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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase <italic>HSD17B10</italic> and the E3 Ubiquitin Ligase <italic>HUWE1</italic> Are Associated with Mental Retardation</title><author><name sortKey="Froyen, Guy" sort="Froyen, Guy" uniqKey="Froyen G" first="Guy" last="Froyen">Guy Froyen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Corbett, Mark" sort="Corbett, Mark" uniqKey="Corbett M" first="Mark" last="Corbett">Mark Corbett</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Vandewalle, Joke" sort="Vandewalle, Joke" uniqKey="Vandewalle J" first="Joke" last="Vandewalle">Joke Vandewalle</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Jarvela, Irma" sort="Jarvela, Irma" uniqKey="Jarvela I" first="Irma" last="Jarvela">Irma Jarvela</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Lawrence, Owen" sort="Lawrence, Owen" uniqKey="Lawrence O" first="Owen" last="Lawrence">Owen Lawrence</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Meldrum, Cliff" sort="Meldrum, Cliff" uniqKey="Meldrum C" first="Cliff" last="Meldrum">Cliff Meldrum</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Bauters, Marijke" sort="Bauters, Marijke" uniqKey="Bauters M" first="Marijke" last="Bauters">Marijke Bauters</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Govaerts, Karen" sort="Govaerts, Karen" uniqKey="Govaerts K" first="Karen" last="Govaerts">Karen Govaerts</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Vandeleur, Lucianne" sort="Vandeleur, Lucianne" uniqKey="Vandeleur L" first="Lucianne" last="Vandeleur">Lucianne Vandeleur</name><affiliation><nlm:aff id="aff3"></nlm:aff></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><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"></nlm:aff></affiliation></author><author><name sortKey="Sanlaville, Damien" sort="Sanlaville, Damien" uniqKey="Sanlaville D" first="Damien" last="Sanlaville">Damien Sanlaville</name><affiliation><nlm:aff id="aff10"></nlm:aff></affiliation></author><author><name sortKey="Van Bokhoven, Hans" sort="Van Bokhoven, Hans" uniqKey="Van Bokhoven H" first="Hans" last="Van Bokhoven">Hans Van Bokhoven</name><affiliation><nlm:aff id="aff11"></nlm:aff></affiliation></author><author><name sortKey="Ropers, Hans Hilger" sort="Ropers, Hans Hilger" uniqKey="Ropers H" first="Hans-Hilger" last="Ropers">Hans-Hilger Ropers</name><affiliation><nlm:aff id="aff12"></nlm:aff></affiliation></author><author><name sortKey="Laumonnier, Frederic" sort="Laumonnier, Frederic" uniqKey="Laumonnier F" first="Frederic" last="Laumonnier">Frederic Laumonnier</name><affiliation><nlm:aff id="aff13"></nlm:aff></affiliation></author><author><name sortKey="Ranieri, Enzo" sort="Ranieri, Enzo" uniqKey="Ranieri E" first="Enzo" last="Ranieri">Enzo Ranieri</name><affiliation><nlm:aff id="aff3"></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="aff14"></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="aff14"></nlm:aff></affiliation></author><author><name sortKey="Tarpey, Patrick S" sort="Tarpey, Patrick S" uniqKey="Tarpey P" first="Patrick S." last="Tarpey">Patrick S. Tarpey</name><affiliation><nlm:aff id="aff15"></nlm:aff></affiliation></author><author><name sortKey="Futreal, P Andrew" sort="Futreal, P Andrew" uniqKey="Futreal P" first="P. Andrew" last="Futreal">P. Andrew Futreal</name><affiliation><nlm:aff id="aff15"></nlm:aff></affiliation></author><author><name sortKey="Whibley, Annabel" sort="Whibley, Annabel" uniqKey="Whibley A" first="Annabel" last="Whibley">Annabel Whibley</name><affiliation><nlm:aff id="aff16"></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="aff16"></nlm:aff></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R." last="Stratton">Michael R. Stratton</name><affiliation><nlm:aff id="aff15"></nlm:aff></affiliation></author><author><name sortKey="Fryns, Jean Pierre" sort="Fryns, Jean Pierre" uniqKey="Fryns J" first="Jean-Pierre" last="Fryns">Jean-Pierre Fryns</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Scott, Rodney" sort="Scott, Rodney" uniqKey="Scott