Mutations in the NR5A1 gene in patients with 46,XY disorders of sex development (DSD): High frequency of familial multi-generational occurrence

COSTANZO, M; GUERCIO, G; MARINO, R; RAMIREZ, P; GALEANO, J; PEREZ GARRIDO, N; CIACCIO, M; WARMAN, M; BAQUEDANO, MS; SARACCO, N; BERENZSTEIN, E; CHALER, E; MACEIRAS, M; LAZZATI, J; RIVAROLA, M; BELGOROSKY, A

Florencia

Congreso; International Congress of Endocrinology Flore 2012; 2012

  The nuclear receptor SF1/NR5A1 regulates transcription of genes involved in reproduction, steroidogenesis and male sexual differentiation. Mutations in humans cause gonadal dysgenesis with or without adrenal failure in both 46,XY and 46,XX individuals. In a cohort of patients with familial 46,XY DSD, we identified 6 heterozygous NR5A1 mutations in 19 subjects from 5 unrelated families (F1-F5). Moreover, a de novo heterozygous mutation in one patient with 46,XY DSD and no affected relatives was also detected. Low ovarian reserve with preserved fertility was detected in females harboring NR5A1 mutations. Extreme within-family variability was found in 46,XY DSD affected patients, with phenotypes ranging from severe fetal undervirilization, prompting female sex of rearing, to spontaneous pubertal development and even preserved fertility. Analyses revealed a W279X heterozygous mutation and an intronic deletion (g3314-3317delTCTC (IVS 4+8) in F1, and a Y183X heterozygous mutation in F2. A novel R313H heterozygous variation was found in F3, and a novel S303R mutation in F4. A novel heterozygous R69H mutation was found in the only 46,XY DSD patient studied in F5, and a de novo G77E mutation in the sporadic case. All new mutations were predicted to affect protein function by prediction models (SIFT, Polyphen and MutationTaster). Mode of inheritance seems to be autosomal dominant with variable penetrance. We emphasize the extreme phenotypic variability, even in siblings with the same mutation. As previously reported, we found spontaneous puberty in 46,XY DSD individuals raised as males, and for the first time we report preserved fertility in one of these affected individuals. Subjects with heterozygous NR5A1 mutations and mild phenotypes, such as isolated hypospadias in 46,XY patients, compensated ovarian dysfunction and early menopause in 46,XX subjects, might easily go undetected. A careful family screening of 46,XY as well as 46,XX individuals is recommended whenever an index case is detected.