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A novel mutation in the accessory DNA-binding domain of human steroidogenic factor 1 causes XY gonadal dysgenesis without adrenal insufficiency.

Reuter AL, Goji K, Bingham NC, Matsuo M, Parker KL
Eur J Endocrinol. 2007 157 (2): 233-8

PMID: 17656604 · DOI:10.1530/EJE-07-0113

OBJECTIVE - Steroidogenic factor 1 (SF1), officially designated NR5A1, is a nuclear receptor that plays key roles in endocrine development and function. Previous reports of human SF1 mutations revealed a spectrum of phenotypes affecting adrenal function and/or gonadal development and sex differentiation. We present the clinical phenotype and functional effects of a novel SF1 mutation.

PATIENT - The patient is a 22-year-old 46, XY Japanese patient who presented with dysgenetic testes, atrophic vasa deferentia and epididymides, lack of Müllerian structures, and clitoromegaly. Endocrine studies revealed normal adrenal function.

RESULTS - Analysis of the SF1 gene revealed compound heterozygosity for a previously described p.G146A polymorphism and a novel missense mutation (p.R84C) in the accessory DNA-binding domain. The father carried the p.G146A polymorphism and the mother had the p.R84C mutation; both were clinically and reproductively normal. Functional studies demonstrated that the p.R84C SF1 had normal nuclear localization but decreased DNA-binding affinity and transcriptional activity compared with wild-type SF1; it did not exhibit any dominant negative activity.

CONCLUSIONS - These results describe the human phenotype that results from compound heterozygosity of the p.G146A polymorphism and a novel p.R84C mutation of SF1, thereby extending the spectrum of human SF1 mutations that impair testis development and sex differentiation in a sex-limited manner while preserving normal adrenal function.

MeSH Terms (20)

Adrenal Insufficiency Adult Cells, Cultured DNA-Binding Proteins DNA Mutational Analysis Electrophoretic Mobility Shift Assay Female Fluorescent Antibody Technique Gonadal Dysgenesis, 46,XY Homeodomain Proteins Humans Luciferases Mutation Plasmids Polymorphism, Genetic Receptors, Cytoplasmic and Nuclear Steroidogenic Factor 1 Thyroid Hormone Receptors alpha Transcription, Genetic Transcription Factors

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