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PLoS One. 2014 Aug 14;9(8):e104838. doi: 10.1371/journal.pone.0104838. eCollection 2014.

Human NR5A1/SF-1 mutations show decreased activity on BDNF (brain-derived neurotrophic factor), an important regulator of energy balance: testing impact of novel SF-1 mutations beyond steroidogenesis.

Author information

1
Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic; Pediatric Endocrinology, Department of Pediatrics and Department of Clinical Research, University Children's Hospital Bern, Bern, Switzerland.
2
Pediatric Endocrinology, Department of Pediatrics and Department of Clinical Research, University Children's Hospital Bern, Bern, Switzerland.
3
Pediatric Endocrinology, Vall d'Hebron Research Institute VHIR, CIBERER, Autonomous University, Barcelona, Spain.
4
Institute of Medical and Molecular Genetics INGEMM, Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
5
Pediatric Endocrinology Service, Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
6
Pediatric Endocrinology, Son Espases University Hospital, Palma de Mallorca, Spain.
7
Genetic Service, Hospital Vall d'Hebron, Barcelona, Spain.
8
Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.

Abstract

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.

PMID:
25122490
PMCID:
PMC4133263
DOI:
10.1371/journal.pone.0104838
[Indexed for MEDLINE]
Free PMC Article

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