Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2007) 13 OC16

SFEBES2007 Oral Communications Young Endocrinologist prize session (1 abstracts)

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

Lin Lin 1 , Pascal Philibert 2 , Bruno Ferraz-de-Souza 1 , Daniel Kelberman 1 , Tessa Homfray 3 , Assunta Albanese 3 , Veruska Molini 4 , Neil Sebire 1 , Silvia Einaudi 4 , Larry Jameson 5 , Charles Sultan 2 , Mehul Dattani 1 & John Achermann 1

1UCL Institute of Child Health, London, United Kingdom; 2Hôpital Lapeyronie et INSERM U540, CHU Montpellier, France; 3St George’s Hospital Medical School, London, United Kingdom; 4Regina Margherita Hospital, Turin, Italy; 5Northwestern University, Chicago, United States.

The nuclear receptor steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a key regulator of adrenal and gonadal development, steroidogenesis and reproduction, and 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 this phenotype, DNA-binding mutations in SF1 have been reported in two 46,XY female patients with primary adrenal failure and uterine structures, but a wider role for SF1 in human disorders is only now emerging. Following Ethical Committee approval, we undertook analysis of NR5A1 in a cohort of individuals with 46,XY disorders of sex development (DSD) (variable gonadal dysgenesis, impaired androgenization) with normal adrenal function. Heterozygous de novo or sex-limited dominant missense mutations in NR5A1/SF1 were found in 4/34 (12%) cases. Detailed in vitro analysis of nuclear receptor function has revealed that these point mutations (V15M, M78I, G91S, L437Q) affect highly conserved domains critical for nuclear receptor action, and impair transcriptional activation of target genes through abnormal DNA binding (V15M, M78I, G91S), aberrant clustering in sub-nuclear complexes (PML/ND10 bodies) (V15M, M78I), or through a predicted disruption of the ligand-binding pocket (L437Q). Taken together, these studies confirm the sensitivity of human testis development and function to dosage-dependent transcriptional activation by SF1, and reveal that SF1 mutations are emerging as one of the most frequent cause of 46,XY disorders of sex development in humans. This condition extends the range of human disorders associated with abnormalities in classic and orphan nuclear receptor transcription factors, and confirms that SF1 is a key regulator of reproductive function in humans.

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