New NR5A1 mutations and phenotypic variations of gonadal dysgenesis

Abstract

Mutations in NR5A1 have been reported as a frequent cause of 46,XY disorders of sex development (DSD) associated to a broad phenotypic spectrum ranging from infertility, ambiguous genitalia, anorchia to gonadal dygenesis and female genitalia. Here we present the clinical follow up of four 46,XY DSD patients with three novel heterozygous mutations in the NR5A1 gene leading to a p.T40P missense mutation and a p.18DKVSG22del nonframeshift deletion in the DNA-binding domain and a familiar p.Y211Tfs*83 frameshift mutation. Functional analysis of the missense and nonframeshift mutation revealed a deleterious character with loss of DNA-binding and transactivation capacity. Both, the mutations in the DNA-binding domain, as well as the familiar frameshift mutation are associated with highly variable endocrine values and phenotypic appearance. Phenotypes vary from males with spontaneous puberty, substantial testosterone production and possible fertility to females with and without Müllerian structures and primary amenorrhea. Exome sequencing of the sibling’s family revealed TBX2 as a possible modifier of gonadal development in patients with NR5A1 mutations.

Novel NR5A1 mutations found in Chinese patients with 46, XY disorders of sex development

“…Recurrent variants are in the upper of the box, novel variants found in this study are in the below of the box the second zinc fingers. 34 In the same region, three other variants, R39P, 35 T40P 34 and V41P 36 had been previously reported, and with the exception of R39P, both the T40P and V41P mutants have been identified as deleterious mutations. Our study shows that N44del decreases the transaction activity of SF-1 to 23% and it is a deleterious mutation.…”

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

“…Patient 4, affected in the same residue 39, was presented with ambiguous genitalia and an initial female sex assignment. Others have also correlated mutations in this domain with DSD; in general, phenotypes are severe and the impact to the protein function is high (Achermann, Ito, Ito, Hindmarsh, & Jameson ; Camats et al., ; Fabbri et al., ; Werner et al, ). Camats et al.…”

“…Patient 4, affected in the same residue 39, was presented with ambiguous genitalia and an initial female sex assignment. Others have also correlated mutations in this domain with DSD; in general, phenotypes are severe and the impact to the protein function is high(Achermann, Ito, Ito, Hindmarsh, & Jameson 1999;Camats et al, 2012;Fabbri et al, 2016;Werner et al, 2017) Camats et al (2012). described 10 mutations scattered through different domains of SF1, and evaluating the impact of such mutations, they observed that variations in the DBD led to markedly F I G U R E 4 Structural analysis of normal and mutant proteins interacting with the DNA molecule.…”

Broad phenotypes in heterozygous NR5A1 46,XY patients with a disorder of sex development: an oligogenic origin?

“…Oligogenic modulators, epigenetic factors, imbalanced transcriptional cis-regulation, developmental switches, and environmental factors have been suggested as possible explanations [5,11]. In fact, a digenic inheritance of gonadal dysgenesis has recently been suggested in a 46,XY DSD patient heterozygous for NR5A1 and MAP3K1 variants [12], and in a family harboring heterozygous NR5A1 mutations manifesting as 46,XY DSD in males and 46,XX POF in females, in whom an additional variant in the TBX2 gene was found in the females [13].…”