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Heterozygous Missense Mutations in Steroidogenic Factor 1 (SF1/Ad4BP, NR5A1) Are Associated with 46,XY Disorders of Sex Development with Normal Adrenal Function

UCL Institute of Child Health (L.L., B.F.-d.-S., D.K., M.T.D., J.C.A.) and Department of Medicine (L.L., B.F.S., G.S.C., J.C.A.), University College London, London WC1N 1EH, United Kingdom; Service d’Hormonologie du Développement et de la Reproduction (P.P., C.S.), Hôpital Lapeyronie et Institut National de la Santé et de la Recherche Médicale U540, Centre Hospitalier Universitaire, and Unité d’Endocrinologie Pédiatrique (C.S.), Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire Montpellier, 34295 Montpellier, France; Departments of Medical Genetics (T.H.) and Paediatric Endocrinology (A.A.), St. George’s Hospital Medical School, London SW17 0RE, United Kingdom; Department of Paediatric Endocrinology (V.M., S.E.), Regina Margherita Hospital, 10126 Turin, Italy; Department of Paediatric Histopathology (N.J.S.), Great Ormond Street Hospital for Children, London WC1N 1LE, United Kingdom; Department of Paediatrics (I.A.H.), University of Cambridge, Cambridge CB2 1TN, United Kingdom; and Feinberg School of Medicine (J.L.J.), Northwestern University, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Dr. John C. Achermann, Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom. E-mail: j.achermann{at}ich.ucl.ac.uk.

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 Müllerian structures in males. Consistent with the murine phenotype, human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian 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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