Mutations in the Desert hedgehog (DHH) Gene in Patients with 46,XY Complete Pure Gonadal Dysgenesis

Abstract

Mutations of SRY are the cause of complete pure gonadal dysgenesis (PGD) in 10-15% of patients. In the remaining individuals, it has been suggested that mutations in other genes involved in the testis-determining pathway could be causative. We describe the first report in which three cases of 46,XY complete PGD are attributed to mutations of the Desert hedgehog (DHH) gene. DHH was sequenced using genomic DNA from paraffin-embedded gonadal tissue from six patients with complete 46,XY PGD. Mutations were found in three patients: a homozygous mutation in exon 2, responsible for a L162P, and a homozygous 1086delG in exon 3. Mutated individuals displayed 46,XY complete PGD, differentiating from the only previously described patient with a homozygous DHH mutation, who exhibited a partial form of PGD with polyneuropathy, suggesting that localization of mutations influence phenotypic expression. This constitutes the first report where mutations of DHH are associated with the presence of 46,XY complete PGD, demonstrating that the genetic origin of this entity is heterogeneous and that disorders in other genes, different from SRY, involved in the testis-determining pathway are implicated in abnormal testicular differentiation in humans. These data extend previous reports demonstrating DHH is a key gene in gonadal differentiation.

Partial duplication of DHH causes minifascicular neuropathy

“…To date, seven DHH mutations have been reported 14, 15, 16. Three of the seven mutations, including the mutation found in the study, cause 46XY GD with neuropathy, whereas some mutations did not cause neuropathy.…”

Swyer’s Syndrome: In a Fifty-Year-Old Female

“…Lin et al and Reuter et al [10,11] demonstrated that SF1 mutations (SFl/AdBP4/FTZF1, NRSA1) Recently, mutations in genes other than SRY gene were also discovered in patients with complete pure gonadal dysgenesis. Canto and colleagues [12] firstly described the mutations of Desert hedgehog (DHH) gene associated with the presence of 46, XY complete pure gonadal dysgenesis. Hence, the genetic origin of this entity seemed to be heterogeneous and the genes other than SRY, might also be involved in the testis-determining pathway implicated in abnormal testicular differentiation [12].…”

“…Canto and colleagues [12] firstly described the mutations of Desert hedgehog (DHH) gene associated with the presence of 46, XY complete pure gonadal dysgenesis. Hence, the genetic origin of this entity seemed to be heterogeneous and the genes other than SRY, might also be involved in the testis-determining pathway implicated in abnormal testicular differentiation [12].…”

Case Report Molecular characterisation of a der(Y)t(Xp;Yp) with Xp functional disomy and sex reversal

“…Gonadal dysgenesis +/-polyneuropathy: homozygous point mutation (Umehara et al, 2000;Canto et al, 2004) LHCGR Leydig cell hypoplasia and under-virilization in 46,XY male, hypergonadotropic hypogonadism in 46,XX females: heterozygous inactivating mutations (Chan, 1998) …”