The novel p.Cys65Tyr mutation in NR5A1gene in three 46,XY siblings with normal testosterone levels and their mother with primary ovarian insufficiency

Abstract

BackgroundDisorders of sex development (DSD) is the term used for congenital conditions in which development of chromosomal, gonadal, or phenotypic sex is atypical. Nuclear receptor subfamily 5, group A, member 1 gene (NR5A1) encodes steroidogenic factor 1 (SF1), a transcription factor that is involved in gonadal development and regulates adrenal steroidogenesis. Mutations in the NR5A1 gene may lead to different 46,XX or 46,XY DSD phenotypes with or without adrenal failure. We report a Brazilian family with a novel NR5A1 mutation causing ambiguous genitalia in 46,XY affected individuals without Müllerian derivatives and apparently normal Leydig function after birth and at puberty, respectively. Their mother, who is also heterozygous for the mutation, presents evidence of primary ovarian insufficiency.Case presentationThree siblings with 46,XY DSD, ambiguous genitalia and normal testosterone production were included in the study. Molecular analyses for AR, SRD5A2 genes did not reveal any mutation. However, NR5A2 sequence analysis indicated that all three siblings were heterozygous for the p.Cys65Tyr mutation which was inherited from their mother. In silico analysis was carried out to elucidate the role of the amino acid change on the protein function. After the mutation was identified, all sibs and the mother had been reevaluated. Basal hormone concentrations were normal except that ACTH levels were slightly elevated. After 1 mcg ACTH stimulation test, only the older sib showed subnormal cortisol response.ConclusionThe p.Cys65Tyr mutation located within the second zinc finger of DNA binding domain was considered deleterious upon analysis with predictive algorithms. The identification of heterozygous individuals with this novel mutation may bring additional knowledge on structural modifications that may influence NR5A1 DNA-binding ability, and may also contribute to genotype-phenotype correlations in DSD. The slightly elevated ACTH basal levels in all three patients with 46,XY DSD and the subnormal cortisol response after 1 mcg ACTH stimulation in the older sib indicate that a long-term follow-up for adrenal function is important for these patients. Our data reinforce that NR5A1 analysis must also be performed in 46,XY DSD patients with normal testosterone levels without AR mutations.

408 Cases of Genital Ambiguity Followed by Single Multidisciplinary Team during 23 Years: Etiologic Diagnosis and Sex of Rearing

“…The identification of a mutation in the specific gene is important for the follow-up of these cases, particularly mutations in WT1 that are associated with risk of kidney cancer and gonadal and renal failure [30, 31]. NR5A1 mutations are associated with risk of adrenal insufficiency and primary ovarian failure [32–34]. In a family with mutation in SRY , there was a wide spectrum of XY gonadal dysgenesis manifestation, varying from partial to complete forms [28].…”

Functional characterization of fiveNR5A1gene mutations found in patients with 46,XY disorders of sex development

“…Adrenal function was normal for all siblings. The mutation c.195G > A (p.Cys65Tyr) was identified within exon 3 in the three siblings and also in the mother (Fabbri et al., ).…”

<b><i>NR5A1</i></b> Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations

“…Patients with normal testosterone production and spontaneous puberty have been described before [Bashamboo et al, 2010;Fabbri et al, 2014], but some presented with progressive gonadal dysgenesis resulting in oligospermia or azoospermia, as in patient 2 [Tantawy et al, 2012]. Pedace et al [2014] suggested that NR5A1 alterations may affect Sertoli cells more severely than Leydig cells, considering that most of the 46,XY patients will produce testosterone during life, maintaining the function of Leydig cells in adulthood, although it might be lower than that of normal cells.…”