Two novel mutations in theNR5A1gene as a cause of disorders of sex development in a Pakistani cohort of 46,XY patients

Abstract

NR5A1 plays a central role in gonadal development and regulation by transcriptional regulation of key modulators involved in steroidogenesis. Mutations in human NR5A1 are frequently associated with 46,XY disorders of sex development (DSD). We analysed a Pakistani cohort of patients with 46,XY DSD, presenting with variable degrees of gonadal dysgenesis, for NR5A1 mutations. The study identified three mutations (p.Tyr03X, p.Glu07X and p.Gln299HisfsX386), of which two are novel, in these patients with 46,XY DSD. The mutations, p.Tyr03X and novel p.Glu07X, are located in the coding region of the gene, corresponding to DNA-binding domain of the predicted protein. In silico analysis for the novel homozygous p.Gln299HisfsX386 mutation in ligand-binding domain of NR5A1 revealed subtle changes in overall tertiary conformation which is predicted to affect the normal physiology of this mutant protein. This study reveals two novel mutations with altered NR5A1 protein in twenty patients with 46,XY DSD, highlighting the critical role of NR5A1 protein in gonadal development and differentiation. In conclusion, the current and previous studies suggest that the NR5A1 mutations are present in around 8-15% of patients with 46,XY DSD presenting with gonadal dysgenesis. For the clinical utility of NR5A1 gene mutations, more comprehensive studies with large 46,XY DSD patient series in different populations are suggested.

Mutation update for theNR5A1gene involved in DSD and infertility

“…Mutations are divided as follows: 109 are missense (58%), 45 represent small deletions and insertions (24%) being 10 in‐frame and 35 frameshift, 22 are nonsense (12.3%), eight are intronic variations (3.3%), and four are extension mutations (<1%). Among the 238 cases reported, only 3% presented homozygous mutations; all the remaining were heterozygous, including four cases with presumed compound heterozygosis (Hussain, Amar, Najeeb, & Khaliq, ; Malikova et al, ; Rehkämper et al, ; Voican et al, ) and two in cis heterozygous mutations (Lourenço et al, ; Robevska et al, ), confirming that inheritance of NR5A1 mutations are neither classical autosomal recessive nor autosomal dominant, but NR5A1 acts in a dose‐dependent manner. An interesting example of that variable action is a patient from our cohort which was independently ascertained with 46,XY PGD due to a heterozygous p.Asp293Asn mutation.…”

Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development

“…Recently, several splice site variants have also been reported in the literature (Fabbri, Ribeiro de Andrade, Maciel‐Guerra, Guerra‐Júnior, & de Mello, ; Hussain et al. ; Swartz et al. ).…”

“…However, a substantial number of frame-shift, nonsense, and in-frame deletions have been described (Barbaro, Cools, Looijenga, Drop, & Wedell, 2011). Recently, several splice site variants have also been reported in the literature (Fabbri, Ribeiro de Andrade, Maciel-Guerra, Guerra-Júnior, & de Mello, 2016;Hussain et al 2016;Swartz et al 2017).…”