stefan A. Haas [Allemagne] ; Eric Haan [Australie] ; Vera M. Kalscheuer [Allemagne] ; Jozef Gecz [Australie]

Source :

American Journal of Human Genetics [ 0002-9297 ] ; 2015.

RBID : PMC:4573269

Descripteurs français

KwdFr :
- ARN messager (génétique), ARN messager (métabolisme), Analyse de séquence d'ADN, Chromosomes X humains (génétique), Données de séquences moléculaires, Humains, Modèles moléculaires, Mutation faux-sens (génétique), Pedigree, Protéines de liaison à l'ARN (), Protéines de liaison à l'ARN (génétique), Retard mental lié à l'X (anatomopathologie), Retard mental lié à l'X (génétique), Syndrome, Séquence d'acides aminés, Séquence nucléotidique, Transport nucléaire actif (génétique).
MESH :
- anatomopathologie : Retard mental lié à l'X.
- génétique : ARN messager, Chromosomes X humains, Mutation faux-sens, Protéines de liaison à l'ARN, Retard mental lié à l'X, Transport nucléaire actif.
- métabolisme : ARN messager.
- Analyse de séquence d'ADN, Données de séquences moléculaires, Humains, Modèles moléculaires, Pedigree, Protéines de liaison à l'ARN, Syndrome, Séquence d'acides aminés, Séquence nucléotidique.

English descriptors

KwdEn :
- Active Transport, Cell Nucleus (genetics), Amino Acid Sequence, Base Sequence, Chromosomes, Human, X (genetics), Humans, Mental Retardation, X-Linked (genetics), Mental Retardation, X-Linked (pathology), Models, Molecular, Molecular Sequence Data, Mutation, Missense (genetics), Pedigree, RNA, Messenger (genetics), RNA, Messenger (metabolism), RNA-Binding Proteins (chemistry), RNA-Binding Proteins (genetics), Sequence Analysis, DNA, Syndrome.
MESH :
- chemical , chemistry : RNA-Binding Proteins.
- chemical , genetics : RNA, Messenger, RNA-Binding Proteins.
- genetics : Active Transport, Cell Nucleus, Chromosomes, Human, X, Mental Retardation, X-Linked, Mutation, Missense.
- chemical , metabolism : RNA, Messenger.
- pathology : Mental Retardation, X-Linked.
- Amino Acid Sequence, Base Sequence, Humans, Models, Molecular, Molecular Sequence Data, Pedigree, 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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573269

DOI: 10.1016/j.ajhg.2015.05.021
PubMed: 26166480
PubMed Central: 4573269

Affiliations:

