Novel homozygous mutations in Desert Hedgehog gene in patients with 46,XY complete gonadal dysgenesis and prediction of its structural and functional implications by computational methods

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.…”

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

“…Recent studies suggest that DHh regulates myelination in the peripheral nervous system through primary cilia (27). The gonadal phenotype of patients with homozygous DHH mutations varied between partial gonadal dysgenesis with an immature uterus, testis on one side and a streak gonad on the other side (20) and complete gonadal dysgenesis with streak gonads and Mullerian structures, ie, a hypoplastic uterus or fallopian tubes (21,22). This is a common finding in the variability of partial gonadal dysgenesis.…”

“…The first patient described presented with a homozygous missense mutation associated with partial gonadal dysgenesis and minifascicular polyneuropathy (20). 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).…”

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

“…On the other hand, although the cluster of residues for interaction with calcium or zinc are conserved in the p.L162P mutant protein with respect to wt-DHH, notable changes were found for the side chains of residues in positions 154, 156, 158, 174, and 178, which are also involved in the interaction with cell adhesion molecules downregulated by oncogenes (CDO) or brother of CDO (BOC) proteins, which have an important role among mammalian Hh proteins, since all of them (SHH, IHH, and DHH) interact with CDO and BOC in a conserved manner (Kavran et al, 2010). Likewise, Das et al (2011) found a p.D90del in DHH-N in 46,XY subjects with complete gonadal dysgenesis, and their docking studies showed that the mutant protein presents an altered binding model with BOC, thus leading to a less stable complex as compared to the wild DHH. In this regard, the p.L162P mutant protein model obtained showed proximity with the region related to the interaction with cell adhesion molecules; likewise, there were also notable conformational changes in the lateral chains of this region (Fig.…”

“…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).…”