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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mutations in <italic>MAP3K1</italic>
Cause 46,XY Disorders of Sex Development and Implicate a Common Signal Transduction Pathway in Human Testis Determination</title>
<author><name sortKey="Pearlman, Alexander" sort="Pearlman, Alexander" uniqKey="Pearlman A" first="Alexander" last="Pearlman">Alexander Pearlman</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Loke, Johnny" sort="Loke, Johnny" uniqKey="Loke J" first="Johnny" last="Loke">Johnny Loke</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Le Caignec, Cedric" sort="Le Caignec, Cedric" uniqKey="Le Caignec C" first="Cedric" last="Le Caignec">Cedric Le Caignec</name>
<affiliation><nlm:aff id="aff2">CHU Nantes, Service de Génétique Medicale, 44093 Nantes, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff3">INSERM, UMR915, l'Institut du thorax, 44007 Nantes, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="White, Stefan" sort="White, Stefan" uniqKey="White S" first="Stefan" last="White">Stefan White</name>
<affiliation><nlm:aff id="aff4">Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chin, Lisa" sort="Chin, Lisa" uniqKey="Chin L" first="Lisa" last="Chin">Lisa Chin</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Friedman, Andrew" sort="Friedman, Andrew" uniqKey="Friedman A" first="Andrew" last="Friedman">Andrew Friedman</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Warr, Nicholas" sort="Warr, Nicholas" uniqKey="Warr N" first="Nicholas" last="Warr">Nicholas Warr</name>
<affiliation><nlm:aff id="aff5">MRC Mammalian Genetics Unit, Harwell, OX11 0RD, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Willan, John" sort="Willan, John" uniqKey="Willan J" first="John" last="Willan">John Willan</name>
<affiliation><nlm:aff id="aff5">MRC Mammalian Genetics Unit, Harwell, OX11 0RD, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Brauer, David" sort="Brauer, David" uniqKey="Brauer D" first="David" last="Brauer">David Brauer</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Farmer, Charles" sort="Farmer, Charles" uniqKey="Farmer C" first="Charles" last="Farmer">Charles Farmer</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Brooks, Eric" sort="Brooks, Eric" uniqKey="Brooks E" first="Eric" last="Brooks">Eric Brooks</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Oddoux, Carole" sort="Oddoux, Carole" uniqKey="Oddoux C" first="Carole" last="Oddoux">Carole Oddoux</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Riley, Bridget" sort="Riley, Bridget" uniqKey="Riley B" first="Bridget" last="Riley">Bridget Riley</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shajahan, Shahin" sort="Shajahan, Shahin" uniqKey="Shajahan S" first="Shahin" last="Shajahan">Shahin Shajahan</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Camerino, Giovanna" sort="Camerino, Giovanna" uniqKey="Camerino G" first="Giovanna" last="Camerino">Giovanna Camerino</name>
<affiliation><nlm:aff id="aff6">Dipartimento di Patologia Umana ed Ereditaria, Università di Pavia, 27100 Pavia, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Homfray, Tessa" sort="Homfray, Tessa" uniqKey="Homfray T" first="Tessa" last="Homfray">Tessa Homfray</name>
<affiliation><nlm:aff id="aff7">Clinical Developmental Sciences, Saint George's Hospital Medical School, London SW17 0RE, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Crosby, Andrew H" sort="Crosby, Andrew H" uniqKey="Crosby A" first="Andrew H." last="Crosby">Andrew H. Crosby</name>
<affiliation><nlm:aff id="aff7">Clinical Developmental Sciences, Saint George's Hospital Medical School, London SW17 0RE, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Couper, Jenny" sort="Couper, Jenny" uniqKey="Couper J" first="Jenny" last="Couper">Jenny Couper</name>
<affiliation><nlm:aff id="aff8">Department of Diabetes & Endocrinology, Women's & Children's Hospital, Adelaide SA 5006, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="David, Albert" sort="David, Albert" uniqKey="David A" first="Albert" last="David">Albert David</name>
<affiliation><nlm:aff id="aff2">CHU Nantes, Service de Génétique Medicale, 44093 Nantes, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Greenfield, Andy" sort="Greenfield, Andy" uniqKey="Greenfield A" first="Andy" last="Greenfield">Andy Greenfield</name>