R" first="Rodney" last="Scott">Rodney Scott</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Peippo, Maarit" sort="Peippo, Maarit" uniqKey="Peippo M" first="Maarit" last="Peippo">Maarit Peippo</name><affiliation><nlm:aff id="aff17"></nlm:aff></affiliation></author><author><name sortKey="Sipponen, Marjatta" sort="Sipponen, Marjatta" uniqKey="Sipponen M" first="Marjatta" last="Sipponen">Marjatta Sipponen</name><affiliation><nlm:aff id="aff17"></nlm:aff></affiliation></author><author><name sortKey="Partington, Michael" sort="Partington, Michael" uniqKey="Partington M" first="Michael" last="Partington">Michael Partington</name><affiliation><nlm:aff id="aff18"></nlm:aff></affiliation></author><author><name sortKey="Mowat, David" sort="Mowat, David" uniqKey="Mowat D" first="David" last="Mowat">David Mowat</name><affiliation><nlm:aff id="aff19"></nlm:aff></affiliation></author><author><name sortKey="Field, Michael" sort="Field, Michael" uniqKey="Field M" first="Michael" last="Field">Michael Field</name><affiliation><nlm:aff id="aff18"></nlm:aff></affiliation></author><author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name><affiliation><nlm:aff id="aff18"></nlm:aff></affiliation></author><author><name sortKey="Marynen, Peter" sort="Marynen, Peter" uniqKey="Marynen P" first="Peter" last="Marynen">Peter Marynen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Turner, Gillian" sort="Turner, Gillian" uniqKey="Turner G" first="Gillian" last="Turner">Gillian Turner</name><affiliation><nlm:aff id="aff18"></nlm:aff></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gécz">Jozef Gécz</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation><affiliation><nlm:aff id="aff20"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">18252223</idno><idno type="pmc">2426915</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2426915</idno><idno type="RBID">PMC:2426915</idno><idno type="doi">10.1016/j.ajhg.2007.11.002</idno><date when="2008">2008</date><idno type="wicri:Area/Pmc/Corpus">001701</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001701</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase <italic>HSD17B10</italic> and the E3 Ubiquitin Ligase <italic>HUWE1</italic> Are Associated with Mental Retardation</title><author><name sortKey="Froyen, Guy" sort="Froyen, Guy" uniqKey="Froyen G" first="Guy" last="Froyen">Guy Froyen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Corbett, Mark" sort="Corbett, Mark" uniqKey="Corbett M" first="Mark" last="Corbett">Mark Corbett</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Vandewalle, Joke" sort="Vandewalle, Joke" uniqKey="Vandewalle J" first="Joke" last="Vandewalle">Joke Vandewalle</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Jarvela, Irma" sort="Jarvela, Irma" uniqKey="Jarvela I" first="Irma" last="Jarvela">Irma Jarvela</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Lawrence, Owen" sort="Lawrence, Owen" uniqKey="Lawrence O" first="Owen" last="Lawrence">Owen Lawrence</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Meldrum, Cliff" sort="Meldrum, Cliff" uniqKey="Meldrum C" first="Cliff" last="Meldrum">Cliff Meldrum</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Bauters, Marijke" sort="Bauters, Marijke" uniqKey="Bauters M" first="Marijke" last="Bauters">Marijke Bauters</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Govaerts, Karen" sort="Govaerts, Karen" uniqKey="Govaerts K" first="Karen" last="Govaerts">Karen Govaerts</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Vandeleur, Lucianne" sort="Vandeleur, Lucianne" uniqKey="Vandeleur L" first="Lucianne" last="Vandeleur">Lucianne Vandeleur</name><affiliation><nlm:aff id="aff3"></nlm:aff></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><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"></nlm:aff></affiliation></author><author><name sortKey="Sanlaville, Damien" sort="Sanlaville, Damien" uniqKey="Sanlaville D" first="Damien" last="Sanlaville">Damien Sanlaville</name><affiliation><nlm:aff