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A Microdeletion in the Ligand Binding Domain of Human Steroidogenic Factor 1 Causes XY Sex Reversal without Adrenal Insufficiency
A Microdeletion in the Ligand Binding Domain of Human Steroidogenic Factor 1 Causes XY Sex Reversal without Adrenal Insufficiency
- Source :
- The Journal of Clinical Endocrinology & Metabolism. 89:1767-1772
- Publication Year :
- 2004
- Publisher :
- The Endocrine Society, 2004.
-
Abstract
- Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that plays key roles in endocrine development and function. Knockout mice lacking SF-1 have adrenal and gonadal agenesis, impaired gonadotropin expression, and structural abnormalities of the ventromedial hypothalamic nucleus. Previous studies have identified three human subjects with mutations in SF-1 causing adrenocortical insufficiency with varying degrees of gonadal dysfunction. We now describe a novel 8-bp microdeletion of SF-1, isolated from a 46, XY patient who presented with gonadal agenesis but normal adrenal function, which causes premature termination upstream of sequences encoding the activation function 2 domain. In cell transfection experiments, the mutated protein possessed no intrinsic transcriptional activity but rather inhibited the function of the wild-type protein in most cell types. To our knowledge, this is the first example of an apparent dominant-negative effect of a SF-1 mutation in humans. These findings, which define a SF-1 mutation that apparently differentially affects its transcriptional activity in vivo in the adrenal cortex and the gonads, may be relevant to the cohort of patients who present with 46, XY sex reversal but normal adrenal function.
- Subjects :
- Adult
Steroidogenic factor 1
medicine.medical_specialty
Transcription, Genetic
Endocrinology, Diabetes and Metabolism
Clinical Biochemistry
Disorders of Sex Development
Fushi Tarazu Transcription Factors
Receptors, Cytoplasmic and Nuclear
Biology
Ligands
Steroidogenic Factor 1
medicine.disease_cause
Biochemistry
Gonadal Agenesis
Endocrinology
Internal medicine
Adrenal Glands
Adrenal insufficiency
medicine
Humans
Disorders of sex development
Adrenocortical Insufficiency
Genes, Dominant
Homeodomain Proteins
Mutation
Base Sequence
Adrenal cortex
Biochemistry (medical)
Genitalia, Female
Sex reversal
medicine.disease
DNA-Binding Proteins
medicine.anatomical_structure
Female
Gene Deletion
Transcription Factors
Subjects
Details
- ISSN :
- 19457197 and 0021972X
- Volume :
- 89
- Database :
- OpenAIRE
- Journal :
- The Journal of Clinical Endocrinology & Metabolism
- Accession number :
- edsair.doi.dedup.....6c3f205b62c56f93422eccd680feb6e1
- Full Text :
- https://doi.org/10.1210/jc.2003-031240