Five novel mutations in steroidogenic factor 1 (SF1,NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency

Birgit Köhler,Dirk Schnabel,Vanessa Schröder,Lin Lin,Peter Heidemann,Heike Biebermann,John C Achermann,Bruno Ferraz-De-Souza,Peter Wieacker,Annette Grüters

doi:10.1002/humu.20588

Abstract

Steroidogenic factor 1 (SF1, NR5A1) is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Human mutations in SF1 were initially found in two 46,XY female patients with severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in SF1 may also be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function. We have analyzed the gene encoding SF1 (NR5A1) in a cohort of 27 patients with 46,XY disorders of sex development (DSD) from the German network of DSD. Heterozygous SF1 mutations were found in 5 out of 27 (18.5%) of cases. Four patients with SF1 mutations presented with the similar phenotype of mild gonadal dysgenesis, severe underandrogenization, and absent Müllerian structures. Of these, two patients harbored missense mutations within the DNA-binding region of SF1 (p.C33S, p.R84H), one patient had a nonsense mutation (p.Y138X) and one patient had a frameshift mutation (c.1277dupT) predicted to disrupt RNA stability or protein function. One additional patient ([c.424_427dupCCCA]+[p.G146A]) displayed a more marked phenotype of severe gonadal dysgenesis, normal female external genitalia, and Müllerian structures. Functional studies of the missense mutants (p.C33S, p.R84H) and of one nonsense mutant (p.Y138X) revealed impaired transcriptional activation of SF1-responsive target genes. To date, adrenal insufficiency has not occurred in any of the patients. Thus, SF1 mutations are a relatively frequent cause of 46,XY DSD in humans.

Highlights

Steroidogenic factor-1 (SF1/Ad4BP, NR5A1; MIM] 184757) is a nuclear receptor that was first identified following the search for a common regulator of the cytochrome P450 steroid hydroxylase family of enzymes [Lala et al, 1992]
Critical regions of SF1 involved in transcriptional regulation include a two zinc finger DNA-binding domain (DBD), an ‘‘A’’ box region found in monomeric nuclear receptors, a hinge region, and a helical ligand-binding domain (LBD) region containing an activation function-2 (AF-2) domain [Parker and Schimmer, 1997]
These findings substantially increase the number of SF1 (NR5A1) mutations reported in humans, and show that mutations in SF1 can be found in patients with a range of phenotypic features (Table 2)

Summary

Introduction

Steroidogenic factor-1 (SF1/Ad4BP, NR5A1; MIM] 184757) is a nuclear receptor that was first identified following the search for a common regulator of the cytochrome P450 steroid hydroxylase family of enzymes [Lala et al, 1992]. Subsequent studies have revealed that SF1 regulates a great number of genes involved in gonadal and adrenal development, reproduction and steroidogenesis [Parker et al, 2002]. Critical regions of SF1 involved in transcriptional regulation include a two zinc finger DNA-binding domain (DBD), an ‘‘A’’ box region found in monomeric nuclear receptors, a hinge region, and a helical ligand-binding domain (LBD) region containing an activation function-2 (AF-2) domain [Parker and Schimmer, 1997]. Targeted disruption of Sf1 (Ftzf1) in mice results in gonadal and adrenal agenesis, persistence of Mullerian structures and abnormalities of the hypothalamus and pituitary gonadotropes [Luo et al, 1994; Majdic et al, 2002]. Heterozygous animals have a milder phenotype including an impaired adrenal stress response and reduced testicular size [Bland et al, 2000]

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Conclusion