id="aff10"></nlm:aff></affiliation></author><author><name sortKey="Van Bokhoven, Hans" sort="Van Bokhoven, Hans" uniqKey="Van Bokhoven H" first="Hans" last="Van Bokhoven">Hans Van Bokhoven</name><affiliation><nlm:aff id="aff11"></nlm:aff></affiliation></author><author><name sortKey="Ropers, Hans Hilger" sort="Ropers, Hans Hilger" uniqKey="Ropers H" first="Hans-Hilger" last="Ropers">Hans-Hilger Ropers</name><affiliation><nlm:aff id="aff12"></nlm:aff></affiliation></author><author><name sortKey="Laumonnier, Frederic" sort="Laumonnier, Frederic" uniqKey="Laumonnier F" first="Frederic" last="Laumonnier">Frederic Laumonnier</name><affiliation><nlm:aff id="aff13"></nlm:aff></affiliation></author><author><name sortKey="Ranieri, Enzo" sort="Ranieri, Enzo" uniqKey="Ranieri E" first="Enzo" last="Ranieri">Enzo Ranieri</name><affiliation><nlm:aff id="aff3"></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="aff14"></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="aff14"></nlm:aff></affiliation></author><author><name sortKey="Tarpey, Patrick S" sort="Tarpey, Patrick S" uniqKey="Tarpey P" first="Patrick S." last="Tarpey">Patrick S. Tarpey</name><affiliation><nlm:aff id="aff15"></nlm:aff></affiliation></author><author><name sortKey="Futreal, P Andrew" sort="Futreal, P Andrew" uniqKey="Futreal P" first="P. Andrew" last="Futreal">P. Andrew Futreal</name><affiliation><nlm:aff id="aff15"></nlm:aff></affiliation></author><author><name sortKey="Whibley, Annabel" sort="Whibley, Annabel" uniqKey="Whibley A" first="Annabel" last="Whibley">Annabel Whibley</name><affiliation><nlm:aff id="aff16"></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="aff16"></nlm:aff></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R." last="Stratton">Michael R. Stratton</name><affiliation><nlm:aff id="aff15"></nlm:aff></affiliation></author><author><name sortKey="Fryns, Jean Pierre" sort="Fryns, Jean Pierre" uniqKey="Fryns J" first="Jean-Pierre" last="Fryns">Jean-Pierre Fryns</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Scott, Rodney" sort="Scott, Rodney" uniqKey="Scott R" first="Rodney" last="Scott">Rodney Scott</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Peippo, Maarit" sort="Peippo, Maarit" uniqKey="Peippo M" first="Maarit" last="Peippo">Maarit Peippo</name><affiliation><nlm:aff id="aff17"></nlm:aff></affiliation></author><author><name sortKey="Sipponen, Marjatta" sort="Sipponen, Marjatta" uniqKey="Sipponen M" first="Marjatta" last="Sipponen">Marjatta Sipponen</name><affiliation><nlm:aff id="aff17"></nlm:aff></affiliation></author><author><name sortKey="Partington, Michael" sort="Partington, Michael" uniqKey="Partington M" first="Michael" last="Partington">Michael Partington</name><affiliation><nlm:aff id="aff18"></nlm:aff></affiliation></author><author><name sortKey="Mowat, David" sort="Mowat, David" uniqKey="Mowat D" first="David" last="Mowat">David Mowat</name><affiliation><nlm:aff id="aff19"></nlm:aff></affiliation></author><author><name sortKey="Field, Michael" sort="Field, Michael" uniqKey="Field M" first="Michael" last="Field">Michael Field</name><affiliation><nlm:aff id="aff18"></nlm:aff></affiliation></author><author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name><affiliation><nlm:aff id="aff18"></nlm:aff></affiliation></author><author><name sortKey="Marynen, Peter" sort="Marynen, Peter" uniqKey="Marynen P" first="Peter" last="Marynen">Peter Marynen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Turner, Gillian" sort="Turner, Gillian" uniqKey="Turner G" first="Gillian" last="Turner">Gillian Turner</name><affiliation><nlm:aff id="aff18"></nlm:aff></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gécz">Jozef Gécz</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation><affiliation><nlm:aff id="aff20"></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="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: <italic>RIBC1</italic>, <italic>HSD17B10</italic>, and <italic>HUWE1</italic>. <italic>RIBC1</italic> could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of <italic>HSD17B10</italic> and <italic>HUWE1</italic> as well as several important genes in their molecular pathways. Loss-of-function mutations of <italic>HSD17B10</italic> have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in <italic>HUWE1</italic> in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of <italic>HSD17B10</italic>, <italic>HUWE1</italic>, or both contribute to the etiology of XLMR and suggest that point mutations in <italic>HUWE1</italic> are associated with this disease too.