title: Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency.
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.
authors: Department of Pediatric Endocrinology, University Children's Hospital, Charité, Humboldt University, Berlin, Germany. birgit.koehler@charite.de
authors: Birgit
authors: B
authors: Köhler
authors: Lin
authors: L
authors: Lin
authors: Bruno
authors: B
authors: Ferraz-de-Souza
authors: Peter
authors: P
authors: Wieacker
authors: Peter
authors: P
authors: Heidemann
authors: Vanessa
authors: V
authors: Schröder
authors: Heike
authors: H
authors: Biebermann
authors: Dirk
authors: D
authors: Schnabel
authors: Annette
authors: A
authors: Grüters
authors: John C
authors: JC
authors: Achermann
mesh_terms: D000293:Adolescent; D000311:Adrenal Glands / Q000378:metabolism; D000309:Adrenal Insufficiency / Q000175:diagnosis; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006061:Gonadal Dysgenesis, 46,XY / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D009154:Mutation; D054339:Steroidogenic Factor 1 / Q000032:analysis / Q000235:genetics*
chemical_list: C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1
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