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Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals.

Abstract

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.

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  • Publisher Full Text
  • Authors

    Camats N, Pandey AV, Fernández-Cancio M, Andaluz P, Janner M, Torán N, Moreno F, Bereket A, Akcay T, García-García E, Muñoz MT, Gracia R, Nistal M, Castaño L, Mullis PE, Carrascosa A, Audí L, Flück CE

    Source

    The Journal of clinical endocrinology and metabolism 97:7 2012 Jul pg E1294-306

    MeSH

    46, XX Disorders of Sex Development
    46, XY Disorders of Sex Development
    Adolescent
    Base Sequence
    Child
    Child, Preschool
    DNA Mutational Analysis
    Female
    Genetic Predisposition to Disease
    Humans
    Male
    Molecular Sequence Data
    Phenotype
    Point Mutation
    Primary Ovarian Insufficiency
    Steroidogenic Factor 1
    Young Adult

    Pub Type(s)

    Journal Article
    Multicenter Study
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22549935