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PMID 22474171
Gene Name NR5A1
Condition Infertility
Association Analysis of NR5A1 revealed two novel heterozygous missense mutations in the ligand-binding domain of SF-1 (patient 1: p.L376F; patient 2: p.G328V). The mutant proteins showed reduced transactivation of the CYP11A promoter in vitro.
PMID 22474171
Gene Name NR5A1
Condition 46,XY patients with disorders of sex development
Association Patients with 46,XY DSD and NR5A1 mutations can produce sufficient testosterone for spontaneous virilization during puberty. Phenotypic females (46,XY) with NR5A1 mutations can present with clitoromegaly at puberty, a phenotype similar to other partial de
Mutation p.L376F, p.G328V
Population size 2
Population details 2 46,XY DSD
Sex Male, female
Infertility type Male infertility, Female infertility
Other associated phenotypes 46,XY patients with disorders of sex development


Testosterone production during puberty in two 46,XY patients with disorders of sex development and novel NR5A1 (SF-1) mutations

Tantawy S, Lin L, Akkurt I, Borck G, Klingmüller D, Hauffa BP, Krude H, Biebermann H, Achermann JC, Köhler B.

BACKGROUND: Steroidogenic factor 1 (SF-1, NR5A1) is a key transcriptional regulator of many genes involved in the hypothalamic-pituitary-gonadal axis and mutations in NR5A1 can result in 46,XY disorders of sex development (DSD). Patients with this condition typically present with ambiguous genitalia, partial gonadal dysgenesis, and absent/rudimentary Müllerian structures. In these cases, testosterone is usually low in early infancy, indicating significantly impaired androgen synthesis. Further, Sertoli cell dysfunction is seen (low inhibin B, anti-Müllerian hormone). However, gonadal function at puberty in patients with NR5A1 mutations is unknown. SUBJECTS AND METHODS: Clinical assessment, endocrine evaluation, and genetic analysis were performed in one female and one male with 46,XY DSD who showed spontaneous virilization during puberty. The female patient presented at adolescence with clitoral hypertrophy, whereas the male patient presented at birth with severe hypospadias and entered puberty spontaneously. Molecular analysis of NR5A1 was performed followed by in vitro functional analysis of the two novel mutations detected. RESULTS: Testosterone levels were normal during puberty in both patients. Analysis of NR5A1 revealed two novel heterozygous missense mutations in the ligand-binding domain of SF-1 (patient 1: p.L376F; patient 2: p.G328V). The mutant proteins showed reduced transactivation of the CYP11A promoter in vitro. CONCLUSION: Patients with 46,XY DSD and NR5A1 mutations can produce sufficient testosterone for spontaneous virilization during puberty. Phenotypic females (46,XY) with NR5A1 mutations can present with clitoromegaly at puberty, a phenotype similar to other partial defects of androgen synthesis or action. Testosterone production in 46,XY males with NR5A1 mutations can be sufficient for virilization at puberty. As progressive gonadal dysgenesis is likely, gonadal function should be monitored in adolescence and adulthood, and early sperm cryopreservation considered in male patients if possible. FAU - Tantawy, Sally AU - Tantawy S AD - Department of Pediatric Endocrinology, University Children's Hospital, Charité, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany. FAU - Lin, Lin AU - Lin L FAU - Akkurt, Ilker AU - Akkurt I FAU - Borck, Guntram AU - Borck G FAU - Klingmüller, Dietrich AU - Klingmüller D FAU - Hauffa, Berthold P AU - Hauffa BP FAU - Krude, Heiko AU - Krude H FAU - Biebermann, Heike AU - Biebermann H FAU - Achermann, John C AU - Achermann JC