Le document en format XML

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 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability</title>
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<author><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name>
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<wicri:regionArea>Institute of Human Genetics, Martin Luther University Halle-Wittenberg, Magdeburger Strasse 2, 06112 Halle (Saale)</wicri:regionArea>
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<author><name sortKey="Zhao, Huiying" sort="Zhao, Huiying" uniqKey="Zhao H" first="Huiying" last="Zhao">Huiying Zhao</name>
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<author><name sortKey="Reed, Robin" sort="Reed, Robin" uniqKey="Reed R" first="Robin" last="Reed">Robin Reed</name>
<affiliation wicri:level="4"><nlm:aff id="aff13">Department of Cell Biology, Harvard Medical School, Harvard University, Boston, MA 02115, USA</nlm:aff>
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<wicri:regionArea>Department of Cell Biology, Harvard Medical School, Harvard University, Boston, MA 02115</wicri:regionArea>
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<author><name sortKey="Hu, Hao" sort="Hu, Hao" uniqKey="Hu H" first="Hao" last="Hu">Hao Hu</name>
<affiliation wicri:level="3"><nlm:aff id="aff7">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin</wicri:regionArea>
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<author><name sortKey="Haas, Stefan A" sort="Haas, Stefan A" uniqKey="Haas S" first="Stefan A." last="Haas">Stefan A. Haas</name>
<affiliation wicri:level="3"><nlm:aff id="aff14">Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin</wicri:regionArea>
<placeName><region type="land" nuts="3">Berlin</region>
<settlement type="city">Berlin</settlement>
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<author><name sortKey="Haan, Eric" sort="Haan, Eric" uniqKey="Haan E" first="Eric" last="Haan">Eric Haan</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff>
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<affiliation wicri:level="1"><nlm:aff id="aff15">South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006</wicri:regionArea>
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<author><name sortKey="Kalscheuer, Vera M" sort="Kalscheuer, Vera M" uniqKey="Kalscheuer V" first="Vera M." last="Kalscheuer">Vera M. Kalscheuer</name>
<affiliation wicri:level="3"><nlm:aff id="aff7">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin</wicri:regionArea>
<placeName><region type="land" nuts="3">Berlin</region>
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<author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000</wicri:regionArea>
<wicri:noRegion>SA 5000</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff16">School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA 5005</wicri:regionArea>
<wicri:noRegion>SA 5005</wicri:noRegion>
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</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">26166480</idno>
<idno type="pmc">4573269</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573269</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>THOC2</italic>
 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability</title>
<author><name sortKey="Kumar, Raman" sort="Kumar, Raman" uniqKey="Kumar R" first="Raman" last="Kumar">Raman Kumar</name>
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<country xml:lang="fr">Australie</country>
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</author>
<author><name sortKey="Corbett, Mark A" sort="Corbett, Mark A" uniqKey="Corbett M" first="Mark A." last="Corbett">Mark A. Corbett</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Van Bon, Bregje W M" sort="Van Bon, Bregje W M" uniqKey="Van Bon B" first="Bregje W. M." last="Van Bon">Bregje W. M. Van Bon</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000</wicri:regionArea>
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</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2">Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen</wicri:regionArea>
