CONTEXT: Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. OBJECTIVE: To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. PATIENTS: 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. METHODS: SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). RESULTS: Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. CONCLUSIONS: Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations.

Department of Pediatrics 2nd Faculty of Medicine Charles University Prague and University Hospital Motol Prague Czech Republic

Genetic Service Hospital Vall d'Hebron Barcelona Spain

Institute of Medical and Molecular Genetics INGEMM Hospital Universitario La Paz Universidad Autónoma de Madrid IdiPAZ Madrid Spain

Pediatric Endocrinology Department of Pediatrics and Department of Clinical Research University Children's Hospital Bern Bern Switzerland

Pediatric Endocrinology Service Hospital Universitario La Paz Universidad Autónoma de Madrid IdiPAZ Madrid Spain

Pediatric Endocrinology Son Espases University Hospital Palma de Mallorca Spain

Pediatric Endocrinology Vall d'Hebron Research Institute VHIR CIBERER Autonomous University Barcelona Spain

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