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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mutations in <italic>USP9X</italic> Are Associated with X-Linked Intellectual Disability and Disrupt Neuronal Cell Migration and Growth</title><author><name sortKey="Homan, Claire C" sort="Homan, Claire C" uniqKey="Homan C" first="Claire C." last="Homan">Claire C. Homan</name><affiliation><nlm:aff id="aff1">School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation></author><author><name sortKey="Kumar, Raman" sort="Kumar, Raman" uniqKey="Kumar R" first="Raman" last="Kumar">Raman Kumar</name><affiliation><nlm:aff id="aff2">Women’s and Children’s Health Research Institute, North Adelaide, SA 5006, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Discipline of Medicine, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation></author><author><name sortKey="Nguyen, Lam Son" sort="Nguyen, Lam Son" uniqKey="Nguyen L" first="Lam Son" last="Nguyen">Lam Son Nguyen</name><affiliation><nlm:aff id="aff4">School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation></author><author><name sortKey="Haan, Eric" sort="Haan, Eric" uniqKey="Haan E" first="Eric" last="Haan">Eric Haan</name><affiliation><nlm:aff id="aff4">School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">South Australian Clinical Genetics Service, SA Pathology at Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia</nlm:aff></affiliation></author><author><name sortKey="Raymond, F Lucy" sort="Raymond, F Lucy" uniqKey="Raymond F" first="F. Lucy" last="Raymond">F. Lucy Raymond</name><affiliation><nlm:aff id="aff6">Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK</nlm:aff></affiliation></author><author><name sortKey="Abidi, Fatima" sort="Abidi, Fatima" uniqKey="Abidi F" first="Fatima" last="Abidi">Fatima Abidi</name><affiliation><nlm:aff id="aff7">J.C. Self Research Institute, Greenwood Genetics Centre, Greenwood, SC 29646, USA</nlm:aff></affiliation></author><author><name sortKey="Raynaud, Martine" sort="Raynaud, Martine" uniqKey="Raynaud M" first="Martine" last="Raynaud">Martine Raynaud</name><affiliation><nlm:aff id="aff8">CHRU de Tours, Service de Génétique, Tours 37000, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Inserm U930, UMR Imagerie et Cerveau, Tours 37000, France</nlm:aff></affiliation></author><author><name sortKey="Schwartz, Charles E" sort="Schwartz, Charles E" uniqKey="Schwartz C" first="Charles E." last="Schwartz">Charles E. Schwartz</name><affiliation><nlm:aff id="aff7">J.C. Self Research Institute, Greenwood Genetics Centre, Greenwood, SC 29646, USA</nlm:aff></affiliation></author><author><name sortKey="Wood, Stephen A" sort="Wood, Stephen A" uniqKey="Wood S" first="Stephen A." last="Wood">Stephen A. Wood</name><affiliation><nlm:aff id="aff10">Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia</nlm:aff></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><nlm:aff id="aff1">School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Women’s and Children’s Health Research Institute, North Adelaide, SA 5006, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Robinson Institute, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation></author><author><name sortKey="Jolly, Lachlan A" sort="Jolly, Lachlan A" uniqKey="Jolly L" first="Lachlan A." last="Jolly">Lachlan A. Jolly</name><affiliation><nlm:aff id="aff4">School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Robinson Institute, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24607389</idno><idno type="pmc">3951929</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951929</idno><idno type="RBID">PMC:3951929</idno><idno type="doi">10.1016/j.ajhg.2014.02.004</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">001208</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001208</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutations in <italic>USP9X</italic> Are Associated with X-Linked Intellectual Disability and Disrupt Neuronal Cell Migration and Growth</title><author><name sortKey="Homan, Claire C" sort="Homan, Claire C" uniqKey="Homan C" first="Claire C." last="Homan">Claire C. Homan</name><affiliation><nlm:aff id="aff1">School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation></author><author><name sortKey="Kumar, Raman" sort="Kumar, Raman" uniqKey="Kumar R" first="Raman" last="Kumar">Raman Kumar</name><affiliation><nlm:aff id="aff2">Women’s and Children’s Health Research Institute, North Adelaide, SA 5006, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Discipline of Medicine, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation></author><author><name sortKey="Nguyen, Lam Son" sort="Nguyen, Lam Son" uniqKey="Nguyen L" first="Lam Son" last="Nguyen">Lam Son Nguyen</name><affiliation><nlm:aff id="aff4">School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation></author><author><name sortKey="Haan, Eric" sort="Haan, Eric" uniqKey="Haan E" first="Eric" last="Haan">Eric Haan</name><affiliation><nlm:aff id="aff4">School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">South Australian Clinical Genetics Service, SA Pathology at Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia</nlm:aff></affiliation></author><author><name