Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals

Abstract

Steroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1-related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever-expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309-320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

Keywords: NR5A1 gene; adrenal insufficiency; disorders of sex development; gonadal dysgenesis; ovotestis; primary ovarian failure.

Figure 1

The ten novel mutations identified in 46,XY DSD patients and their localization on the NR5A1 protein. DBD, DNA‐binding domain; LBD, ligand‐binding domain; AF2, activation function domain.

Figure 2

(A) Energy distributions of the native NR5A1 LBD domain and mutated molecules. A higher energy is associated with a less stable molecule compared to the native due loss of amino acid contacts. (B) Energy distributions of the native NR5A1 DBD domain and its p.Gly26Glu mutated molecule. A smaller energy is associated to a more stable molecule, compared to the native due additional amino acids contacts.

Figure 3

Superimposed Models: Superimposition of the native (white) and mutated smallest energy NR5A1 models (colored): (A) DBD domain showing Glu26 and Arg79 salt bridge; (B) LBD domain showing Try302Cys; (C) LBD hydrophobic network with Leu358Pro in the center; and (D) LBD helix‐9 rotated and unrolled half a turn with the Glu385 deletion.

Figure 4

Transcriptional activation of target gene promoters by wild‐type (WT) and mutant NR5A1 in human embryonic kidney TSA‐201 cells. In vitro activation of CYP11A1 and CYP19 gene promoters by the novel NR5A1 mutant p.Leu358Pro was reduced, in comparison to WT NR5A1 (29% and 18% of WT, respectively). Notably, the degree of transcriptional activity impairment at the CYP11A1 promoter by p.Leu358Pro NR5A1 was comparable to that of the well‐known NR5A1 mutant p.Gly35Glu (Lin et al., 2007) and more severe than p.Arg92Gln (Achermann et al., 2002). Results represent the mean (SEM) for three assays, each performed in triplicate, and shown relative to wild‐type transactivation. RLU, relative luciferase units.