<wicri:noRegion>6500 HB Nijmegen</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Woenig, Joshua A" sort="Woenig, Joshua A" uniqKey="Woenig J" first="Joshua A." last="Woenig">Joshua A. Woenig</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Weir, Lloyd" sort="Weir, Lloyd" uniqKey="Weir L" first="Lloyd" last="Weir">Lloyd Weir</name>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Douglas, Evelyn" sort="Douglas, Evelyn" uniqKey="Douglas E" first="Evelyn" last="Douglas">Evelyn Douglas</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Friend, Kathryn L" sort="Friend, Kathryn L" uniqKey="Friend K" first="Kathryn L." last="Friend">Kathryn L. Friend</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Gardner, Alison" sort="Gardner, Alison" uniqKey="Gardner A" first="Alison" last="Gardner">Alison Gardner</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000</wicri:regionArea>
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</author>
<author><name sortKey="Shaw, Marie" sort="Shaw, Marie" uniqKey="Shaw M" first="Marie" last="Shaw">Marie Shaw</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff>
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</author>
<author><name sortKey="Jolly, Lachlan A" sort="Jolly, Lachlan A" uniqKey="Jolly L" first="Lachlan A." last="Jolly">Lachlan A. Jolly</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff>
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<wicri:regionArea>School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000</wicri:regionArea>
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</author>
<author><name sortKey="Tan, Chuan" sort="Tan, Chuan" uniqKey="Tan C" first="Chuan" last="Tan">Chuan Tan</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff>
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<wicri:regionArea>School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000</wicri:regionArea>
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</author>
<author><name sortKey="Hunter, Matthew F" sort="Hunter, Matthew F" uniqKey="Hunter M" first="Matthew F." last="Hunter">Matthew F. Hunter</name>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>Monash Genetics, Monash Medical Centre, Clayton, VIC 3168</wicri:regionArea>
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</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff5">Department of Paediatrics, Monash University, Clayton, VIC 3168, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Paediatrics, Monash University, Clayton, VIC 3168</wicri:regionArea>
<wicri:noRegion>VIC 3168</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name>
<affiliation wicri:level="1"><nlm:aff id="aff6">Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Field, Michael" sort="Field, Michael" uniqKey="Field M" first="Michael" last="Field">Michael Field</name>
<affiliation wicri:level="1"><nlm:aff id="aff6">Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298</wicri:regionArea>
<wicri:noRegion>NSW 2298</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Palmer, Elizabeth E" sort="Palmer, Elizabeth E" uniqKey="Palmer E" first="Elizabeth E." last="Palmer">Elizabeth E. Palmer</name>
<affiliation wicri:level="1"><nlm:aff id="aff6">Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Leffler, Melanie" sort="Leffler, Melanie" uniqKey="Leffler M" first="Melanie" last="Leffler">Melanie Leffler</name>
<affiliation wicri:level="1"><nlm:aff id="aff6">Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298</wicri:regionArea>
<wicri:noRegion>NSW 2298</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Rogers, Carolyn" sort="Rogers, Carolyn" uniqKey="Rogers C" first="Carolyn" last="Rogers">Carolyn Rogers</name>
<affiliation wicri:level="1"><nlm:aff id="aff6">Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Boyle, Jackie" sort="Boyle, Jackie" uniqKey="Boyle J" first="Jackie" last="Boyle">Jackie Boyle</name>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298</wicri:regionArea>
<wicri:noRegion>NSW 2298</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Bienek, Melanie" sort="Bienek, Melanie" uniqKey="Bienek M" first="Melanie" last="Bienek">Melanie Bienek</name>
<affiliation wicri:level="3"><nlm:aff id="aff7">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin</wicri:regionArea>
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<settlement type="city">Berlin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Jensen, Corinna" sort="Jensen, Corinna" uniqKey="Jensen C" first="Corinna" last="Jensen">Corinna Jensen</name>
<affiliation wicri:level="3"><nlm:aff id="aff7">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin</wicri:regionArea>
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<settlement type="city">Berlin</settlement>
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</affiliation>
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<author><name sortKey="Van Buggenhout, Griet" sort="Van Buggenhout, Griet" uniqKey="Van Buggenhout G" first="Griet" last="Van Buggenhout">Griet Van Buggenhout</name>
