Loss of Function Mutation in the Palmitoyl-Transferase HHAT Leads to Syndromic 46,XY Disorder of Sex Development by Impeding Hedgehog Protein Palmitoylation and Signaling
Identifieur interne : 001486 ( Pmc/Checkpoint ); précédent : 001485; suivant : 001487Loss of Function Mutation in the Palmitoyl-Transferase HHAT Leads to Syndromic 46,XY Disorder of Sex Development by Impeding Hedgehog Protein Palmitoylation and Signaling
Auteurs : Patrick Callier [Suisse, France] ; Pierre Calvel [Suisse] ; Armine Matevossian [États-Unis] ; Periklis Makrythanasis [Suisse] ; Pascal Bernard [Australie] ; Hiroshi Kurosaka [États-Unis] ; Anne Vannier [Suisse] ; Christel Thauvin-Robinet [France] ; Christelle Borel [Suisse] ; Séverine Mazaud-Guittot [France] ; Antoine Rolland [France] ; Christèle Desdoits-Lethimonier [France] ; Michel Guipponi [Suisse] ; Céline Zimmermann [Suisse] ; Isabelle Stévant [Suisse] ; Françoise Kuhne [Suisse] ; Béatrice Conne [Suisse] ; Federico Santoni [Suisse] ; Sandy Lambert [France] ; Frederic Huet [France] ; Francine Mugneret [France] ; Jadwiga Jaruzelska [Pologne] ; Laurence Faivre [France] ; Dagmar Wilhelm [Australie] ; Bernard Jégou [France] ; Paul A. Trainor [États-Unis] ; Marilyn D. Resh [États-Unis] ; Stylianos E. Antonarakis [Suisse] ; Serge Nef [Suisse]Source :
- PLoS Genetics [ 1553-7390 ] ; 2014.
Abstract
The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems. Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency. However, the biological impact of lipid modifications on Hh ligand distribution and signal reception in humans remains unclear. In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (
Url:
DOI: 10.1371/journal.pgen.1004340
PubMed: 24784881
PubMed Central: 4006744
Affiliations:
- Australie, France, Pologne, Suisse, États-Unis
- Bourgogne, Bourgogne-Franche-Comté, Canton de Genève, Kansas, Missouri (État), Région Bretagne, État de New York
- Dijon, Genève, Rennes
- Université de Bourgogne, Université de Genève, Université de Rennes 1
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PMC:4006744Le document en format XML
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<author><name sortKey="Stevant, Isabelle" sort="Stevant, Isabelle" uniqKey="Stevant I" first="Isabelle" last="Stévant">Isabelle Stévant</name>
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<author><name sortKey="Kuhne, Francoise" sort="Kuhne, Francoise" uniqKey="Kuhne F" first="Françoise" last="Kuhne">Françoise Kuhne</name>
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<author><name sortKey="Conne, Beatrice" sort="Conne, Beatrice" uniqKey="Conne B" first="Béatrice" last="Conne">Béatrice Conne</name>
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<author><name sortKey="Santoni, Federico" sort="Santoni, Federico" uniqKey="Santoni F" first="Federico" last="Santoni">Federico Santoni</name>
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<author><name sortKey="Lambert, Sandy" sort="Lambert, Sandy" uniqKey="Lambert S" first="Sandy" last="Lambert">Sandy Lambert</name>
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<author><name sortKey="Huet, Frederic" sort="Huet, Frederic" uniqKey="Huet F" first="Frederic" last="Huet">Frederic Huet</name>
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<author><name sortKey="Wilhelm, Dagmar" sort="Wilhelm, Dagmar" uniqKey="Wilhelm D" first="Dagmar" last="Wilhelm">Dagmar Wilhelm</name>
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<country xml:lang="fr">Australie</country>
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<affiliation wicri:level="2"><nlm:aff id="aff8"><addr-line>Stowers Institute for Medical Research, Kansas City, Missouri, United States of America</addr-line>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Stowers Institute for Medical Research, Kansas City, Missouri</wicri:regionArea>
<placeName><region type="state">Missouri (État)</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff12"><addr-line>Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas</wicri:regionArea>
<placeName><region type="state">Kansas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Resh, Marilyn D" sort="Resh, Marilyn D" uniqKey="Resh M" first="Marilyn D." last="Resh">Marilyn D. Resh</name>
<affiliation wicri:level="2"><nlm:aff id="aff4"><addr-line>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff5"><addr-line>Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff6"><addr-line>Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Antonarakis, Stylianos E" sort="Antonarakis, Stylianos E" uniqKey="Antonarakis S" first="Stylianos E." last="Antonarakis">Stylianos E. Antonarakis</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff13"><addr-line>iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva</wicri:regionArea>
