A heterozygous mutation in the desert hedgehog gene in patients with mixed gonadal dysgenesis

Abstract

Aetiology of mixed gonadal dysgenesis (MGD) has not been completely elucidated. Molecular analyses have failed to demonstrate the presence of mutations in sex-determining region on Y chromosome (SRY); it has been suggested that these individuals may bear mutations in other genes involved in the testis-determining pathway. Desert hedgehog's (DHH) importance regarding male sex differentiation has been demonstrated in various studies we describe here, for the first time, two cases of MGD in which a monoallelic single base deletion in DHH is associated with the disorder. Genomic DNA was isolated from paraffin-embedded gonad tissue from 10 unrelated patients with MGD and three controls; in addition to, DNA from peripheral blood leukocytes in 100 controls. Coding sequence abnormalities in DHH were assessed by exon-specific PCR, single-stranded conformation polymorphism (SSCP) and direct sequencing. In two patients, a heterozygous 1086delG in exon 3 was found. Comparing previously described mutations in DHH to the one observed in this study, we can affirm that the phenotypic spectrum of patients with gonadal dysgenesis due to mutations in DHH is variable. This study continues to demonstrate the importance that DHH has in mammalian male sexual differentiation, providing extended evidence that DHH constitutes a key gene in gonadal differentiation.

The Role of <i>SRY</i> Mutations in the Etiology of Gonadal Dysgenesis in Patients with 45,X/46,XY Disorder of Sex Development and Variants

“…Canto et al [25], analyzing the desert hedgehog (DHH) gene in patients with MGD, described a mutation c.1086delG in 2 of 10 individuals, in heterozygous state. This mutation leads to a premature stop codon, resulting in a truncated protein.…”

Origin, Development and Regulation of Human Leydig Cells

“…Although most data concerning the role of Desert hedgehog (Dhh) in the regulation of fetal Leydig cells have been obtained in rodents, there are also reports on the significant role of Dhh signaling in the development normal testicular phenotype in humans [20,21]. In rodents, Dhh is known to be required for the differentiation and expansion of fetal Leydig cells during the embryonic phase.…”

In Vitro and Molecular Modeling Analysis of Two Mutant Desert Hedgehog Proteins Associated with 46,XY Gonadal Dysgenesis

“…Studies in animals show that Dhh is involved in testicular differentiation (Clark et al, 2000;Pierucci-Alves et al, 2001;Yao et al, 2002;Kawai et al, 2011) (Canto et al, 2005). However, DHH is the signaling molecule of the HH family least-studied since; so far, there are only five reports of mutations in this gene and there are no functional studies of mutated DHH proteins.…”

“…Kawai et al (2011) reported a missense mutation in the Dhh gene that resulted in impaired Leydig cell development in mp/mp rats, suggesting that this mutation was responsible for the presence of pseudohermaphrodite phenotypes of mp/mp rats. Furthermore, in 46,XY subjects with gonadal dysgenesis, mutations in this gene have been described (Umehara et al, 2000;Canto et al, 2004Canto et al, , 2005Das et al, 2011;Paliwal et al, 2011).…”

“…In previous studies, our research group reported mutations in the DHH gene in three individuals with 46,XY complete pure gonadal dysgenesis (PGD), as well as in two individuals with mixed gonadal dysgenesis (MGD) (Canto et al, 2004(Canto et al, , 2005. One individual with complete PGD had a mutation located in the amino-terminal domain of the DHH protein (p.L162P), while four individuals (two with complete PGD and two with MGD) had a mutation in the carboxyterminal domain, consisting of a deletion of one nucleotide in exon 3 (D1086delG, p.L362).…”