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
Malikova, Jana (P University Children's Hospital Bern)
Camats Tarruella, Núria (University Children's Hospital Bern (Suïssa))
Fernández Cancio, Mónica (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Heath, Karen E (Instituto de Investigación Sanitaria del Hospital Universitario La Paz)
González, Isabel (Instituto de Investigación Sanitaria del Hospital Universitario La Paz)
Caimarí, María (Hospital Universitari Son Espases (Palma de Mallorca, Balears))
del Campo Casanelles, Miguel (Hospital Universitari Vall d'Hebron)
Albisu, Marian (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Kolouskova, Stanislava (University Hospital Motol, Prague)
Audí, Laura (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Flück, Christa E. (University Children's Hospital Bern (Suïssa))
Universitat Autònoma de Barcelona

Data:	2014
Resum:	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. To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. 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. 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). Two novel NR5A1 /SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4 th reported SF-1 mutation causing DSD 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. 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.
Ajuts:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR-3
Nota:	Altres ajuts: Instituto de Salud Carlos III CIBERER U-712
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	PloS one, Vol. 9 (august 2014) , ISSN 1932-6203

DOI: 10.1371/journal.pone.0104838
PMID: 25122490

9 p, 459.3 KB

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