<orgName type="university">Université de Genève</orgName>
<placeName><settlement type="city">Genève</settlement>
<region nuts="3" type="region">Canton de Genève</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Nef, Serge" sort="Nef, Serge" uniqKey="Nef S" first="Serge" last="Nef">Serge Nef</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff13"><addr-line>iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva</wicri:regionArea>
<orgName type="university">Université de Genève</orgName>
<placeName><settlement type="city">Genève</settlement>
<region nuts="3" type="region">Canton de Genève</region>
</placeName>
</affiliation>
</author>
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<idno type="pmc">4006744</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Loss of Function Mutation in the Palmitoyl-Transferase HHAT Leads to Syndromic 46,XY Disorder of Sex Development by Impeding Hedgehog Protein Palmitoylation and Signaling</title>
<author><name sortKey="Callier, Patrick" sort="Callier, Patrick" uniqKey="Callier P" first="Patrick" last="Callier">Patrick Callier</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff2"><addr-line>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon</wicri:regionArea>
<placeName><region type="region">Bourgogne-Franche-Comté</region>
<region type="old region">Bourgogne</region>
<settlement type="city">Dijon</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon</wicri:regionArea>
<placeName><region type="region">Bourgogne-Franche-Comté</region>
<region type="old region">Bourgogne</region>
<settlement type="city">Dijon</settlement>
<settlement type="city">Dijon</settlement>
</placeName>
<orgName type="university">Université de Bourgogne</orgName>
</affiliation>
</author>
<author><name sortKey="Calvel, Pierre" sort="Calvel, Pierre" uniqKey="Calvel P" first="Pierre" last="Calvel">Pierre Calvel</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Matevossian, Armine" sort="Matevossian, Armine" uniqKey="Matevossian A" first="Armine" last="Matevossian">Armine Matevossian</name>
<affiliation wicri:level="2"><nlm:aff id="aff4"><addr-line>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff5"><addr-line>Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff6"><addr-line>Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Makrythanasis, Periklis" sort="Makrythanasis, Periklis" uniqKey="Makrythanasis P" first="Periklis" last="Makrythanasis">Periklis Makrythanasis</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Bernard, Pascal" sort="Bernard, Pascal" uniqKey="Bernard P" first="Pascal" last="Bernard">Pascal Bernard</name>
<affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Anatomy and Developmental Biology, Monash University, Clayton</wicri:regionArea>
<wicri:noRegion>Clayton</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Kurosaka, Hiroshi" sort="Kurosaka, Hiroshi" uniqKey="Kurosaka H" first="Hiroshi" last="Kurosaka">Hiroshi Kurosaka</name>
<affiliation wicri:level="2"><nlm:aff id="aff8"><addr-line>Stowers Institute for Medical Research, Kansas City, Missouri, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Stowers Institute for Medical Research, Kansas City, Missouri</wicri:regionArea>
<placeName><region type="state">Missouri (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Vannier, Anne" sort="Vannier, Anne" uniqKey="Vannier A" first="Anne" last="Vannier">Anne Vannier</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Thauvin Robinet, Christel" sort="Thauvin Robinet, Christel" uniqKey="Thauvin Robinet C" first="Christel" last="Thauvin-Robinet">Christel Thauvin-Robinet</name>
<affiliation wicri:level="3"><nlm:aff id="aff2"><addr-line>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon</wicri:regionArea>
<placeName><region type="region">Bourgogne-Franche-Comté</region>
<region type="old region">Bourgogne</region>
<settlement type="city">Dijon</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon</wicri:regionArea>
<placeName><region type="region">Bourgogne-Franche-Comté</region>
<region type="old region">Bourgogne</region>
<settlement type="city">Dijon</settlement>
<settlement type="city">Dijon</settlement>
</placeName>
<orgName type="university">Université de Bourgogne</orgName>
</affiliation>
</author>
<author><name sortKey="Borel, Christelle" sort="Borel, Christelle" uniqKey="Borel C" first="Christelle" last="Borel">Christelle Borel</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mazaud Guittot, Severine" sort="Mazaud Guittot, Severine" uniqKey="Mazaud Guittot S" first="Séverine" last="Mazaud-Guittot">Séverine Mazaud-Guittot</name>
