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

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.

Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review

“…Finally, a mutation in the Hedgehog acetyl transferase gene, impeding Hedgehog protein signaling, has been reported in a syndromic form of 46,XY disorder of sex development with complete GD and skeletal malformations. This male showed dysplastic immature seminiferous tubules delimited with a dense interstitial compartment containing a greatly reduced portion of steroidogenic cells, confirming that DHH signaling plays a role in testis cord formation and differentiation of fetal Leydig cells [18]. …”

A Case of Wiedemann-Steiner Syndrome Associated with a 46,XY Disorder of Sexual Development and Gonadal Dysgenesis

“…The raw data were analyzed using our bioinformatic pipeline hosted on the Vital-IT Center of the Swiss Institute of Bioinformatics (SIB; http://www.vital-it.ch), as previously described [Callier et al, 2014]. All experiments were performed using the manufacturer's instructions without modifications.…”

46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome Sequencing

“…Later a few patients with homozygous DHH mutations and complete gonadal dysgenesis also have been reported (21,22). A recently described mutation in the Hedgehog acetyl-transferase gene (HHAT), which is required for N-terminal palmitoylation of Hedgehog impedes Hedgehog protein signaling and leads to a syndromic form of 46,XY DSD with complete gonadal dysgenesis and skeletal malformations (23). The male patient had dysplastic immature seminiferous tubules delimited with a dense interstitial compartment containing a greatly reduced portion of steroidogenic cells, indicated by CYP11A1 expression.…”