</p></div></front></TEI><pmc article-type="research-article"><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-title>American Journal of Human Genetics</journal-title><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>American Society of Human Genetics</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">18252223</article-id><article-id pub-id-type="pmc">2426915</article-id><article-id pub-id-type="publisher-id">AJHG35</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2007.11.002</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase <italic>HSD17B10</italic> and the E3 Ubiquitin Ligase <italic>HUWE1</italic> Are Associated with Mental Retardation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Froyen</surname><given-names>Guy</given-names></name><email>guy.froyen@med.kuleuven.be</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Corbett</surname><given-names>Mark</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Vandewalle</surname><given-names>Joke</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Jarvela</surname><given-names>Irma</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>Lawrence</surname><given-names>Owen</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Meldrum</surname><given-names>Cliff</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Bauters</surname><given-names>Marijke</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Govaerts</surname><given-names>Karen</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Vandeleur</surname><given-names>Lucianne</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Van Esch</surname><given-names>Hilde</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Chelly</surname><given-names>Jamel</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>Sanlaville</surname><given-names>Damien</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>van Bokhoven</surname><given-names>Hans</given-names></name><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Ropers</surname><given-names>Hans-Hilger</given-names></name><xref rid="aff12" ref-type="aff">12</xref></contrib><contrib contrib-type="author"><name><surname>Laumonnier</surname><given-names>Frederic</given-names></name><xref rid="aff13" ref-type="aff">13</xref></contrib><contrib contrib-type="author"><name><surname>Ranieri</surname><given-names>Enzo</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Schwartz</surname><given-names>Charles E.</given-names></name><xref rid="aff14" ref-type="aff">14</xref></contrib><contrib contrib-type="author"><name><surname>Abidi</surname><given-names>Fatima</given-names></name><xref rid="aff14" ref-type="aff">14</xref></contrib><contrib contrib-type="author"><name><surname>Tarpey</surname><given-names>Patrick S.</given-names></name><xref rid="aff15" ref-type="aff">15</xref></contrib><contrib contrib-type="author"><name><surname>Futreal</surname><given-names>P. Andrew</given-names></name><xref rid="aff15" ref-type="aff">15</xref></contrib><contrib contrib-type="author"><name><surname>Whibley</surname><given-names>Annabel</given-names></name><xref rid="aff16" ref-type="aff">16</xref></contrib><contrib contrib-type="author"><name><surname>Raymond</surname><given-names>F. Lucy</given-names></name><xref rid="aff16" ref-type="aff">16</xref></contrib><contrib contrib-type="author"><name><surname>Stratton</surname><given-names>Michael R.