<affiliation wicri:level="4"><nlm:aff id="aff9"><addr-line>Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, Rennes, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, Rennes</wicri:regionArea>
<placeName><region type="region">Région Bretagne</region>
<region type="old region">Région Bretagne</region>
<settlement type="city">Rennes</settlement>
<settlement type="city">Rennes</settlement>
</placeName>
<orgName type="university">Université de Rennes 1</orgName>
</affiliation>
</author>
<author><name sortKey="Rolland, Antoine" sort="Rolland, Antoine" uniqKey="Rolland A" first="Antoine" last="Rolland">Antoine Rolland</name>
<affiliation wicri:level="4"><nlm:aff id="aff9"><addr-line>Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, Rennes, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, Rennes</wicri:regionArea>
<placeName><region type="region">Région Bretagne</region>
<region type="old region">Région Bretagne</region>
<settlement type="city">Rennes</settlement>
<settlement type="city">Rennes</settlement>
</placeName>
<orgName type="university">Université de Rennes 1</orgName>
</affiliation>
</author>
<author><name sortKey="Desdoits Lethimonier, Christele" sort="Desdoits Lethimonier, Christele" uniqKey="Desdoits Lethimonier C" first="Christèle" last="Desdoits-Lethimonier">Christèle Desdoits-Lethimonier</name>
<affiliation wicri:level="4"><nlm:aff id="aff9"><addr-line>Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, Rennes, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, Rennes</wicri:regionArea>
<placeName><region type="region">Région Bretagne</region>
<region type="old region">Région Bretagne</region>
<settlement type="city">Rennes</settlement>
<settlement type="city">Rennes</settlement>
</placeName>
<orgName type="university">Université de Rennes 1</orgName>
</affiliation>
</author>
<author><name sortKey="Guipponi, Michel" sort="Guipponi, Michel" uniqKey="Guipponi M" first="Michel" last="Guipponi">Michel Guipponi</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Zimmermann, Celine" sort="Zimmermann, Celine" uniqKey="Zimmermann C" first="Céline" last="Zimmermann">Céline Zimmermann</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Stevant, Isabelle" sort="Stevant, Isabelle" uniqKey="Stevant I" first="Isabelle" last="Stévant">Isabelle Stévant</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Kuhne, Francoise" sort="Kuhne, Francoise" uniqKey="Kuhne F" first="Françoise" last="Kuhne">Françoise Kuhne</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Conne, Beatrice" sort="Conne, Beatrice" uniqKey="Conne B" first="Béatrice" last="Conne">Béatrice Conne</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Santoni, Federico" sort="Santoni, Federico" uniqKey="Santoni F" first="Federico" last="Santoni">Federico Santoni</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lambert, Sandy" sort="Lambert, Sandy" uniqKey="Lambert S" first="Sandy" last="Lambert">Sandy Lambert</name>
<affiliation wicri:level="3"><nlm:aff id="aff2"><addr-line>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon</wicri:regionArea>
<placeName><region type="region">Bourgogne-Franche-Comté</region>
<region type="old region">Bourgogne</region>
<settlement type="city">Dijon</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Huet, Frederic" sort="Huet, Frederic" uniqKey="Huet F" first="Frederic" last="Huet">Frederic Huet</name>
<affiliation wicri:level="3"><nlm:aff id="aff2"><addr-line>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon</wicri:regionArea>
<placeName><region type="region">Bourgogne-Franche-Comté</region>
<region type="old region">Bourgogne</region>
<settlement type="city">Dijon</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon</wicri:regionArea>
<placeName><region type="region">Bourgogne-Franche-Comté</region>
<region type="old region">Bourgogne</region>
<settlement type="city">Dijon</settlement>
<settlement type="city">Dijon</settlement>
</placeName>
<orgName type="university">Université de Bourgogne</orgName>
</affiliation>
</author>
<author><name sortKey="Mugneret, Francine" sort="Mugneret, Francine" uniqKey="Mugneret F" first="Francine" last="Mugneret">Francine Mugneret</name>
<affiliation wicri:level="3"><nlm:aff id="aff2"><addr-line>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon</wicri:regionArea>
<placeName><region type="region">Bourgogne-Franche-Comté</region>
<region type="old region">Bourgogne</region>
<settlement type="city">Dijon</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Jaruzelska, Jadwiga" sort="Jaruzelska, Jadwiga" uniqKey="Jaruzelska J" first="Jadwiga" last="Jaruzelska">Jadwiga Jaruzelska</name>
<affiliation wicri:level="1"><nlm:aff id="aff10"><addr-line>Polish Academy of Sciences, Institute of Human Genetics, Poznań, Poland</addr-line>
