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.
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.
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.
Patrick
P
Callier
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Pierre
P
Calvel
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.
Armine
A
Matevossian
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Periklis
P
Makrythanasis
Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
Pascal
P
Bernard
Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.
Hiroshi
H
Kurosaka
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Anne
A
Vannier
FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.
Christel
C
Thauvin-Robinet
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Christelle
C
Borel
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.
Séverine
S
Mazaud-Guittot
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.
Antoine
A
Rolland
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.
Christèle
C
Desdoits-Lethimonier
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Michel
M
Guipponi
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Céline
C
Zimmermann
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Isabelle
I
Stévant
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Françoise
F
Kuhne
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Béatrice
B
Conne
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Federico
F
Santoni
FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France.
Sandy
S
Lambert
FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.
Frederic
F
Huet
FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France.
Francine
F
Mugneret
Polish Academy of Sciences, Institute of Human Genetics, Poznań, Poland.
Jadwiga
J
Jaruzelska
FHU-TRANSLAD, Département de Génétique, Hôpital Le Bocage, CHU, Dijon, France; EA 4271 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.
Laurence
L
Faivre
Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
Dagmar
D
Wilhelm
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.
Bernard
B
Jégou
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.
Paul A
PA
Trainor
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.
Marilyn D
MD
Resh
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.
Stylianos E
SE
Antonarakis
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.
Serge
S
Nef
D000217:Acyltransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics*; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D054878:Lipoylation / Q000235:genetics*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics*; D013737:Testis / Q000196:embryology
D053823:Hedgehog Proteins; D000217:Acyltransferases; C105599:HHAT protein, human