sortKey="Raymond, F Lucy" sort="Raymond, F Lucy" uniqKey="Raymond F" first="F. Lucy" last="Raymond">F. Lucy Raymond</name><affiliation><nlm:aff id="aff6">Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK</nlm:aff></affiliation></author><author><name sortKey="Abidi, Fatima" sort="Abidi, Fatima" uniqKey="Abidi F" first="Fatima" last="Abidi">Fatima Abidi</name><affiliation><nlm:aff id="aff7">J.C. Self Research Institute, Greenwood Genetics Centre, Greenwood, SC 29646, USA</nlm:aff></affiliation></author><author><name sortKey="Raynaud, Martine" sort="Raynaud, Martine" uniqKey="Raynaud M" first="Martine" last="Raynaud">Martine Raynaud</name><affiliation><nlm:aff id="aff8">CHRU de Tours, Service de Génétique, Tours 37000, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Inserm U930, UMR Imagerie et Cerveau, Tours 37000, France</nlm:aff></affiliation></author><author><name sortKey="Schwartz, Charles E" sort="Schwartz, Charles E" uniqKey="Schwartz C" first="Charles E." last="Schwartz">Charles E. Schwartz</name><affiliation><nlm:aff id="aff7">J.C. Self Research Institute, Greenwood Genetics Centre, Greenwood, SC 29646, USA</nlm:aff></affiliation></author><author><name sortKey="Wood, Stephen A" sort="Wood, Stephen A" uniqKey="Wood S" first="Stephen A." last="Wood">Stephen A. Wood</name><affiliation><nlm:aff id="aff10">Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia</nlm:aff></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><nlm:aff id="aff1">School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Women’s and Children’s Health Research Institute, North Adelaide, SA 5006, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Robinson Institute, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation></author><author><name sortKey="Jolly, Lachlan A" sort="Jolly, Lachlan A" uniqKey="Jolly L" first="Lachlan A." last="Jolly">Lachlan A. Jolly</name><affiliation><nlm:aff id="aff4">School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Robinson Institute, University of Adelaide, Adelaide, SA 5005, Australia</nlm:aff></affiliation></author></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="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>With a wealth of disease-associated DNA variants being recently reported, the challenges of providing their functional characterization are mounting. Previously, as part of a large systematic resequencing of the X chromosome in 208 unrelated families with nonsyndromic X-linked intellectual disability, we identified three unique variants (two missense and one protein truncating) in <italic>USP9X</italic>. To assess the functional significance of these variants, we took advantage of the <italic>Usp9x</italic> knockout mouse we generated. Loss of <italic>Usp9x</italic> causes reduction in both axonal growth and neuronal cell migration. Although overexpression of wild-type human <italic>USP9X</italic> rescued these defects, all three <italic>USP9X</italic> variants failed to rescue axonal growth, caused reduced USP9X protein localization in axonal growth cones, and (in 2/3 variants) failed to rescue neuronal cell migration. Interestingly, in one of these families, the proband was subsequently identified to have a microdeletion encompassing <italic>ARID1B</italic>, a known ID gene. Given our findings it is plausible that loss of function of both genes contributes to the individual's phenotype. This case highlights the complexity of the interpretations of genetic findings from genome-wide investigations. We also performed proteomics analysis of neurons from both the wild-type and <italic>Usp9x</italic> knockout embryos and identified disruption of the cytoskeleton as the main underlying consequence of the loss of <italic>Usp9x</italic>. Detailed clinical assessment of all three families with <italic>USP9X</italic> variants identified hypotonia and behavioral and morphological defects as common features in addition to ID. Together our data support involvement of all three <italic>USP9X</italic> variants in ID in these families and provide likely cellular and molecular mechanisms involved.</p></div></front></TEI><pmc article-type="brief-report"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-id journal-id-type="iso-abbrev">Am. J. Hum. Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24607389</article-id><article-id pub-id-type="pmc">3951929</article-id><article-id pub-id-type="publisher-id">S0002-9297(14)00062-7</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2014.02.004</article-id><article-categories><subj-group subj-group-type="heading"><subject>Report</subject></subj-group></article-categories><title-group><article-title>Mutations in <italic>USP9X</italic> Are Associated with X-Linked Intellectual Disability and Disrupt Neuronal Cell Migration and Growth</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Homan</surname><given-names>Claire C.