<affiliation><nlm:aff id="aff5">MRC Mammalian Genetics Unit, Harwell, OX11 0RD, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sinclair, Andrew" sort="Sinclair, Andrew" uniqKey="Sinclair A" first="Andrew" last="Sinclair">Andrew Sinclair</name>
<affiliation><nlm:aff id="aff4">Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ostrer, Harry" sort="Ostrer, Harry" uniqKey="Ostrer H" first="Harry" last="Ostrer">Harry Ostrer</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">21129722</idno>
<idno type="pmc">2997363</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997363</idno>
<idno type="RBID">PMC:2997363</idno>
<idno type="doi">10.1016/j.ajhg.2010.11.003</idno>
<date when="2010">2010</date>
<idno type="wicri:Area/Pmc/Corpus">001222</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001222</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutations in <italic>MAP3K1</italic>
Cause 46,XY Disorders of Sex Development and Implicate a Common Signal Transduction Pathway in Human Testis Determination</title>
<author><name sortKey="Pearlman, Alexander" sort="Pearlman, Alexander" uniqKey="Pearlman A" first="Alexander" last="Pearlman">Alexander Pearlman</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Loke, Johnny" sort="Loke, Johnny" uniqKey="Loke J" first="Johnny" last="Loke">Johnny Loke</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Le Caignec, Cedric" sort="Le Caignec, Cedric" uniqKey="Le Caignec C" first="Cedric" last="Le Caignec">Cedric Le Caignec</name>
<affiliation><nlm:aff id="aff2">CHU Nantes, Service de Génétique Medicale, 44093 Nantes, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff3">INSERM, UMR915, l'Institut du thorax, 44007 Nantes, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="White, Stefan" sort="White, Stefan" uniqKey="White S" first="Stefan" last="White">Stefan White</name>
<affiliation><nlm:aff id="aff4">Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chin, Lisa" sort="Chin, Lisa" uniqKey="Chin L" first="Lisa" last="Chin">Lisa Chin</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Friedman, Andrew" sort="Friedman, Andrew" uniqKey="Friedman A" first="Andrew" last="Friedman">Andrew Friedman</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Warr, Nicholas" sort="Warr, Nicholas" uniqKey="Warr N" first="Nicholas" last="Warr">Nicholas Warr</name>
<affiliation><nlm:aff id="aff5">MRC Mammalian Genetics Unit, Harwell, OX11 0RD, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Willan, John" sort="Willan, John" uniqKey="Willan J" first="John" last="Willan">John Willan</name>
<affiliation><nlm:aff id="aff5">MRC Mammalian Genetics Unit, Harwell, OX11 0RD, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Brauer, David" sort="Brauer, David" uniqKey="Brauer D" first="David" last="Brauer">David Brauer</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Farmer, Charles" sort="Farmer, Charles" uniqKey="Farmer C" first="Charles" last="Farmer">Charles Farmer</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Brooks, Eric" sort="Brooks, Eric" uniqKey="Brooks E" first="Eric" last="Brooks">Eric Brooks</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Oddoux, Carole" sort="Oddoux, Carole" uniqKey="Oddoux C" first="Carole" last="Oddoux">Carole Oddoux</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Riley, Bridget" sort="Riley, Bridget" uniqKey="Riley B" first="Bridget" last="Riley">Bridget Riley</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shajahan, Shahin" sort="Shajahan, Shahin" uniqKey="Shajahan S" first="Shahin" last="Shajahan">Shahin Shajahan</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Camerino, Giovanna" sort="Camerino, Giovanna" uniqKey="Camerino G" first="Giovanna" last="Camerino">Giovanna Camerino</name>
<affiliation><nlm:aff id="aff6">Dipartimento di Patologia Umana ed Ereditaria, Università di Pavia, 27100 Pavia, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Homfray, Tessa" sort="Homfray, Tessa" uniqKey="Homfray T" first="Tessa" last="Homfray">Tessa Homfray</name>
<affiliation><nlm:aff id="aff7">Clinical Developmental Sciences, Saint George's Hospital Medical School, London SW17 0RE, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Crosby, Andrew H" sort="Crosby, Andrew H" uniqKey="Crosby A" first="Andrew H." last="Crosby">Andrew H. Crosby</name>