<affiliation wicri:level="1"><nlm:aff id="aff8">Center for Human Genetics, University Hospitals Leuven, Leuven 3000, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Center for Human Genetics, University Hospitals Leuven, Leuven 3000</wicri:regionArea>
<wicri:noRegion>Leuven 3000</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name>
<affiliation wicri:level="1"><nlm:aff id="aff8">Center for Human Genetics, University Hospitals Leuven, Leuven 3000, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Center for Human Genetics, University Hospitals Leuven, Leuven 3000</wicri:regionArea>
<wicri:noRegion>Leuven 3000</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hoffmann, Katrin" sort="Hoffmann, Katrin" uniqKey="Hoffmann K" first="Katrin" last="Hoffmann">Katrin Hoffmann</name>
<affiliation wicri:level="1"><nlm:aff id="aff9">Institute of Human Genetics, Martin Luther University Halle-Wittenberg, Magdeburger Strasse 2, 06112 Halle (Saale), Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Human Genetics, Martin Luther University Halle-Wittenberg, Magdeburger Strasse 2, 06112 Halle (Saale)</wicri:regionArea>
<wicri:noRegion>06112 Halle (Saale)</wicri:noRegion>
<wicri:noRegion>06112 Halle (Saale)</wicri:noRegion>
<wicri:noRegion>06112 Halle (Saale)</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Raynaud, Martine" sort="Raynaud, Martine" uniqKey="Raynaud M" first="Martine" last="Raynaud">Martine Raynaud</name>
<affiliation wicri:level="1"><nlm:aff id="aff10">INSERM U930, Imaging and Brain, François-Rabelais University, 37000 Tours, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>INSERM U930, Imaging and Brain, François-Rabelais University, 37000 Tours</wicri:regionArea>
<wicri:noRegion>37000 Tours</wicri:noRegion>
<wicri:noRegion>37000 Tours</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff11">INSERM U930, Service de Génétique, Centre Hospitalier Régional Universitaire, 37000 Tours, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>INSERM U930, Service de Génétique, Centre Hospitalier Régional Universitaire, 37000 Tours</wicri:regionArea>
<wicri:noRegion>37000 Tours</wicri:noRegion>
<wicri:noRegion>37000 Tours</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Zhao, Huiying" sort="Zhao, Huiying" uniqKey="Zhao H" first="Huiying" last="Zhao">Huiying Zhao</name>
<affiliation wicri:level="1"><nlm:aff id="aff12">QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029</wicri:regionArea>
<wicri:noRegion>QLD 4029</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Reed, Robin" sort="Reed, Robin" uniqKey="Reed R" first="Robin" last="Reed">Robin Reed</name>
<affiliation wicri:level="4"><nlm:aff id="aff13">Department of Cell Biology, Harvard Medical School, Harvard University, Boston, MA 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Cell Biology, Harvard Medical School, Harvard University, Boston, MA 02115</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
<settlement type="city">Cambridge (Massachusetts)</settlement>
</placeName>
<orgName type="university">Université Harvard</orgName>
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</author>
<author><name sortKey="Hu, Hao" sort="Hu, Hao" uniqKey="Hu H" first="Hao" last="Hu">Hao Hu</name>
<affiliation wicri:level="3"><nlm:aff id="aff7">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin</wicri:regionArea>
<placeName><region type="land" nuts="3">Berlin</region>
<settlement type="city">Berlin</settlement>
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</affiliation>
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<author><name sortKey="Haas, Stefan A" sort="Haas, Stefan A" uniqKey="Haas S" first="Stefan A." last="Haas">Stefan A. Haas</name>
<affiliation wicri:level="3"><nlm:aff id="aff14">Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin</wicri:regionArea>
<placeName><region type="land" nuts="3">Berlin</region>
<settlement type="city">Berlin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Haan, Eric" sort="Haan, Eric" uniqKey="Haan E" first="Eric" last="Haan">Eric Haan</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000</wicri:regionArea>
<wicri:noRegion>SA 5000</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff15">South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006</wicri:regionArea>
<wicri:noRegion>SA 5006</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Kalscheuer, Vera M" sort="Kalscheuer, Vera M" uniqKey="Kalscheuer V" first="Vera M." last="Kalscheuer">Vera M. Kalscheuer</name>
