• PMID: 22028768
• Gene Name: NR5A1
• Condition: Infertility
• Association: Mutations in NR5A1 were observed in 5/77 (6.5%) cases of 46,XY DSD including hypospadias.Excluding the cases of 46,XY gonadal dysgenesis the incidence of NR5A1 mutations was 5/66 (7.6%). An individual with isolated distal hypopadias carried a de novo hete
• Mutation: p.Trp279Arg, p.Arg39Pro, c.390delG, c.140_141insCACG, p.Arg313Cys
• Population size: 77
• Population details: 77 (11 partial gonadal dysgenesis, 33 ambiguous external genitalia without uterus, 28 hypospadias had a normal penis length and palpable inguinal or intrascrotal gonads bilaterally,5 hypospadias had a normal penis length and palpable inguinal or intrasc
• Age: 0-17 yrs
• Sex: Male , Female
• Infertility type: Male infertility, Female infertility
• Other associated phenotypes: disorders of sex development, hypospadias

Mutation analysis of NR5A1 encoding steroidogenic factor 1 in 77 patients with 46, XY disorders of sex development (DSD) including hypospadias

Allali S, Muller JB, Brauner R, Lourenço D, Boudjenah R, Karageorgou V, Trivin C, Lottmann H, Lortat-Jacob S, Nihoul-Fékété C, De Dreuzy O, McElreavey K, Bashamboo A.

BACKGROUND: Mutations of the NR5A1 gene encoding steroidogenic factor-1 have been reported in association with a wide spectrum of 46,XY DSD (Disorder of Sex Development) phenotypes including severe forms of hypospadias. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the frequency of NR5A1 gene mutations in a large series of patients presenting with 46,XY DSD and hypospadias. Based on their clinical presentation 77 patients were classified either as complete or partial gonadal dysgenesis (uterus seen at genitography and/or surgery, n = 11), ambiguous external genitalia without uterus (n = 33) or hypospadias (n = 33). We identified heterozygous NR5A1 mutations in 4 cases of ambiguous external genitalia without uterus (12.1%; p.Trp279Arg, pArg39Pro, c.390delG, c140_141insCACG) and a de novo missense mutation in one case with distal hypospadias (3%; p.Arg313Cys). Mutant proteins showed reduced transactivation activity and mutants p.Arg39Pro and p.Arg313Cys did not synergize with the GATA4 cofactor to stimulate reporter gene activity, although they retained their ability to physically interact with the GATA4 protein. CONCLUSIONS/SIGNIFICANCE: Mutations in NR5A1 were observed in 5/77 (6.5%) cases of 46,XY DSD including hypospadias. Excluding the cases of 46,XY gonadal dysgenesis the incidence of NR5A1 mutations was 5/66 (7.6%). An individual with isolated distal hypopadias carried a de novo heterozygous missense mutation, thus extending the range of phenotypes associated with NR5A1 mutations and suggesting that this group of patients should be screened for NR5A1 mutations. FAU - Allali, Slimane AU - Allali S AD - Université Paris Descartes, Faculté de médecine and AP-HP, Hôpital Bicêtre, Unité d'Endocrinologie, Pédiatrique, Le Kremlin Bicêtre, France. FAU - Muller, Jean-Baptiste AU - Muller JB FAU - Brauner, Raja AU - Brauner R FAU - Lourenço, Diana AU - Lourenço D FAU - Boudjenah, Radia AU - Boudjenah R FAU - Karageorgou, Vasiliki AU - Karageorgou V FAU - Trivin, Christine AU - Trivin C FAU - Lottmann, Henri AU - Lottmann H FAU - Lortat-Jacob, Stephen AU - Lortat-Jacob S FAU - Nihoul-Fékété, Claire AU - Nihoul-Fékété C FAU - De Dreuzy, Olivier AU - De Dreuzy O FAU - McElreavey, Ken AU - McElreavey K