</nlm:aff>
<country xml:lang="fr">Pologne</country>
<wicri:regionArea>Polish Academy of Sciences, Institute of Human Genetics, Poznań</wicri:regionArea>
<wicri:noRegion>Poznań</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Faivre, Laurence" sort="Faivre, Laurence" uniqKey="Faivre L" first="Laurence" last="Faivre">Laurence Faivre</name>
<affiliation wicri:level="3"><nlm:aff id="aff2"><addr-line>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon</wicri:regionArea>
<placeName><region type="region">Bourgogne-Franche-Comté</region>
<region type="old region">Bourgogne</region>
<settlement type="city">Dijon</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon</wicri:regionArea>
<placeName><region type="region">Bourgogne-Franche-Comté</region>
<region type="old region">Bourgogne</region>
<settlement type="city">Dijon</settlement>
<settlement type="city">Dijon</settlement>
</placeName>
<orgName type="university">Université de Bourgogne</orgName>
</affiliation>
</author>
<author><name sortKey="Wilhelm, Dagmar" sort="Wilhelm, Dagmar" uniqKey="Wilhelm D" first="Dagmar" last="Wilhelm">Dagmar Wilhelm</name>
<affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Anatomy and Developmental Biology, Monash University, Clayton</wicri:regionArea>
<wicri:noRegion>Clayton</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Jegou, Bernard" sort="Jegou, Bernard" uniqKey="Jegou B" first="Bernard" last="Jégou">Bernard Jégou</name>
<affiliation wicri:level="4"><nlm:aff id="aff9"><addr-line>Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, Rennes, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, Rennes</wicri:regionArea>
<placeName><region type="region">Région Bretagne</region>
<region type="old region">Région Bretagne</region>
<settlement type="city">Rennes</settlement>
<settlement type="city">Rennes</settlement>
</placeName>
<orgName type="university">Université de Rennes 1</orgName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff11"><addr-line>EHESP School of Public Health, Rennes, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>EHESP School of Public Health, Rennes</wicri:regionArea>
<placeName><region type="region">Région Bretagne</region>
<region type="old region">Région Bretagne</region>
<settlement type="city">Rennes</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Trainor, Paul A" sort="Trainor, Paul A" uniqKey="Trainor P" first="Paul A." last="Trainor">Paul A. Trainor</name>
<affiliation wicri:level="2"><nlm:aff id="aff8"><addr-line>Stowers Institute for Medical Research, Kansas City, Missouri, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Stowers Institute for Medical Research, Kansas City, Missouri</wicri:regionArea>
<placeName><region type="state">Missouri (État)</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff12"><addr-line>Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas</wicri:regionArea>
<placeName><region type="state">Kansas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Resh, Marilyn D" sort="Resh, Marilyn D" uniqKey="Resh M" first="Marilyn D." last="Resh">Marilyn D. Resh</name>
<affiliation wicri:level="2"><nlm:aff id="aff4"><addr-line>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff5"><addr-line>Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="aff6"><addr-line>Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Antonarakis, Stylianos E" sort="Antonarakis, Stylianos E" uniqKey="Antonarakis S" first="Stylianos E." last="Antonarakis">Stylianos E. Antonarakis</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff13"><addr-line>iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva</wicri:regionArea>
<orgName type="university">Université de Genève</orgName>
<placeName><settlement type="city">Genève</settlement>
<region nuts="3" type="region">Canton de Genève</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Nef, Serge" sort="Nef, Serge" uniqKey="Nef S" first="Serge" last="Nef">Serge Nef</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff13"><addr-line>iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva</wicri:regionArea>
<orgName type="university">Université de Genève</orgName>
<placeName><settlement type="city">Genève</settlement>
<region nuts="3" type="region">Canton de Genève</region>
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</author>
</analytic>
<series><title level="j">PLoS Genetics</title>
<idno type="ISSN">1553-7390</idno>
<idno type="eISSN">1553-7404</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>The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems. Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency. However, the biological impact of lipid modifications on Hh ligand distribution and signal reception in humans remains unclear. In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (<italic>HHAT</italic>
