Lin, L; Philibert, P; Ferraz-de-Souza, B; Kelberman, D; Homfray, T; Albanese, A; Molini, V; ... Achermann, JC; + view all Lin, L; Philibert, P; Ferraz-de-Souza, B; Kelberman, D; Homfray, T; Albanese, A; Molini, V; Sebire, NJ; Einaudi, S; Conway, GS; Hughes, IA; Jameson, JL; Sultan, C; Dattani, MT; Achermann, JC; - view fewer (2007) Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function. The Journal of Clinical Endocrinology & Metabolism , 92 (3) 991 - 999. 10.1210/jc.2006-1672.

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Abstract

Context: Steroidogenic factor 1 ( SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis, and reproduction. Targeted deletion of Nr5a1 ( Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Mullerian structures in males. Consistent with the murine phenotype, human mutations in SF1 were described initially in two 46, XY individuals with female external genitalia, Mullerian structures ( uterus), and primary adrenal failure.Objective: Given recent case reports of haploinsufficiency of SF1 affecting testicular function in humans, we aimed to identify SF1 mutations in a cohort of individuals with a phenotypic spectrum of 46, XY gonadal dysgenesis/impaired androgenization ( now termed 46, XY disorders of sex development) with normal adrenal function.Methods and Patients: The study included mutational analysis of NR5A1 in 30 individuals with 46, XY disorders of sex development, followed by functional studies of SF1 activity.Results: Heterozygous missense mutations in NR5A1 were found in four individuals ( four of 30, 13%) with this phenotype. These mutations ( V15M, M78I, G91S, L437Q) were shown to impair transcriptional activation through abnormal DNA binding ( V15M, M78I, G91S), altered subnuclear localization ( V15M, M78I), or disruption of the putative ligand-binding pocket ( L437Q). Two mutations appeared to be de novo or germline changes. The other two mutations appeared to be inherited in a sex-limited dominant manner because the mother is heterozygous for the change.Conclusions: These studies demonstrate that SF1 mutations are more frequent than previously suspected causes of impaired fetal and postnatal testicular function in 46, XY individuals.

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