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Androgen resistance caused by mutations in the androgen receptor gene
M J McPhaul1, M Marcelli, W D Tilley
1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8857.
Abstract:
Defects in the human androgen receptor cause a spectrum of defects in male phenotypic sexual development associated with abnormalities in the receptor protein assayed in cultured fibroblasts and in broken cell assays. In some patients these abnormalities are associated with absent ligand binding, in other qualitative or quantitative abnormalities of ligand binding are present, and in some no abnormality of ligand binding is detected. Analysis of the androgen gene structure in such patients has permitted identification of the causative mutation in many families. Although results of these studies often reinforce concepts established by in vitro mutagenesis studies of other steroid receptors, some mutations have provided unusual insight into the structural organization of the androgen receptor molecule.
Insights
Defects in the human androgen receptor (AR) cause disorders in male sexual development. Mutations in the AR gene are identified, revealing insights into AR structure and function.
Area of Science:
- Endocrinology
- Genetics
- Molecular Biology
Background:
- Androgen receptor (AR) defects lead to a range of male phenotypic sexual development disorders.
- Abnormalities in AR protein are detected through cultured fibroblast and broken cell assays.
- Ligand binding can be absent, qualitatively or quantitatively abnormal, or undetectable in affected individuals.
Purpose of the Study:
- To investigate the molecular basis of male sexual development disorders caused by androgen receptor defects.
- To identify specific mutations in the androgen receptor gene responsible for these conditions.
- To understand the structural organization of the androgen receptor molecule through patient-derived mutations.
Main Methods:
- Assay of androgen receptor protein in cultured fibroblasts.
- Broken cell assays to evaluate receptor function.
- Analysis of androgen receptor gene structure to identify causative mutations.
Main Results:
- Identified specific mutations in the androgen receptor gene in numerous families with male sexual development disorders.
- Correlated specific mutations with varying abnormalities in ligand binding (absent, altered, or normal).
- Observed that some mutations provided novel insights into the structural organization of the androgen receptor.
Conclusions:
- Androgen receptor gene mutations are a significant cause of male phenotypic sexual development disorders.
- The spectrum of ligand-binding abnormalities reflects diverse AR defects.
- Patient-derived mutations offer unique perspectives on AR structure-function relationships, complementing in vitro studies.