<affiliation wicri:level="3"><nlm:aff id="aff7">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin</wicri:regionArea>
<placeName><region type="land" nuts="3">Berlin</region>
<settlement type="city">Berlin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000</wicri:regionArea>
<wicri:noRegion>SA 5000</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff16">School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA 5005</wicri:regionArea>
<wicri:noRegion>SA 5005</wicri:noRegion>
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</analytic>
<series><title level="j">American Journal of Human Genetics</title>
<idno type="ISSN">0002-9297</idno>
<idno type="eISSN">1537-6605</idno>
<imprint><date when="2015">2015</date>
</imprint>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Active Transport, Cell Nucleus (genetics)</term>
<term>Amino Acid Sequence</term>
<term>Base Sequence</term>
<term>Chromosomes, Human, X (genetics)</term>
<term>Humans</term>
<term>Mental Retardation, X-Linked (genetics)</term>
<term>Mental Retardation, X-Linked (pathology)</term>
<term>Models, Molecular</term>
<term>Molecular Sequence Data</term>
<term>Mutation, Missense (genetics)</term>
<term>Pedigree</term>
<term>RNA, Messenger (genetics)</term>
<term>RNA, Messenger (metabolism)</term>
<term>RNA-Binding Proteins (chemistry)</term>
<term>RNA-Binding Proteins (genetics)</term>
<term>Sequence Analysis, DNA</term>
<term>Syndrome</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>ARN messager (génétique)</term>
<term>ARN messager (métabolisme)</term>
<term>Analyse de séquence d'ADN</term>
<term>Chromosomes X humains (génétique)</term>
<term>Données de séquences moléculaires</term>
<term>Humains</term>
<term>Modèles moléculaires</term>
<term>Mutation faux-sens (génétique)</term>
<term>Pedigree</term>
<term>Protéines de liaison à l'ARN ()</term>
<term>Protéines de liaison à l'ARN (génétique)</term>
<term>Retard mental lié à l'X (anatomopathologie)</term>
<term>Retard mental lié à l'X (génétique)</term>
<term>Syndrome</term>
<term>Séquence d'acides aminés</term>
<term>Séquence nucléotidique</term>
<term>Transport nucléaire actif (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>RNA-Binding Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>RNA, Messenger</term>
<term>RNA-Binding Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Retard mental lié à l'X</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Active Transport, Cell Nucleus</term>
<term>Chromosomes, Human, X</term>
<term>Mental Retardation, X-Linked</term>
<term>Mutation, Missense</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ARN messager</term>
<term>Chromosomes X humains</term>
<term>Mutation faux-sens</term>
<term>Protéines de liaison à l'ARN</term>
<term>Retard mental lié à l'X</term>
<term>Transport nucléaire actif</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>RNA, Messenger</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>ARN messager</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Mental Retardation, X-Linked</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term>
<term>Base Sequence</term>
<term>Humans</term>
<term>Models, Molecular</term>
<term>Molecular Sequence Data</term>
<term>Pedigree</term>
<term>Sequence Analysis, DNA</term>
<term>Syndrome</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Analyse de séquence d'ADN</term>
<term>Données de séquences moléculaires</term>
<term>Humains</term>
<term>Modèles moléculaires</term>
<term>Pedigree</term>
<term>Protéines de liaison à l'ARN</term>
<term>Syndrome</term>
<term>Séquence d'acides aminés</term>
<term>Séquence nucléotidique</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>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 <italic>THOC2</italic>
, 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 <italic>THOC2</italic>
 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.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Allemagne</li>
<li>Australie</li>
<li>Belgique</li>
<li>France</li>
<li>Pays-Bas</li>
<li>États-Unis</li>
</country>
<region><li>Berlin</li>
<li>Massachusetts</li>
</region>
<settlement><li>Berlin</li>
<li>Cambridge (Massachusetts)</li>
</settlement>
<orgName><li>Université Harvard</li>
</orgName>
</list>
<tree><country name="Australie"><noRegion><name sortKey="Kumar, Raman" sort="Kumar, Raman" uniqKey="Kumar R" first="Raman" last="Kumar">Raman Kumar</name>
</noRegion>
<name sortKey="Boyle, Jackie" sort="Boyle, Jackie" uniqKey="Boyle J" first="Jackie" last="Boyle">Jackie Boyle</name>