</given-names></name><xref rid="aff15" ref-type="aff">15</xref></contrib><contrib contrib-type="author"><name><surname>Fryns</surname><given-names>Jean-Pierre</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Scott</surname><given-names>Rodney</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Peippo</surname><given-names>Maarit</given-names></name><xref rid="aff17" ref-type="aff">17</xref></contrib><contrib contrib-type="author"><name><surname>Sipponen</surname><given-names>Marjatta</given-names></name><xref rid="aff17" ref-type="aff">17</xref></contrib><contrib contrib-type="author"><name><surname>Partington</surname><given-names>Michael</given-names></name><xref rid="aff18" ref-type="aff">18</xref></contrib><contrib contrib-type="author"><name><surname>Mowat</surname><given-names>David</given-names></name><xref rid="aff19" ref-type="aff">19</xref></contrib><contrib contrib-type="author"><name><surname>Field</surname><given-names>Michael</given-names></name><xref rid="aff18" ref-type="aff">18</xref></contrib><contrib contrib-type="author"><name><surname>Hackett</surname><given-names>Anna</given-names></name><xref rid="aff18" ref-type="aff">18</xref></contrib><contrib contrib-type="author"><name><surname>Marynen</surname><given-names>Peter</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Turner</surname><given-names>Gillian</given-names></name><xref rid="aff18" ref-type="aff">18</xref></contrib><contrib contrib-type="author"><name><surname>Gécz</surname><given-names>Jozef</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff20" ref-type="aff">20</xref></contrib></contrib-group><aff id="aff1"><addr-line><sup>1</sup>Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium</addr-line></aff><aff id="aff2"><addr-line><sup>2</sup>Human Genome Laboratory, Department of Human Genetics, K.U.Leuven, B-3000 Leuven, Belgium</addr-line></aff><aff id="aff3"><addr-line><sup>3</sup>Department of Genetic Medicine, Women's and Children's Hospital, Adelaide SA 5005, Australia</addr-line></aff><aff id="aff4"><addr-line><sup>4</sup>Laboratory of Molecular Genetics, Helsinki University Central Hospital (Laboratory Services), 00290 Helsinki, Finland</addr-line></aff><aff id="aff5"><addr-line><sup>5</sup>Department of Medical Genetics, University of Helsinki, 00290 Helsinki, Finland</addr-line></aff><aff id="aff6"><addr-line><sup>6</sup>Molecular Genetics Laboratory HAPS, John Hunter Hospital, Newcastle NSW 2305, Australia</addr-line></aff><aff id="aff7"><addr-line><sup>7</sup>University Hospital Leuven, Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium</addr-line></aff><aff id="aff8"><addr-line><sup>8</sup>Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), F-75014 Paris, France</addr-line></aff><aff id="aff9"><addr-line><sup>9</sup>Inserm, U567, F-75014 Paris, France</addr-line></aff><aff id="aff10"><addr-line><sup>10</sup>Genetic Department, Necker Enfants Malades Hospital, F-75935 Paris, France</addr-line></aff><aff id="aff11"><addr-line><sup>11</sup>Department of Human Genetics, University Medical Centre, NL-6500 Nijmegen, The Netherlands</addr-line></aff><aff id="aff12"><addr-line><sup>12</sup>Max-Planck Institute for Molecular Genetics, D-14195 Berlin, Germany</addr-line></aff><aff id="aff13"><addr-line><sup>13</sup>INSERM, U619, Centre Hospitalier Universitaire Bretonneau, Université François Rabelais, F-37044 Tours, France</addr-line></aff><aff id="aff14"><addr-line><sup>14</sup>Greenwood Genetic Center, JC Self Research Institute of Human Genetics, Greenwood, SC 29646, USA</addr-line></aff><aff id="aff15"><addr-line><sup>15</sup>The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK</addr-line></aff><aff id="aff16"><addr-line><sup>16</sup>Cambridge Institute of Medical Research, Cambridge CB2 2XY, UK</addr-line></aff><aff id="aff17"><addr-line><sup>17</sup>The Family Federation of Finland, 00101 Helsinki, Finland</addr-line></aff><aff id="aff18"><addr-line><sup>18</sup>The GOLD service Hunter Genetics University of Newcastle, New South Wales NSW 2308, Australia</addr-line></aff><aff id="aff19"><addr-line><sup>19</sup>Department of Genetics, Sydney Children's Hospital, New South Wales NSW 2308, Australia</addr-line></aff><aff