) gene. This mutation occurred in the conserved membrane bound <italic>O</italic>
-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH. Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and <italic>Hhat</italic>
loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans. In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells. Altogether, these results shed new light on the mechanisms of action of Hh proteins. Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Genet</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Genet</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosgen</journal-id>
<journal-title-group><journal-title>PLoS Genetics</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-7390</issn>
<issn pub-type="epub">1553-7404</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">24784881</article-id>
<article-id pub-id-type="pmc">4006744</article-id>
<article-id pub-id-type="publisher-id">PGENETICS-D-13-03093</article-id>
<article-id pub-id-type="doi">10.1371/journal.pgen.1004340</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Developmental Biology</subject>
<subj-group><subject>Morphogenesis</subject>
<subj-group><subject>Sex Determination</subject>
</subj-group>
</subj-group>
<subj-group><subject>Cell Differentiation</subject>
<subject>Cell Fate Determination</subject>
</subj-group>
</subj-group>
<subj-group><subject>Genetics</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Loss of Function Mutation in the Palmitoyl-Transferase HHAT Leads to Syndromic 46,XY Disorder of Sex Development by Impeding Hedgehog Protein Palmitoylation and Signaling</article-title>
<alt-title alt-title-type="running-head">46,XY DSD due to Impaired HHAT Activity</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Callier</surname>
<given-names>Patrick</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Calvel</surname>
<given-names>Pierre</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Matevossian</surname>
<given-names>Armine</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Makrythanasis</surname>
<given-names>Periklis</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bernard</surname>
<given-names>Pascal</given-names>
</name>
<xref ref-type="aff" rid="aff7"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kurosaka</surname>
<given-names>Hiroshi</given-names>
</name>
<xref ref-type="aff" rid="aff8"><sup>8</sup>
</xref>
</contrib>
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<given-names>Anne</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Thauvin-Robinet</surname>
<given-names>Christel</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Borel</surname>
<given-names>Christelle</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mazaud-Guittot</surname>
<given-names>Séverine</given-names>
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<xref ref-type="aff" rid="aff9"><sup>9</sup>
</xref>
</contrib>
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<given-names>Antoine</given-names>
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<xref ref-type="aff" rid="aff9"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Desdoits-Lethimonier</surname>
<given-names>Christèle</given-names>
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<xref ref-type="aff" rid="aff9"><sup>9</sup>
</xref>
</contrib>
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<given-names>Michel</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
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<given-names>Céline</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
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<given-names>Isabelle</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
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<given-names>Françoise</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
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<given-names>Béatrice</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
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<given-names>Federico</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
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<given-names>Sandy</given-names>
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<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
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<given-names>Frederic</given-names>
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<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
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<given-names>Francine</given-names>
