Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 92, Issue 3, Pages 991-999Publisher
ENDOCRINE SOC
DOI: 10.1210/jc.2006-1672
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Funding
- NICHD NIH HHS [R01 HD044801, HD044801] Funding Source: Medline
- Wellcome Trust [079666, 068061] Funding Source: Medline
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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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