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<publisher>HAL CCSD</publisher>
<title 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>
<creator>Callier, Patrick</creator>
<creator>Calvel, Pierre</creator>
<creator>Matevossian, Armine</creator>
<creator>Makrythanasis, Periklis</creator>
<creator>Bernard, Pascal</creator>
<creator>Kurosaka, Hiroshi</creator>
<creator>Vannier, Anne</creator>
<creator>Thauvin-Robinet, Christel</creator>
<creator>Borel, Christelle</creator>
<creator>Mazaud-Guittot, Séverine</creator>
<creator>Rolland, Antoine</creator>
<creator>Desdoits-Lethimonier, Christèle</creator>
<creator>Guipponi, Michel</creator>
<creator>Zimmermann, Céline</creator>
<creator>Stévant, Isabelle</creator>
<creator>Kuhne, Françoise</creator>
<creator>Conne, Béatrice</creator>
<creator>Santoni, Federico</creator>
<creator>Lambert, Sandy</creator>
<creator>Huet, Frederic</creator>
<creator>Mugneret, Francine</creator>
<creator>Jaruzelska, Jadwiga</creator>
<creator>Faivre, Laurence</creator>
<creator>Wilhelm, Dagmar</creator>
<creator>Jégou, Bernard</creator>
<creator>Trainor, Paul A.</creator>
<creator>Resh, Marilyn D.</creator>
<creator>Antonarakis, Stylianos E.</creator>
<creator>Nef, Serge</creator>
<contributor>Laboratoire de cytogénétique (CHU de Dijon) ; Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)</contributor>
<contributor>Génétique des Anomalies du Développement (GAD) ; Université de Bourgogne (UB) - IFR100 - Structure fédérative de recherche Santé-STIC</contributor>
<contributor>Department of Genetic Medicine and Development ; University of Geneva Medical School</contributor>
<contributor>Monash University [Clayton]</contributor>
<contributor>Department of Experimental Cardiology ; Academic Medical Center [Amsterdam] (AMC) ; University of Amsterdam [Amsterdam] (UvA) - University of Amsterdam [Amsterdam] (UvA) - Heart Failure Research Center (HFRC)</contributor>
<contributor>Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon) ; Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)</contributor>
<contributor>Université de Genève (UNIGE)</contributor>
<contributor>Environnement viral et chimique & reproduction ; Institut de recherche, santé, environnement et travail [Rennes] (Irset) ; Université d'Angers (UA) - Université des Antilles et de la Guyane (UAG) - Université de Rennes 1 (UR1) - École des Hautes Études en Santé Publique [EHESP] (EHESP) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) - Université d'Angers (UA) - Université des Antilles et de la Guyane (UAG) - Université de Rennes 1 (UR1) - École des Hautes Études en Santé Publique [EHESP] (EHESP) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )</contributor>
<contributor>Institut de recherche, santé, environnement et travail [Rennes] (Irset) ; Université d'Angers (UA) - Université des Antilles et de la Guyane (UAG) - Université de Rennes 1 (UR1) - École des Hautes Études en Santé Publique [EHESP] (EHESP) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )</contributor>
<contributor>Service de Biologie Moléculaire ; Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)</contributor>
<contributor>Virus, Environnement et Reproduction ; Groupe d'Etude de la Reproduction Chez l'Homme et les Mammiferes (GERHM) ; Université de Rennes 1 (UR1) - IFR140 - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université de Rennes 1 (UR1) - IFR140 - Institut National de la Santé et de la Recherche Médicale (INSERM) - Department of Genetic Medicine and Development ; University of Geneva Medical School - University of Geneva Medical School</contributor>
<description>International audience</description>
<source>ISSN: 1553-7390</source>
<source>EISSN: 1553-7404</source>
<source>PLoS Genetics</source>
<publisher>Public Library of Science</publisher>
<identifier>hal-01063929</identifier>
<identifier>https://hal.archives-ouvertes.fr/hal-01063929</identifier>
<source>https://hal.archives-ouvertes.fr/hal-01063929</source>
<source>PLoS Genetics, Public Library of Science, 2014, 10 (5), pp.e1004340. 〈10.1371/journal.pgen.1004340〉</source>
<identifier>DOI : 10.1371/journal.pgen.1004340</identifier>
<relation>info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pgen.1004340</relation>
<identifier>PUBMED : 24784881</identifier>
<relation>info:eu-repo/semantics/altIdentifier/pmid/24784881</relation>
<language>en</language>
<subject>[SDV] Life Sciences [q-bio]</subject>
<type>info:eu-repo/semantics/article</type>
<type>Journal articles</type>
<description 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.</description>
<date>2014</date>
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