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<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
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<contrib contrib-type="author"><name><surname>Jaruzelska</surname>
<given-names>Jadwiga</given-names>
</name>
<xref ref-type="aff" rid="aff10"><sup>10</sup>
</xref>
</contrib>
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<given-names>Laurence</given-names>
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<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wilhelm</surname>
<given-names>Dagmar</given-names>
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<xref ref-type="aff" rid="aff7"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jégou</surname>
<given-names>Bernard</given-names>
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<xref ref-type="aff" rid="aff9"><sup>9</sup>
</xref>
<xref ref-type="aff" rid="aff11"><sup>11</sup>
</xref>
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<given-names>Paul A.</given-names>
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<xref ref-type="aff" rid="aff8"><sup>8</sup>
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<xref ref-type="aff" rid="aff12"><sup>12</sup>
</xref>
</contrib>
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<given-names>Marilyn D.</given-names>
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<xref ref-type="aff" rid="aff4"><sup>4</sup>
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<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
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<given-names>Stylianos E.</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
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<xref ref-type="aff" rid="aff13"><sup>13</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nef</surname>
<given-names>Serge</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff13"><sup>13</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France</addr-line>
</aff>
<aff id="aff4"><label>4</label>
<addr-line>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America</addr-line>
</aff>
<aff id="aff5"><label>5</label>
<addr-line>Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America</addr-line>
</aff>
<aff id="aff6"><label>6</label>
<addr-line>Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States of America</addr-line>
</aff>
<aff id="aff7"><label>7</label>
<addr-line>Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia</addr-line>
</aff>
<aff id="aff8"><label>8</label>
<addr-line>Stowers Institute for Medical Research, Kansas City, Missouri, United States of America</addr-line>
</aff>
<aff id="aff9"><label>9</label>
<addr-line>Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, Rennes, France</addr-line>
</aff>
<aff id="aff10"><label>10</label>
<addr-line>Polish Academy of Sciences, Institute of Human Genetics, Poznań, Poland</addr-line>
</aff>
<aff id="aff11"><label>11</label>
<addr-line>EHESP School of Public Health, Rennes, France</addr-line>
</aff>
<aff id="aff12"><label>12</label>
<addr-line>Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America</addr-line>
</aff>
<aff id="aff13"><label>13</label>
<addr-line>iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Mundlos</surname>
<given-names>Stefan</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>Max Planck Institute for Molecular Genetics, Germany</addr-line>
</aff>
<author-notes><corresp id="cor1">* E-mail: <email>Serge.Nef@unige.ch</email>
</corresp>
<fn fn-type="conflict"><p>The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con"><p>Conceived and designed the experiments: PCalv SN SEA. Performed the experiments: PCalv AM PM PB CZ FK BC IS. Analyzed the data: PCalv PCall AV DW CB MG FS IS. Contributed reagents/materials/analysis tools: PCall AM MDR HK CTR SMG AR CDL SL FH FM JJ LF BJ PAT. Wrote the paper: PCalv PM SN MDR.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><month>5</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>1</day>
<month>5</month>
<year>2014</year>
</pub-date>
<volume>10</volume>
<issue>5</issue>
<elocation-id>e1004340</elocation-id>
<history><date date-type="received"><day>8</day>
<month>11</month>
<year>2013</year>
</date>
<date date-type="accepted"><day>7</day>
<month>3</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© 2014 Callier et al</copyright-statement>
<copyright-year>2014</copyright-year>
<copyright-holder>Callier et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p>
</license>
</permissions>
<abstract><p>The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems. Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency. However, the biological impact of lipid modifications on Hh ligand distribution and signal reception in humans remains unclear. In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (<italic>HHAT</italic>
