title: Two novel mutations in the NR5A1 gene 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.
authors.affiliation: Department of Biochemistry, University of Health Sciences, Lahore, Pakistan.
authors.forename: S
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Department Human Genetics & Molecular Biology, University of Health Sciences, Lahore, Pakistan.
authors.forename: A
authors.initials: A
authors.lastname: Amar
authors.affiliation: Department of Biochemistry, Quaid-e-Azam Medical Collage, Bahawalpur, Pakistan.
authors.forename: M N
authors.initials: MN
authors.lastname: Najeeb
authors.affiliation: Department Human Genetics & Molecular Biology, University of Health Sciences, Lahore, Pakistan.
authors.forename: S
authors.initials: S
authors.lastname: Khaliq
mesh_terms: D000293:Adolescent; D018389:Codon, Nonsense; D015331:Cohort Studies; D003241:Consanguinity; D004252:DNA Mutational Analysis; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics*; D016368:Frameshift Mutation; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D010154:Pakistan; D020641:Polymorphism, Single Nucleotide; D000072417:Protein Domains; D054339:Steroidogenic Factor 1 / Q000737:chemistry / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D050505:Mutant Proteins; C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1
keywords: 46XY DSD; DNA sequencing; NR5A1; gonadal dysgenesis