<affiliation><nlm:aff id="aff7">Clinical Developmental Sciences, Saint George's Hospital Medical School, London SW17 0RE, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Couper, Jenny" sort="Couper, Jenny" uniqKey="Couper J" first="Jenny" last="Couper">Jenny Couper</name>
<affiliation><nlm:aff id="aff8">Department of Diabetes & Endocrinology, Women's & Children's Hospital, Adelaide SA 5006, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="David, Albert" sort="David, Albert" uniqKey="David A" first="Albert" last="David">Albert David</name>
<affiliation><nlm:aff id="aff2">CHU Nantes, Service de Génétique Medicale, 44093 Nantes, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Greenfield, Andy" sort="Greenfield, Andy" uniqKey="Greenfield A" first="Andy" last="Greenfield">Andy Greenfield</name>
<affiliation><nlm:aff id="aff5">MRC Mammalian Genetics Unit, Harwell, OX11 0RD, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sinclair, Andrew" sort="Sinclair, Andrew" uniqKey="Sinclair A" first="Andrew" last="Sinclair">Andrew Sinclair</name>
<affiliation><nlm:aff id="aff4">Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ostrer, Harry" sort="Ostrer, Harry" uniqKey="Ostrer H" first="Harry" last="Ostrer">Harry Ostrer</name>
<affiliation><nlm:aff id="aff1">Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</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="2010">2010</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Investigations of humans with disorders of sex development (DSDs) resulted in the discovery of many of the now-known mammalian sex-determining genes, including <italic>SRY, RSPO1, SOX9</italic>
, <italic>NR5A1</italic>
, <italic>WT1</italic>
, <italic>NR0B1</italic>
, and <italic>WNT4</italic>
. Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21. A splice-acceptor mutation (c.634-8T>A) in <italic>MAP3K1</italic>
segregated with the phenotype in the first family and disrupted RNA splicing. Mutations were demonstrated in the second family (p.Gly616Arg) and in two of 11 sporadic cases (p.Leu189Pro, p.Leu189Arg)—18% prevalence in this cohort of sporadic cases. In cultured primary lymphoblastoid cells from family 1 and the two sporadic cases, these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex. <italic>Map3k1</italic>
within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination. Thus, mutations in <italic>MAP3K1</italic>
that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination.</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-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">21129722</article-id>
<article-id pub-id-type="pmc">2997363</article-id>
<article-id pub-id-type="publisher-id">AJHG792</article-id>
<article-id pub-id-type="doi">10.1016/j.ajhg.2010.11.003</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Report</subject>
</subj-group>
</article-categories>
<title-group><article-title>Mutations in <italic>MAP3K1</italic>
Cause 46,XY Disorders of Sex Development and Implicate a Common Signal Transduction Pathway in Human Testis Determination</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Pearlman</surname>
<given-names>Alexander</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Loke</surname>
<given-names>Johnny</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Le Caignec</surname>
<given-names>Cedric</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="aff3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>White</surname>
<given-names>Stefan</given-names>
</name>
<xref rid="aff4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chin</surname>
<given-names>Lisa</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Friedman</surname>
<given-names>Andrew</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Warr</surname>
<given-names>Nicholas</given-names>
</name>
<xref rid="aff5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Willan</surname>
<given-names>John</given-names>
</name>
<xref rid="aff5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brauer</surname>
<given-names>David</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Farmer</surname>
<given-names>Charles</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brooks</surname>
