2. Academic Validation
  3. 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

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

  • PLoS Genet. 2014 May 1;10(5):e1004340. doi: 10.1371/journal.pgen.1004340.
Patrick Callier 1,  Pierre Calvel 2,  Armine Matevossian 3,  Periklis Makrythanasis 2,  Pascal Bernard 4,  Hiroshi Kurosaka 5,  Anne Vannier 2,  Christel Thauvin-Robinet 6,  Christelle Borel 2,  Séverine Mazaud-Guittot 7,  Antoine Rolland 7,  Christèle Desdoits-Lethimonier 7,  Michel Guipponi 2,  Céline Zimmermann 2,  Isabelle Stévant 2,  Françoise Kuhne 2,  Béatrice Conne 2,  Federico Santoni 2,  Sandy Lambert 8,  Frederic Huet 6,  Francine Mugneret 8,  Jadwiga Jaruzelska 9,  Laurence Faivre 6,  Dagmar Wilhelm 4,  Bernard Jégou 10,  Paul A Trainor 11,  Marilyn D Resh 3,  Stylianos E Antonarakis 12,  Serge Nef 12
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
  • 3 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.
  • 4 Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
  • 5 Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.
  • 6 FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.
  • 7 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.
  • 8 FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France.
  • 9 Polish Academy of Sciences, Institute of Human Genetics, Poznań, Poland.
  • 10 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.
  • 11 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.
  • 12 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.
PMID: 24784881 DOI: 10.1371/journal.pgen.1004340
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.

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