) gene. This mutation occurred in the conserved membrane bound <italic>O</italic>
-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH. Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and <italic>Hhat</italic>
loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans. In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells. Altogether, these results shed new light on the mechanisms of action of Hh proteins. Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p>Disorders of gonadal development represent a clinically and genetically heterogeneous class of DSD caused by defects in gonadal development and/or a failure of testis/ovarian differentiation. Unfortunately, in many cases the genetic aetiology of DSD is unknown, indicating that our knowledge of the factors mediating sex determination is limited. Using exome sequencing on a case of autosomal recessive syndromic 46,XY DSD with testicular dysgenesis and chondrodysplasia, we found a homozygous missense mutation (G287V) within the coding sequence of the O-acetyl-transferase <italic>HHAT</italic>
gene. The <italic>HHAT</italic>
gene encodes an enzyme required for the attachment of palmitoyl residues that are critical for multimerization and long range signaling potency of hedgehog secreted proteins. We found that <italic>HHAT</italic>
is widely expressed in human organs during fetal development, including testes and ovaries around the time of sex determination. <italic>In vitro</italic>
assays show that G287V mutation impairs HHAT palmitoyl-transferase activity and mice lacking functional <italic>Hhat</italic>
exhibit testicular dysgenesis as well as other skeletal, neuronal and growth defects that recapitulate most aspects of the syndromic 46,XY DSD patient. These data provide the first clinical evidence of the essential role played by lipid modification of Hedgehog proteins in human testicular organogenesis and embryonic development.</p>
</abstract>
<funding-group><funding-statement>This work was supported by The Gerbert Rüf Stiftung, the Fondation Gertrude von Meissner, the Novartis Foundation for medical-biological research and by the Département de L'instruction Publique of the State of Geneva to SN; the US National Institutes of Health to MDR; the Bodossaki Foundation to PM; the regional council of Burgundy (grant STIC11) to PCall, CTR and LF; the Swiss National Science Foundation, the Gerbert Rüf Stiftung and ERC (EU) grants to SEA; and the Stowers Institute for Medical Research and the National Institute for Dental and Craniofacial Research (DE-01682) to PAT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><page-count count="12"></page-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Australie</li>
<li>France</li>
<li>Pologne</li>
<li>Suisse</li>
<li>États-Unis</li>
</country>
<region><li>Bourgogne</li>
<li>Bourgogne-Franche-Comté</li>
<li>Canton de Genève</li>
<li>Kansas</li>
<li>Missouri (État)</li>
<li>Région Bretagne</li>
<li>État de New York</li>
</region>
<settlement><li>Dijon</li>
<li>Genève</li>
<li>Rennes</li>
</settlement>
<orgName><li>Université de Bourgogne</li>
<li>Université de Genève</li>
<li>Université de Rennes 1</li>
</orgName>
</list>
<tree><country name="Suisse"><noRegion><name sortKey="Callier, Patrick" sort="Callier, Patrick" uniqKey="Callier P" first="Patrick" last="Callier">Patrick Callier</name>
</noRegion>
<name sortKey="Antonarakis, Stylianos E" sort="Antonarakis, Stylianos E" uniqKey="Antonarakis S" first="Stylianos E." last="Antonarakis">Stylianos E. Antonarakis</name>
<name sortKey="Antonarakis, Stylianos E" sort="Antonarakis, Stylianos E" uniqKey="Antonarakis S" first="Stylianos E." last="Antonarakis">Stylianos E. Antonarakis</name>
<name sortKey="Borel, Christelle" sort="Borel, Christelle" uniqKey="Borel C" first="Christelle" last="Borel">Christelle Borel</name>
<name sortKey="Calvel, Pierre" sort="Calvel, Pierre" uniqKey="Calvel P" first="Pierre" last="Calvel">Pierre Calvel</name>
<name sortKey="Conne, Beatrice" sort="Conne, Beatrice" uniqKey="Conne B" first="Béatrice" last="Conne">Béatrice Conne</name>
<name sortKey="Guipponi, Michel" sort="Guipponi, Michel" uniqKey="Guipponi M" first="Michel" last="Guipponi">Michel Guipponi</name>
<name sortKey="Kuhne, Francoise" sort="Kuhne, Francoise" uniqKey="Kuhne F" first="Françoise" last="Kuhne">Françoise Kuhne</name>
<name sortKey="Makrythanasis, Periklis" sort="Makrythanasis, Periklis" uniqKey="Makrythanasis P" first="Periklis" last="Makrythanasis">Periklis Makrythanasis</name>
<name sortKey="Nef, Serge" sort="Nef, Serge" uniqKey="Nef S" first="Serge" last="Nef">Serge Nef</name>
