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 : 003691 ( PubMed/Curation ); précédent : 003690; suivant : 003692Loss 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 [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 [ 1553-7404 ] ; 2014.
Descripteurs français
- KwdFr :
- Acyltransferases (), Acyltransferases (génétique), Acyltransferases (métabolisme), Animaux, Données de séquences moléculaires, Femelle, Homozygote, Humains, Lipoylation (génétique), Mutation faux-sens, Mâle, Pedigree, Protéines Hedgehog (métabolisme), Similitude de séquences d'acides aminés, Souris, Séquence d'acides aminés, Testicule (embryologie), Transduction du signal (génétique), Troubles du développement sexuel de sujets 46, XY (génétique).
- MESH :
- embryologie : Testicule.
- génétique : Acyltransferases, Lipoylation, Transduction du signal, Troubles du développement sexuel de sujets 46, XY.
- métabolisme : Acyltransferases, Protéines Hedgehog.
- Acyltransferases, Animaux, Données de séquences moléculaires, Femelle, Homozygote, Humains, Mutation faux-sens, Mâle, Pedigree, Similitude de séquences d'acides aminés, Souris, Séquence d'acides aminés.
English descriptors
- KwdEn :
- 46, XY Disorders of Sex Development (genetics), Acyltransferases (chemistry), Acyltransferases (genetics), Acyltransferases (metabolism), Amino Acid Sequence, Animals, Female, Hedgehog Proteins (metabolism), Homozygote, Humans, Lipoylation (genetics), Male, Mice, Molecular Sequence Data, Mutation, Missense, Pedigree, Sequence Homology, Amino Acid, Signal Transduction (genetics), Testis (embryology).
- MESH :
- chemical , chemistry : Acyltransferases.
- embryology : Testis.
- genetics : 46, XY Disorders of Sex Development, Acyltransferases, Lipoylation, Signal Transduction.
- chemical , metabolism : Acyltransferases, Hedgehog Proteins.
- Amino Acid Sequence, Animals, Female, Homozygote, Humans, Male, Mice, Molecular Sequence Data, Mutation, Missense, Pedigree, Sequence Homology, Amino Acid.
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 (HHAT) gene. This mutation occurred in the conserved membrane bound O-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 Hhat 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.
DOI: 10.1371/journal.pgen.1004340
PubMed: 24784881
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Mazaud-Guittot</name><affiliation wicri:level="1"><nlm:affiliation>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.</nlm:affiliation><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></affiliation></author><author><name sortKey="Rolland, Antoine" sort="Rolland, Antoine" uniqKey="Rolland A" first="Antoine" last="Rolland">Antoine Rolland</name><affiliation wicri:level="1"><nlm:affiliation>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.</nlm:affiliation><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></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="1"><nlm:affiliation>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.</nlm:affiliation><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></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></affiliation></author><author><name sortKey="Lambert, Sandy" sort="Lambert, Sandy" uniqKey="Lambert S" first="Sandy" last="Lambert">Sandy Lambert</name><affiliation wicri:level="1"><nlm:affiliation>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon</wicri:regionArea></affiliation></author><author><name sortKey="Huet, Frederic" sort="Huet, Frederic" uniqKey="Huet F" first="Frederic" last="Huet">Frederic Huet</name><affiliation wicri:level="1"><nlm:affiliation>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon</wicri:regionArea></affiliation></author><author><name sortKey="Mugneret, Francine" sort="Mugneret, Francine" uniqKey="Mugneret F" first="Francine" last="Mugneret">Francine Mugneret</name><affiliation wicri:level="1"><nlm:affiliation>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon</wicri:regionArea></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:affiliation>Polish Academy of Sciences, Institute of Human Genetics, Poznań, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Polish Academy of Sciences, Institute of Human Genetics, Poznań</wicri:regionArea></affiliation></author><author><name sortKey="Faivre, Laurence" sort="Faivre, Laurence" uniqKey="Faivre L" first="Laurence" last="Faivre">Laurence Faivre</name><affiliation wicri:level="1"><nlm:affiliation>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon</wicri:regionArea></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:affiliation>Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Anatomy and Developmental Biology, Monash University, Clayton</wicri:regionArea></affiliation></author><author><name sortKey="Jegou, Bernard" sort="Jegou, Bernard" uniqKey="Jegou B" first="Bernard" last="Jégou">Bernard Jégou</name><affiliation wicri:level="1"><nlm:affiliation>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; EHESP School of Public Health, Rennes, France.</nlm:affiliation><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, France; EHESP School of Public Health, Rennes</wicri:regionArea></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="1"><nlm:affiliation>Stowers Institute for Medical Research, Kansas City, Missouri, United States of America; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Stowers Institute for Medical Research, Kansas City, Missouri, United States of America; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas</wicri:regionArea></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="1"><nlm:affiliation>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:24784881</idno><idno type="pmid">24784881</idno><idno type="doi">10.1371/journal.pgen.1004340</idno><idno type="wicri:Area/PubMed/Corpus">003805</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">003805</idno><idno type="wicri:Area/PubMed/Curation">003691</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">003691</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></affiliation></author><author><name sortKey="Matevossian, Armine" sort="Matevossian, Armine" uniqKey="Matevossian A" first="Armine" last="Matevossian">Armine Matevossian</name><affiliation wicri:level="1"><nlm:affiliation>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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:affiliation>Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Anatomy and Developmental Biology, Monash University, Clayton</wicri:regionArea></affiliation></author><author><name sortKey="Kurosaka, Hiroshi" sort="Kurosaka, Hiroshi" uniqKey="Kurosaka H" first="Hiroshi" last="Kurosaka">Hiroshi Kurosaka</name><affiliation wicri:level="1"><nlm:affiliation>Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Stowers Institute for Medical Research, Kansas City, Missouri</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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="1"><nlm:affiliation>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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="1"><nlm:affiliation>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.