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

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 differentiat...

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Published in:European journal of endocrinology 2007-08, Vol.157 (2), p.233-238
Main Authors: Reuter, Anne L, Goji, Katsumi, Bingham, Nathan C, Matsuo, Masafumi, Parker, Keith L
Format: Article
Language:English
Subjects:
Adrenal Insufficiency - genetics
Adrenal Insufficiency - physiopathology
Adrenals. Adrenal axis. Renin-angiotensin system (diseases)
Adult
Biological and medical sciences
Case Reports
Cells, Cultured
DNA Mutational Analysis
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Electrophoretic Mobility Shift Assay
Endocrinopathies
Female
Fluorescent Antibody Technique
Fundamental and applied biological sciences. Psychology
Gonadal Dysgenesis, 46,XY - genetics
Gonadal Dysgenesis, 46,XY - metabolism
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Luciferases - genetics
Medical sciences
Mutation - physiology
Non tumoral diseases. Target tissue resistance. Benign neoplasms
Plasmids - genetics
Polymorphism, Genetic - genetics
Polymorphism, Genetic - physiology
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Cytoplasmic and Nuclear - metabolism
Steroidogenic Factor 1
Thyroid Hormone Receptors alpha - genetics
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic
Vertebrates: endocrinology
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Summary: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 Mùˆllerian 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.
ISSN:0804-4643
1479-683X
DOI:10.1530/EJE-07-0113