title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: Jana
authors.initials: J
authors.lastname: Malikova
authors.affiliation: Pediatric Endocrinology, Department of Pediatrics and Department of Clinical Research, University Children's Hospital Bern, Bern, Switzerland.
authors.forename: Núria
authors.initials: N
authors.lastname: Camats
authors.affiliation: Pediatric Endocrinology, Vall d'Hebron Research Institute VHIR, CIBERER, Autonomous University, Barcelona, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Fernández-Cancio
authors.affiliation: Institute of Medical and Molecular Genetics INGEMM, Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Karen
authors.initials: K
authors.lastname: Heath
authors.affiliation: Pediatric Endocrinology Service, Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: González
authors.affiliation: Pediatric Endocrinology, Son Espases University Hospital, Palma de Mallorca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Caimarí
authors.affiliation: Genetic Service, Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: del Campo
authors.affiliation: Pediatric Endocrinology, Vall d'Hebron Research Institute VHIR, CIBERER, Autonomous University, Barcelona, Spain.
authors.forename: Marian
authors.initials: M
authors.lastname: Albisu
authors.affiliation: Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Stanislava
authors.initials: S
authors.lastname: Kolouskova
authors.affiliation: Pediatric Endocrinology, Vall d'Hebron Research Institute VHIR, CIBERER, Autonomous University, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Audí
authors.affiliation: Pediatric Endocrinology, Department of Pediatrics and Department of Clinical Research, University Children's Hospital Bern, Bern, Switzerland.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Flück
mesh_terms: D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D054339:Steroidogenic Factor 1 / Q000235:genetics*; D013256:Steroids / Q000096:biosynthesis*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1; D013256:Steroids