</nlm:affiliation><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></affiliation></author><author><name sortKey="Rolland, Antoine" sort="Rolland, Antoine" uniqKey="Rolland A" first="Antoine" last="Rolland">Antoine Rolland</name><affiliation wicri:level="1"><nlm:affiliation>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.</nlm:affiliation><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></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="1"><nlm:affiliation>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.</nlm:affiliation><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></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</wicri:regionArea></affiliation></author><author><name sortKey="Lambert, Sandy" sort="Lambert, Sandy" uniqKey="Lambert S" first="Sandy" last="Lambert">Sandy Lambert</name><affiliation wicri:level="1"><nlm:affiliation>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon</wicri:regionArea></affiliation></author><author><name sortKey="Huet, Frederic" sort="Huet, Frederic" uniqKey="Huet F" first="Frederic" last="Huet">Frederic Huet</name><affiliation wicri:level="1"><nlm:affiliation>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon</wicri:regionArea></affiliation></author><author><name sortKey="Mugneret, Francine" sort="Mugneret, Francine" uniqKey="Mugneret F" first="Francine" last="Mugneret">Francine Mugneret</name><affiliation wicri:level="1"><nlm:affiliation>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon</wicri:regionArea></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:affiliation>Polish Academy of Sciences, Institute of Human Genetics, Poznań, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Polish Academy of Sciences, Institute of Human Genetics, Poznań</wicri:regionArea></affiliation></author><author><name sortKey="Faivre, Laurence" sort="Faivre, Laurence" uniqKey="Faivre L" first="Laurence" last="Faivre">Laurence Faivre</name><affiliation wicri:level="1"><nlm:affiliation>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon</wicri:regionArea></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:affiliation>Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Anatomy and Developmental Biology, Monash University, Clayton</wicri:regionArea></affiliation></author><author><name sortKey="Jegou, Bernard" sort="Jegou, Bernard" uniqKey="Jegou B" first="Bernard" last="Jégou">Bernard Jégou</name><affiliation wicri:level="1"><nlm:affiliation>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; EHESP School of Public Health, Rennes, France.</nlm:affiliation><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, France; EHESP School of Public Health, Rennes</wicri:regionArea></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="1"><nlm:affiliation>Stowers Institute for Medical Research, Kansas City, Missouri, United States of America; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Stowers Institute for Medical Research, Kansas City, Missouri, United States of America; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas</wicri:regionArea></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="1"><nlm:affiliation>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva</wicri:regionArea></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:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS genetics</title><idno type="eISSN">1553-7404</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>46, XY Disorders of Sex Development (genetics)</term><term>Acyltransferases (chemistry)</term><term>Acyltransferases (genetics)</term><term>Acyltransferases (metabolism)</term><term>Amino Acid Sequence</term><term>Animals</term><term>Female</term><term>Hedgehog Proteins (metabolism)</term><term>Homozygote</term><term>Humans</term><term>Lipoylation (genetics)</term><term>Male</term><term>Mice</term><term>Molecular Sequence Data</term><term>Mutation, Missense</term><term>Pedigree</term><term>Sequence Homology, Amino Acid</term><term>Signal Transduction (genetics)</term><term>Testis (embryology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acyltransferases ()</term><term>Acyltransferases (génétique)</term><term>Acyltransferases (métabolisme)</term><term>Animaux</term><term>Données de séquences moléculaires</term><term>Femelle</term><term>Homozygote</term><term>Humains</term><term>Lipoylation (génétique)</term><term>Mutation faux-sens</term><term>Mâle</term><term>Pedigree</term><term>Protéines Hedgehog (métabolisme)</term><term>Similitude de séquences d'acides aminés</term><term>Souris</term><term>Séquence d'acides aminés</term><term>Testicule (embryologie)</term><term>Transduction du signal (génétique)</term><term>Troubles du développement sexuel de sujets 46, XY (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Acyltransferases</term></keywords><keywords scheme="MESH" qualifier="embryologie" xml:lang="fr"><term>Testicule</term></keywords><keywords scheme="MESH" qualifier="embryology" xml:lang="en"><term>Testis</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>46, XY Disorders of Sex Development</term><term>Acyltransferases</term><term>Lipoylation</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Acyltransferases</term><term>Lipoylation</term><term>Transduction du signal</term><term>Troubles du développement sexuel de sujets 46, XY</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Acyltransferases</term><term>Hedgehog Proteins</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Acyltransferases</term><term>Protéines Hedgehog</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Female</term><term>Homozygote</term><term>Humans</term><term>Male</term><term>Mice</term><term>Molecular Sequence Data</term><term>Mutation, Missense</term><term>Pedigree</term><term>Sequence Homology, Amino Acid</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Acyltransferases</term><term>Animaux</term><term>Données de séquences moléculaires</term><term>Femelle</term><term>Homozygote</term><term>Humains</term><term>Mutation faux-sens</term><term>Mâle</term><term>Pedigree</term><term>Similitude de séquences d'acides aminés</term><term>Souris</term><term>Séquence d'acides aminés</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 (HHAT) gene. This mutation occurred in the conserved membrane bound O-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 Hhat 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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">24784881</PMID><DateCreated><Year>2014</Year><Month>05</Month><Day>05</Day></DateCreated><DateCompleted><Year>2014</Year><Month>11</Month><Day>25</Day></DateCompleted><DateRevised><Year>2017</Year><Month>02</Month><Day>20</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">1553-7404</ISSN><JournalIssue CitedMedium="Internet"><Volume>10</Volume><Issue>5</Issue><PubDate><Year>2014</Year><Month>May</Month></PubDate></JournalIssue><Title>PLoS genetics</Title><ISOAbbreviation>PLoS Genet.