<given-names>Eric</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Oddoux</surname>
<given-names>Carole</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Riley</surname>
<given-names>Bridget</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shajahan</surname>
<given-names>Shahin</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Camerino</surname>
<given-names>Giovanna</given-names>
</name>
<xref rid="aff6" ref-type="aff">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Homfray</surname>
<given-names>Tessa</given-names>
</name>
<xref rid="aff7" ref-type="aff">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Crosby</surname>
<given-names>Andrew H.</given-names>
</name>
<xref rid="aff7" ref-type="aff">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Couper</surname>
<given-names>Jenny</given-names>
</name>
<xref rid="aff8" ref-type="aff">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>David</surname>
<given-names>Albert</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Greenfield</surname>
<given-names>Andy</given-names>
</name>
<xref rid="aff5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sinclair</surname>
<given-names>Andrew</given-names>
</name>
<xref rid="aff4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ostrer</surname>
<given-names>Harry</given-names>
</name>
<email>harry.ostrer@nyumc.org</email>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="cor1" ref-type="corresp">∗</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
Human Genetics Program, New York University School of Medicine, New York, NY 10016, USA</aff>
<aff id="aff2"><label>2</label>
CHU Nantes, Service de Génétique Medicale, 44093 Nantes, France</aff>
<aff id="aff3"><label>3</label>
INSERM, UMR915, l'Institut du thorax, 44007 Nantes, France</aff>
<aff id="aff4"><label>4</label>
Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia</aff>
<aff id="aff5"><label>5</label>
MRC Mammalian Genetics Unit, Harwell, OX11 0RD, UK</aff>
<aff id="aff6"><label>6</label>
Dipartimento di Patologia Umana ed Ereditaria, Università di Pavia, 27100 Pavia, Italy</aff>
<aff id="aff7"><label>7</label>
Clinical Developmental Sciences, Saint George's Hospital Medical School, London SW17 0RE, UK</aff>
<aff id="aff8"><label>8</label>
Department of Diabetes & Endocrinology, Women's & Children's Hospital, Adelaide SA 5006, Australia</aff>
<author-notes><corresp id="cor1"><label>∗</label>
Corresponding author <email>harry.ostrer@nyumc.org</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><day>10</day>
<month>12</month>
<year>2010</year>
</pub-date>
<volume>87</volume>
<issue>6</issue>
<fpage>898</fpage>
<lpage>904</lpage>
<history><date date-type="received"><day>24</day>
<month>9</month>
<year>2010</year>
</date>
<date date-type="rev-recd"><day>2</day>
<month>11</month>
<year>2010</year>
</date>
<date date-type="accepted"><day>9</day>
<month>11</month>
<year>2010</year>
</date>
</history>
<permissions><copyright-statement>© 2010 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement>
<copyright-year>2010</copyright-year>
<copyright-holder>The American Society of Human Genetics</copyright-holder>
</permissions>
<abstract><p>Investigations of humans with disorders of sex development (DSDs) resulted in the discovery of many of the now-known mammalian sex-determining genes, including <italic>SRY, RSPO1, SOX9</italic>
, <italic>NR5A1</italic>
, <italic>WT1</italic>
, <italic>NR0B1</italic>
, and <italic>WNT4</italic>
. Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21. A splice-acceptor mutation (c.634-8T>A) in <italic>MAP3K1</italic>
segregated with the phenotype in the first family and disrupted RNA splicing. Mutations were demonstrated in the second family (p.Gly616Arg) and in two of 11 sporadic cases (p.Leu189Pro, p.Leu189Arg)—18% prevalence in this cohort of sporadic cases. In cultured primary lymphoblastoid cells from family 1 and the two sporadic cases, these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex. <italic>Map3k1</italic>
within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination. Thus, mutations in <italic>MAP3K1</italic>
that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination.</p>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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