<name sortKey="Nef, Serge" sort="Nef, Serge" uniqKey="Nef S" first="Serge" last="Nef">Serge Nef</name>
<name sortKey="Santoni, Federico" sort="Santoni, Federico" uniqKey="Santoni F" first="Federico" last="Santoni">Federico Santoni</name>
<name sortKey="Stevant, Isabelle" sort="Stevant, Isabelle" uniqKey="Stevant I" first="Isabelle" last="Stévant">Isabelle Stévant</name>
<name sortKey="Vannier, Anne" sort="Vannier, Anne" uniqKey="Vannier A" first="Anne" last="Vannier">Anne Vannier</name>
<name sortKey="Zimmermann, Celine" sort="Zimmermann, Celine" uniqKey="Zimmermann C" first="Céline" last="Zimmermann">Céline Zimmermann</name>
</country>
<country name="France"><region name="Bourgogne-Franche-Comté"><name sortKey="Callier, Patrick" sort="Callier, Patrick" uniqKey="Callier P" first="Patrick" last="Callier">Patrick Callier</name>
</region>
<name sortKey="Callier, Patrick" sort="Callier, Patrick" uniqKey="Callier P" first="Patrick" last="Callier">Patrick Callier</name>
<name sortKey="Desdoits Lethimonier, Christele" sort="Desdoits Lethimonier, Christele" uniqKey="Desdoits Lethimonier C" first="Christèle" last="Desdoits-Lethimonier">Christèle Desdoits-Lethimonier</name>
<name sortKey="Faivre, Laurence" sort="Faivre, Laurence" uniqKey="Faivre L" first="Laurence" last="Faivre">Laurence Faivre</name>
<name sortKey="Faivre, Laurence" sort="Faivre, Laurence" uniqKey="Faivre L" first="Laurence" last="Faivre">Laurence Faivre</name>
<name sortKey="Huet, Frederic" sort="Huet, Frederic" uniqKey="Huet F" first="Frederic" last="Huet">Frederic Huet</name>
<name sortKey="Huet, Frederic" sort="Huet, Frederic" uniqKey="Huet F" first="Frederic" last="Huet">Frederic Huet</name>
<name sortKey="Jegou, Bernard" sort="Jegou, Bernard" uniqKey="Jegou B" first="Bernard" last="Jégou">Bernard Jégou</name>
<name sortKey="Jegou, Bernard" sort="Jegou, Bernard" uniqKey="Jegou B" first="Bernard" last="Jégou">Bernard Jégou</name>
<name sortKey="Lambert, Sandy" sort="Lambert, Sandy" uniqKey="Lambert S" first="Sandy" last="Lambert">Sandy Lambert</name>
<name sortKey="Mazaud Guittot, Severine" sort="Mazaud Guittot, Severine" uniqKey="Mazaud Guittot S" first="Séverine" last="Mazaud-Guittot">Séverine Mazaud-Guittot</name>
<name sortKey="Mugneret, Francine" sort="Mugneret, Francine" uniqKey="Mugneret F" first="Francine" last="Mugneret">Francine Mugneret</name>
<name sortKey="Rolland, Antoine" sort="Rolland, Antoine" uniqKey="Rolland A" first="Antoine" last="Rolland">Antoine Rolland</name>
<name sortKey="Thauvin Robinet, Christel" sort="Thauvin Robinet, Christel" uniqKey="Thauvin Robinet C" first="Christel" last="Thauvin-Robinet">Christel Thauvin-Robinet</name>
<name sortKey="Thauvin Robinet, Christel" sort="Thauvin Robinet, Christel" uniqKey="Thauvin Robinet C" first="Christel" last="Thauvin-Robinet">Christel Thauvin-Robinet</name>
</country>
<country name="États-Unis"><region name="État de New York"><name sortKey="Matevossian, Armine" sort="Matevossian, Armine" uniqKey="Matevossian A" first="Armine" last="Matevossian">Armine Matevossian</name>
</region>
<name sortKey="Kurosaka, Hiroshi" sort="Kurosaka, Hiroshi" uniqKey="Kurosaka H" first="Hiroshi" last="Kurosaka">Hiroshi Kurosaka</name>
<name sortKey="Matevossian, Armine" sort="Matevossian, Armine" uniqKey="Matevossian A" first="Armine" last="Matevossian">Armine Matevossian</name>
<name sortKey="Matevossian, Armine" sort="Matevossian, Armine" uniqKey="Matevossian A" first="Armine" last="Matevossian">Armine Matevossian</name>
<name sortKey="Resh, Marilyn D" sort="Resh, Marilyn D" uniqKey="Resh M" first="Marilyn D." last="Resh">Marilyn D. Resh</name>
<name sortKey="Resh, Marilyn D" sort="Resh, Marilyn D" uniqKey="Resh M" first="Marilyn D." last="Resh">Marilyn D. Resh</name>
<name sortKey="Resh, Marilyn D" sort="Resh, Marilyn D" uniqKey="Resh M" first="Marilyn D." last="Resh">Marilyn D. Resh</name>
<name sortKey="Trainor, Paul A" sort="Trainor, Paul A" uniqKey="Trainor P" first="Paul A." last="Trainor">Paul A. Trainor</name>
<name sortKey="Trainor, Paul A" sort="Trainor, Paul A" uniqKey="Trainor P" first="Paul A." last="Trainor">Paul A. Trainor</name>
</country>
<country name="Australie"><noRegion><name sortKey="Bernard, Pascal" sort="Bernard, Pascal" uniqKey="Bernard P" first="Pascal" last="Bernard">Pascal Bernard</name>
</noRegion>
<name sortKey="Wilhelm, Dagmar" sort="Wilhelm, Dagmar" uniqKey="Wilhelm D" first="Dagmar" last="Wilhelm">Dagmar Wilhelm</name>
</country>
<country name="Pologne"><noRegion><name sortKey="Jaruzelska, Jadwiga" sort="Jaruzelska, Jadwiga" uniqKey="Jaruzelska J" first="Jadwiga" last="Jaruzelska">Jadwiga Jaruzelska</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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