</ISOAbbreviation></Journal><ArticleTitle>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.</ArticleTitle><Pagination><MedlinePgn>e1004340</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1371/journal.pgen.1004340</ELocationID><Abstract><AbstractText>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 (HHAT) gene. This mutation occurred in the conserved membrane bound O-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 Hhat 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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Callier</LastName><ForeName>Patrick</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Calvel</LastName><ForeName>Pierre</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Matevossian</LastName><ForeName>Armine</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Makrythanasis</LastName><ForeName>Periklis</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bernard</LastName><ForeName>Pascal</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kurosaka</LastName><ForeName>Hiroshi</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vannier</LastName><ForeName>Anne</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Thauvin-Robinet</LastName><ForeName>Christel</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Borel</LastName><ForeName>Christelle</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mazaud-Guittot</LastName><ForeName>Séverine</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rolland</LastName><ForeName>Antoine</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Desdoits-Lethimonier</LastName><ForeName>Christèle</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Guipponi</LastName><ForeName>Michel</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zimmermann</LastName><ForeName>Céline</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stévant</LastName><ForeName>Isabelle</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kuhne</LastName><ForeName>Françoise</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Conne</LastName><ForeName>Béatrice</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Santoni</LastName><ForeName>Federico</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, 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ValidYN="Y"><LastName>Jaruzelska</LastName><ForeName>Jadwiga</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Polish Academy of Sciences, Institute of Human Genetics, Poznań, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Faivre</LastName><ForeName>Laurence</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wilhelm</LastName><ForeName>Dagmar</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jégou</LastName><ForeName>Bernard</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>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; EHESP School of Public Health, Rennes, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Trainor</LastName><ForeName>Paul A</ForeName><Initials>PA</Initials><AffiliationInfo><Affiliation>Stowers Institute for Medical Research, Kansas City, Missouri, United States of America; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Resh</LastName><ForeName>Marilyn D</ForeName><Initials>MD</Initials><AffiliationInfo><Affiliation>Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Antonarakis</LastName><ForeName>Stylianos E</ForeName><Initials>SE</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nef</LastName><ForeName>Serge</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>P30 CA008748</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 GM057966</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>DE-01682</GrantID><Acronym>DE</Acronym><Agency>NIDCR NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>05</Month><Day>01</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>PLoS Genet</MedlineTA><NlmUniqueID>101239074</NlmUniqueID><ISSNLinking>1553-7390</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D053823">Hedgehog Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.-</RegistryNumber><NameOfSubstance UI="D000217">Acyltransferases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.1.-</RegistryNumber><NameOfSubstance UI="C105599">HHAT protein, human</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>Hum Mutat. 2011 Nov;32(11):1326-31</RefSource><PMID Version="1">21898657</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Endocr Res. 2002 Nov;28(4):497-504</RefSource><PMID Version="1">12530654</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Biochemistry. 2001 Apr 10;40(14):4359-71</RefSource><PMID 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Version="1">19277064</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D058490" MajorTopicYN="N">46, XY Disorders of Sex Development</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000217" MajorTopicYN="N">Acyltransferases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000595" MajorTopicYN="N">Amino Acid Sequence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D053823" MajorTopicYN="N">Hedgehog 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MajorTopicYN="N">Pedigree</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017386" MajorTopicYN="N">Sequence Homology, Amino Acid</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013737" MajorTopicYN="N">Testis</DescriptorName><QualifierName UI="Q000196" MajorTopicYN="N">embryology</QualifierName></MeshHeading></MeshHeadingList><OtherID Source="NLM">PMC4006744</OtherID></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2013</Year><Month>11</Month><Day>08</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2014</Year><Month>03</Month><Day>07</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2014</Year><Month>5</Month><Day>3</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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