id="aff20"><addr-line><sup>20</sup>Department of Pediatrics and School of Molecular and Biomedical Science, University of Adelaide, Adelaide SA 5005, Australia</addr-line></aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>guy.froyen@med.kuleuven.be</email></corresp></author-notes><pub-date pub-type="ppub"><day>08</day><month>2</month><year>2008</year></pub-date><pub-date pub-type="epub"><day>01</day><month>2</month><year>2008</year></pub-date><volume>82</volume><issue>2</issue><fpage>432</fpage><lpage>443</lpage><history><date date-type="received"><day>10</day><month>9</month><year>2007</year></date><date date-type="rev-recd"><day>17</day><month>10</month><year>2007</year></date><date date-type="accepted"><day>1</day><month>11</month><year>2007</year></date></history><permissions><copyright-statement>© 2008 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved..</copyright-statement><copyright-year>2008</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder><license><p>This document may be redistributed and reused, subject to <ext-link ext-link-type="uri" xlink:href="http://www.elsevier.com/wps/find/authorsview.authors/supplementalterms1.0">certain conditions</ext-link>.</p></license></permissions><abstract><p>Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: <italic>RIBC1</italic>, <italic>HSD17B10</italic>, and <italic>HUWE1</italic>. <italic>RIBC1</italic> could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of <italic>HSD17B10</italic> and <italic>HUWE1</italic> as well as several important genes in their molecular pathways. Loss-of-function mutations of <italic>HSD17B10</italic> have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in <italic>HUWE1</italic> in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of <italic>HSD17B10</italic>, <italic>HUWE1</italic>, or both contribute to the etiology of XLMR and suggest that point mutations in <italic>HUWE1</italic> are associated with this disease too.</p></abstract></article-meta></front><floats-wrap><fig id="fig1"><label>Figure 1</label><caption><p>Pictures of the Three Affected Individuals of FAM3 with a Duplication at Xp11.22</p><p>Facial features of the sons (from left to right; III-3, III-2, and III-1). Note hypertelorism, short and upslanting palpebral fissures, epicanthi, lateral flare of eyebrows, broad nose, simple protruding ears, open mouth, and thick lips.</p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Pedigrees of Families with a Microduplication at Xp11.22</p><p>(A) FAM3, (B) MRX17, (C) MRX31, (D) A057, (E) A119, and (F) P083. Family members that could be tested for the duplication are indicated as N (do not carry the duplication) or D (carry the duplication).</p></caption><graphic xlink:href="gr2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>Pedigrees of Families with a Sequence Change in <italic>HUWE1</italic></p><p>(A) A323, (B) UK444, and (C) UK106. Additional family members that were screened are indicated on the pedigrees as WT or WT/WT (do not carry the likely mutation), mut (carry the mutation), or WT/mut (heterozygous for the mutation). For the large family A323, the <italic>HUWE1</italic> gene is located within the linked interval.<xref rid="bib18" ref-type="bibr"><sup>18</sup></xref> Female I.2 of family UK106 most probably is germline mosaic. Pictures of the affected individual III-6 and III-7 of family UK106 are shown.</p></caption><graphic xlink:href="gr3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>X Chromosome-Specific Array-CGH Plots Obtained for Probands of Four Families Revealing the Duplications at Xp11.22</p><p>These families are (A) FAM3, (B) MRX17, (C) MRX31, and (D) A057. DNA from two unrelated MR patients were differentially labeled and cohybridized onto the X array. The log<sub>2</sub> normalized intensity ratios of the Cy5 (patient with duplication) and Cy3 (unrelated MR patient, named pat A–D) signals is plotted (y axis) against the position on the X chromosome (in Mb), from Xpter to Xqter (x axis). The duplications are visible as clones with aberrant ratios >0.3 at ∼53 Mb. For A057, an additional polymorphic duplication is visible as three aberrant clones at 38 Mb. Other clones outside the normal interval (log<sub>2</sub> ratio of −0.3 to 0.3) are polymorphic clones or outliers.