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Kumar</surname><given-names>Raman</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Nguyen</surname><given-names>Lam Son</given-names></name><xref rid="aff4" ref-type="aff">4</xref><xref rid="fn1" ref-type="fn">12</xref></contrib><contrib contrib-type="author"><name><surname>Haan</surname><given-names>Eric</given-names></name><xref rid="aff4" ref-type="aff">4</xref><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Raymond</surname><given-names>F. Lucy</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Abidi</surname><given-names>Fatima</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Raynaud</surname><given-names>Martine</given-names></name><xref rid="aff8" ref-type="aff">8</xref><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Schwartz</surname><given-names>Charles E.</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Wood</surname><given-names>Stephen A.</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Gecz</surname><given-names>Jozef</given-names></name><email>jozef.gecz@adelaide.edu.au</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff4" ref-type="aff">4</xref><xref rid="aff11" ref-type="aff">11</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Jolly</surname><given-names>Lachlan A.</given-names></name><email>lachlan.jolly@adelaide.edu.au</email><xref rid="aff4" ref-type="aff">4</xref><xref rid="aff11" ref-type="aff">11</xref><xref rid="cor2" ref-type="corresp">∗∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia</aff><aff id="aff2"><label>2</label>Women’s and Children’s Health Research Institute, North Adelaide, SA 5006, Australia</aff><aff id="aff3"><label>3</label>Discipline of Medicine, University of Adelaide, Adelaide, SA 5005, Australia</aff><aff id="aff4"><label>4</label>School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia</aff><aff id="aff5"><label>5</label>South Australian Clinical Genetics Service, SA Pathology at Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia</aff><aff id="aff6"><label>6</label>Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK</aff><aff id="aff7"><label>7</label>J.C. Self Research Institute, Greenwood Genetics Centre, Greenwood, SC 29646, USA</aff><aff id="aff8"><label>8</label>CHRU de Tours, Service de Génétique, Tours 37000, France</aff><aff id="aff9"><label>9</label>Inserm U930, UMR Imagerie et Cerveau, Tours 37000, France</aff><aff id="aff10"><label>10</label>Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia</aff><aff id="aff11"><label>11</label>Robinson Institute, University of Adelaide, Adelaide, SA 5005, Australia</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>jozef.gecz@adelaide.edu.au</email></corresp><corresp id="cor2"><label>∗∗</label>Corresponding author <email>lachlan.jolly@adelaide.edu.au</email></corresp><fn id="fn1"><label>12</label><p>Present address: Foundation Imagine, Hôpital Necker-Enfants Malades, Paris 75015, France</p></fn></author-notes><pub-date pub-type="ppub"><day>06</day><month>3</month><year>2014</year></pub-date><volume>94</volume><issue>3</issue><fpage>470</fpage><lpage>478</lpage><history><date date-type="received"><day>3</day><month>9</month><year>2013</year></date><date date-type="accepted"><day>13</day><month>2</month><year>2014</year></date></history><permissions><copyright-statement>© 2014 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement><copyright-year>2014</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><abstract><p>With a wealth of disease-associated DNA variants being recently reported, the challenges of providing their functional characterization are mounting. Previously, as part of a large systematic resequencing of the X chromosome in 208 unrelated families with nonsyndromic X-linked intellectual disability, we identified three unique variants (two missense and one protein truncating) in <italic>USP9X</italic>. To assess the functional significance of these variants, we took advantage of the <italic>Usp9x</italic> knockout mouse we generated. Loss of <italic>Usp9x</italic> causes reduction in both axonal growth and neuronal cell migration. Although overexpression of wild-type human <italic>USP9X</italic> rescued these defects, all three <italic>USP9X</italic> variants failed to rescue axonal growth, caused reduced USP9X protein localization in axonal growth cones, and (in 2/3 variants) failed to rescue neuronal cell migration. Interestingly, in one of these families, the proband was subsequently identified to have a microdeletion encompassing <italic>ARID1B</italic>, a known ID gene. Given our findings it is plausible that loss of function of both genes contributes to the individual's phenotype. This case highlights the complexity of the interpretations of genetic findings from genome-wide investigations. We also performed proteomics analysis of neurons from both the wild-type and <italic>Usp9x</italic> knockout embryos and identified disruption of the cytoskeleton as the main underlying consequence of the loss of <italic>Usp9x</italic>. Detailed clinical assessment of all three families with <italic>USP9X</italic> variants identified hypotonia and behavioral and morphological defects as common features in addition to ID. Together our data support involvement of all three <italic>USP9X</italic> variants in ID in these families and provide likely cellular and molecular mechanisms involved.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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