Document Detail

Ten Novel Mutations in the NR5A1 Gene Cause Disordered Sex Development in 46,XY and Ovarian Insufficiency in 46,XX Individuals.
MedLine Citation:
PMID:  22549935     Owner:  NLM     Status:  Publisher    
Context:Steroidogenic factor-1 (SF-1/NR5A1) is a nuclear receptor that regulates adrenal and reproductive development and function. NR5A1 mutations have been detected in 46,XY individuals with disorders of sexual development (DSD) but apparently normal adrenal function and in 46,XX women with normal sexual development yet primary ovarian insufficiency (POI).Objective:A group of 100 46,XY DSD and two POI was studied for NR5A1 mutations and their impact.Design:Clinical, biochemical, histological, genetic, and functional characteristics of the patients with NR5A1 mutations are reported.Setting:Patients were referred from different centers in Spain, Switzerland, and Turkey. Histological and genetic studies were performed in Barcelona, Spain. In vitro studies were performed in Bern, Switzerland.Patients:A total of 65 Spanish and 35 Turkish patients with 46,XY DSD and two Swiss 46,XX patients with POI were investigated.Main Outcome:Ten novel heterozygote NR5A1 mutations were detected and characterized (five missense, one nonsense, three frameshift mutations, and one duplication).Results:The novel NR5A1 mutations were tested in vitro by promoter transactivation assays showing grossly reduced activity for mutations in the DNA binding domain and variably reduced activity for other mutations. Dominant negative effect of the mutations was excluded. We found high variability and thus no apparent genotype-structure-function-phenotype correlation. Histological studies of testes revealed vacuolization of Leydig cells due to fat accumulation.Conclusions:SF-1/NR5A1 mutations are frequently found in 46,XY DSD individuals (9%) and manifest with a broad phenotype. Testes histology is characteristic for fat accumulation and degeneration over time, similar to findings observed in patients with lipoid congenital adrenal hyperplasia (due to StAR mutations). Genotype-structure-function-phenotype correlation remains elusive.
N Camats; A V Pandey; M Fernández-Cancio; P Andaluz; M Janner; N Torán; F Moreno; A Bereket; T Akcay; E García-García; M T Muñoz; R Gracia; M Nistal; L Castaño; P E Mullis; A Carrascosa; L Audí; C E Flück
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-1
Journal Detail:
Title:  The Journal of clinical endocrinology and metabolism     Volume:  -     ISSN:  1945-7197     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0375362     Medline TA:  J Clin Endocrinol Metab     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Pediatric Endocrinology Research Unit (N.C., M.F.-C., P.A., A.C., L.A.), Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 08035 Barcelona, Spain; Pediatric Endocrinology (N.C., A.V.P., M.J., P.E.M., C.E.F.), Department of Pediatrics and Department of Clinical Research, University Children's Hospital Bern, 3010 Bern, Switzerland; Pathology Department (N.T.), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, 0835 Barcelona, Spain; Pediatric Endocrinology (F.M.), Hospital Universitari I Politècnic La Fe, 46026 Valencia, Spain; Department of Pediatrics (A.B.), Division of Pediatric Endocrinology, Marmara University, 34722 Istanbul, Turkey; Department of Pediatrics (T.A.), Division of Pediatric Endocrinology, Sisli Etfal Education and Research Hospital, 34377 Istanbul, Turkey; Pediatric Endocrinology (E.G.-G.), Hospital Vírgen del Rocío, 41013 Sevilla, Spain; Pediatric Endocrinology (M.T.M.), Hospital Infantil Universitario del Niño Jesús, Pediatric Department, Autonomous University, 28049 Madrid, Spain; Pediatric Endocrinology (R.G.), and Pathology Departments (M.N.), Hospital La Paz, 28046 Madrid, Spain; and Research Institute (L.C.), Hospital de Cruces/Universidad del País Vasco-Euskal Herriko Unibertsitatea, CIBERER, Instituto de Salud Carlos III, 48903 Barakaldo, Bizkaia, Spain.
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