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This version published online on January 2, 2007
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-1672
A more recent version of this article appeared on March 1, 2007
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*OMIM

Submitted on August 2, 2006
Accepted on December 26, 2006

Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function

Lin Lin, Pascal Philibert, Bruno Ferraz-de-Souza, Daniel Kelberman, Tessa Homfray, Assunta Albanese, Veruska Molini, Neil J. Sebire, Silvia Einaudi, Gerard S. Conway, Ieuan A. Hughes, J. Larry Jameson, Charles Sultan, Mehul T. Dattani, and John C. Achermann*

UCL Institute of Child Health (L.L., B.F.S., D.K., M.T.D., J.C.A.) & Department of Medicine (L.L., B.F.S., G.S.C., J.C.A.), University College London, London, UK; Service d'Hormonologie du Développement et de la Reproduction (P.P, C.S.), Hôpital Lapeyronie et INSERM U540, CHU Montpellier, France; Department of Medical Genetics (T.H.) and Department of Paediatric Endocrinology (A.A), St George's Hospital Medical School, London, UK; Department of Paediatric Endocrinology (V.M., S.E.), Regina Margherita Hospital, Turin, Italy; Department of Paediatric Histopathology (N.J.S.), Great Ormond Street Hospital for Children, London, UK; Department of Paediatrics (I.A.H.), University of Cambridge, Cambridge, UK; Feinberg School of Medicine (J.L.J.), Northwestern University, Chicago, Il, USA; Unité d'Endocrinologie Pédiatrique (C.S.), Hôpital Arnaud de Villeneuve, CHU Montpellier, France

* To whom correspondence should be addressed. 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, DSD) with normal adrenal function.

Methods & Patients: Mutational analysis of NR5A1 in 30 individuals with 46,XY DSD, followed by functional studies of SF1 activity.

Results: Heterozygous missense mutations in NR5A1 were found in four individuals (4/30, 13%) with this phenotype. These mutations (V15M, M78I, G91S, L437Q) were shown to impair transcriptional activation through abnormal DNA binding (V15M, M78I, G91S), altered sub-nuclear localization (V15M, M78I), or through 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, as 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.
Key words: SF-1 • gonadal dysgenesis • steroidogenesis • androgen • DSD • male pseudohermaphroditism • nuclear receptor • adrenal development




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