</p></caption><graphic xlink:href="gr4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Schematic Representation of the Xp11.22 Region Showing the Duplications</p><p>(A) Indicated from top to bottom: the location of the qPCR primer sets (1–20), genomic BAC or PAC clones, and annotated genes present in the interval composed of the six duplications. This region is represented for each family by the arrows indicating the genomic clones from the X array with their corresponding log<sub>2</sub> ratios. Clones with aberrant ratios are in green; those with ratios in the normal interval are open. For each family, the mapped duplicated region, defined by qPCR, is given as solid blue bars above these clones, indicating that the primer sets within these bars yielded relative copy numbers of ∼2.0 whereas the primer pairs outside (indicated with the gray bars) gave values ∼1.0. Proximal and distal breakpoints must lie between these bars (no bars).</p><p>(B) For P083, only qPCR data are shown. The maximal common duplicated region is boxed (broken red line) and entirely contains the genes <italic>RIBC1</italic>, <italic>HSD17B10</italic>, and <italic>HUWE1</italic>.</p></caption><graphic xlink:href="gr5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>Representative FISH Data on Chromosomes from Probands of Families MRX17, MRX31, and A057</p><p>(A) Labeled DNA of RP6-29D12 (red) and RP1-154P24 (green) were hybridized to metaphase spreads and show signals for both probes only at Xp11.</p><p>(B) On interphase chromosomes, alternating red-green-red-green signals are indicative of a tandem duplication event.</p></caption><graphic xlink:href="gr6"></graphic></fig><fig id="fig7"><label>Figure 7</label><caption><p>mRNA Expression Analysis of <italic>SMC1A</italic>, <italic>HSD17B10</italic>, and <italic>HUWE1</italic> in All Six Families with a Duplication at Xp11.22</p><p>cDNA was prepared from RNA extracted from blood (controls and FAM3) or EBV-transformed PBL cell lines (controls, MRX17, MRX31, A057, A119, and P083). Compared to controls, all affected individuals showed significantly increased mRNA levels for all three genes except for <italic>SMC1A</italic> in family P083. Expression was determined by real-time RT-PCR with the comparative ddCt method and normalized to the expression of <italic>HPRT</italic> and <italic>ACTB</italic> (FAM3, P083) or with the standard curve method with <italic>ACTB</italic> for normalization (MRX17, MRX31, A057, and A119). Expression levels are calculated relative to the mean levels obtained in the control samples (fold difference; y axis). Standard deviations of at least two independent experiments are indicated for each bar.</p></caption><graphic xlink:href="gr7"></graphic></fig><fig id="fig8"><label>Figure 8</label><caption><p>Missense Changes in the <italic>HUWE1</italic> Gene Identified in Three XLMR Families</p><p>Partial ClustalW alignments of HUWE1 orthologs in the regions surrounding (A) R2981H (UK106), (B) R4013W (A323), and (C) R4187C (UK444) amino acid changes. Whereas the R2981 is invariable across all orthologs, R4013 and R4187 are highly conserved. In (D), the position of these arginine residues within the HUWE1 protein is indicated with the arrows. The cartoon above the conservation plot (Scorecons) indicates domains within the HUWE1 protein. Pfam 06012 (aa 104–374) and Pfam 06025 (aa 424–704 and 762–815) domains are of unknown function, WWE domain (aa 1617–1678) might be involved in the regulation of ubiquitin-mediated proteolysis, and HECT domain (aa 4036–4374) is the catalytic domain of HUWE1 ubiquitin protein ligase.</p></caption><graphic xlink:href="gr8"></graphic></fig></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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