Steroidogenic factor-1 (SF-1, NR5A1) and human disease

Abstract

Steroidogenic factor-1 (SF-1, Ad4BP, encoded by NR5A1) is a key regulator of adrenal and reproductive development and function. Based upon the features found in Nr5a1 null mice, initial attempts to identify SF-1 changes in humans focused on those rare individuals with primary adrenal failure, a 46,XY karyotype, complete gonadal dysgenesis and Müllerian structures. Although alterations affecting DNA-binding of SF-1 were found in two such cases, disruption of SF-1 is not commonly found in patients with adrenal failure. In contrast, it is emerging that variations in SF-1 can be found in association with a range of human reproductive phenotypes such as 46,XY disorders of sex development (DSD), hypospadias, anorchia, male factor infertility, or primary ovarian insufficiency in women. Overexpression or overactivity of SF-1 is also reported in some adrenal tumors or endometriosis. Therefore, the clinical spectrum of phenotypes associated with variations in SF-1 is expanding and the importance of this nuclear receptor in human endocrine disease is now firmly established.

Fig. 1

Overview of SF-1 mutations associated with adrenal failure and 46,XY DSD. (A) Cartoon of SF-1 showing key functional domains and the position of the two SF-1 variants associated with this phenotype. (B) The amino-acid structure of the zinc fingers of the DNA-binding domain of SF-1 showing the proximal (P)-box motif and the glycine residue that is altered by the p.G35E mutation. (C) Streak-like gonads removed from the patient with the p.G35E change in late childhood (upper panel), containing poorly formed seminiferous tubules and connective tissue (lower panel). (D) Model of the DNA-binding domain of SF-1 bound to DNA based on the crystal structure of NGFI-B. The glycine at amino acid 35 (green) of the P-box forms the primary DNA-binding interface with the major groove of DNA and heterozygous disruption of this residue with replacement by glutamic acid is associated with a severe phenotype. In contrast, the arginine at amino acid 92 (yellow) affects the A-box of SF-1, which is important in stabilizing nuclear receptor binding. In this situation, homozygous disruption of the residue was associated with the severe adrenogonadal phenotype. Panels B and C reproduced with permission from Achermann et al. (1999) (copyright: Nature Publishing Group 1999). Panel D reproduced with permission from Achermann et al. (2002) (copyright: The Endocrine Society 2002).

Fig. 2

Overview of reported changes in SF-1/NR5A1 in humans. The approximate location of the change within the predicted structure of SF-1 is shown. Yellow shaded areas represent changes found in 46,XX girls or women. Grey and white areas represent changes in individuals with a 46,XY karyotype. Underlined changes were detected in a homozygous state. All other changes were present in a heterozygous state. An asterisk denotes cases where the p.G146A polymorphism was also detected. The missense mutation shown in italics is predicted to disrupt function, but data from functional assays have not been reported. In addition, deletion of NR5A1 on one allele has been reported as part of a contiguous gene deletion syndrome. AI, adrenal insufficiency; DSD, disorder of sex development, POI, primary ovarian insufficiency. Modified with permission from Lin et al. (2007) (copyright: The Endocrine Society 2002). For a complete overview of clinical and biochemical features associated with these changes, see Köhler & Achermann (2010).

Fig. 3

Gonadal histology in 46,XY and 46,XX patients with NR5A1 mutations. (A and B) Partial testicular dysgenesis in a patient with 46,XY DSD without adrenal failure. Testicular architecture was largely intact but seminiferous tubules were reduced in size. Sertoli, germ and Leydig cells were present. (original magnification 100× and 400× respectively; germ cells shown by arrows). (C) Testicular biopsy in a boy with severe penoscrotal hypospadias (original magnification 100×; seminiferous tubule hyalinization shown by arrowheads). (D) Ovarian dysgenesis in a patient with 46,XX primary ovarian insufficiency. Panels A–C reproduced with permission from Lin et al. (2007) (copyright: The Endocrine Society 2007). Panel D reproduced with permission from Lourenco et al. (2009) (copyright: © 2009 Massachusetts Medical Society).

Fig. 4

The spectrum of phenotypes that have been reported in association with SF-1/NR5A1 changes in humans (46,XY).