<name sortKey="Corbett, Mark A" sort="Corbett, Mark A" uniqKey="Corbett M" first="Mark A." last="Corbett">Mark A. Corbett</name>
<name sortKey="Douglas, Evelyn" sort="Douglas, Evelyn" uniqKey="Douglas E" first="Evelyn" last="Douglas">Evelyn Douglas</name>
<name sortKey="Field, Michael" sort="Field, Michael" uniqKey="Field M" first="Michael" last="Field">Michael Field</name>
<name sortKey="Friend, Kathryn L" sort="Friend, Kathryn L" uniqKey="Friend K" first="Kathryn L." last="Friend">Kathryn L. Friend</name>
<name sortKey="Gardner, Alison" sort="Gardner, Alison" uniqKey="Gardner A" first="Alison" last="Gardner">Alison Gardner</name>
<name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name>
<name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name>
<name sortKey="Haan, Eric" sort="Haan, Eric" uniqKey="Haan E" first="Eric" last="Haan">Eric Haan</name>
<name sortKey="Haan, Eric" sort="Haan, Eric" uniqKey="Haan E" first="Eric" last="Haan">Eric Haan</name>
<name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name>
<name sortKey="Hunter, Matthew F" sort="Hunter, Matthew F" uniqKey="Hunter M" first="Matthew F." last="Hunter">Matthew F. Hunter</name>
<name sortKey="Hunter, Matthew F" sort="Hunter, Matthew F" uniqKey="Hunter M" first="Matthew F." last="Hunter">Matthew F. Hunter</name>
<name sortKey="Jolly, Lachlan A" sort="Jolly, Lachlan A" uniqKey="Jolly L" first="Lachlan A." last="Jolly">Lachlan A. Jolly</name>
<name sortKey="Leffler, Melanie" sort="Leffler, Melanie" uniqKey="Leffler M" first="Melanie" last="Leffler">Melanie Leffler</name>
<name sortKey="Palmer, Elizabeth E" sort="Palmer, Elizabeth E" uniqKey="Palmer E" first="Elizabeth E." last="Palmer">Elizabeth E. Palmer</name>
<name sortKey="Rogers, Carolyn" sort="Rogers, Carolyn" uniqKey="Rogers C" first="Carolyn" last="Rogers">Carolyn Rogers</name>
<name sortKey="Shaw, Marie" sort="Shaw, Marie" uniqKey="Shaw M" first="Marie" last="Shaw">Marie Shaw</name>
<name sortKey="Tan, Chuan" sort="Tan, Chuan" uniqKey="Tan C" first="Chuan" last="Tan">Chuan Tan</name>
<name sortKey="Van Bon, Bregje W M" sort="Van Bon, Bregje W M" uniqKey="Van Bon B" first="Bregje W. M." last="Van Bon">Bregje W. M. Van Bon</name>
<name sortKey="Weir, Lloyd" sort="Weir, Lloyd" uniqKey="Weir L" first="Lloyd" last="Weir">Lloyd Weir</name>
<name sortKey="Woenig, Joshua A" sort="Woenig, Joshua A" uniqKey="Woenig J" first="Joshua A." last="Woenig">Joshua A. Woenig</name>
<name sortKey="Zhao, Huiying" sort="Zhao, Huiying" uniqKey="Zhao H" first="Huiying" last="Zhao">Huiying Zhao</name>
</country>
<country name="Pays-Bas"><noRegion><name sortKey="Van Bon, Bregje W M" sort="Van Bon, Bregje W M" uniqKey="Van Bon B" first="Bregje W. M." last="Van Bon">Bregje W. M. Van Bon</name>
</noRegion>
</country>
<country name="Allemagne"><region name="Berlin"><name sortKey="Bienek, Melanie" sort="Bienek, Melanie" uniqKey="Bienek M" first="Melanie" last="Bienek">Melanie Bienek</name>
</region>
<name sortKey="Haas, Stefan A" sort="Haas, Stefan A" uniqKey="Haas S" first="Stefan A." last="Haas">Stefan A. Haas</name>
<name sortKey="Hoffmann, Katrin" sort="Hoffmann, Katrin" uniqKey="Hoffmann K" first="Katrin" last="Hoffmann">Katrin Hoffmann</name>
<name sortKey="Hu, Hao" sort="Hu, Hao" uniqKey="Hu H" first="Hao" last="Hu">Hao Hu</name>
<name sortKey="Jensen, Corinna" sort="Jensen, Corinna" uniqKey="Jensen C" first="Corinna" last="Jensen">Corinna Jensen</name>
<name sortKey="Kalscheuer, Vera M" sort="Kalscheuer, Vera M" uniqKey="Kalscheuer V" first="Vera M." last="Kalscheuer">Vera M. Kalscheuer</name>
</country>
<country name="Belgique"><noRegion><name sortKey="Van Buggenhout, Griet" sort="Van Buggenhout, Griet" uniqKey="Van Buggenhout G" first="Griet" last="Van Buggenhout">Griet Van Buggenhout</name>
</noRegion>
<name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name>
</country>
<country name="France"><noRegion><name sortKey="Raynaud, Martine" sort="Raynaud, Martine" uniqKey="Raynaud M" first="Martine" last="Raynaud">Martine Raynaud</name>
</noRegion>
<name sortKey="Raynaud, Martine" sort="Raynaud, Martine" uniqKey="Raynaud M" first="Martine" last="Raynaud">Martine Raynaud</name>
</country>
<country name="États-Unis"><region name="Massachusetts"><name sortKey="Reed, Robin" sort="Reed, Robin" uniqKey="Reed R" first="Robin" last="Reed">Robin Reed</name>
</region>
</country>
</tree>
</affiliations>
</record>

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

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

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