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Androgen receptor mutations
A O Brinkmann1, G Jenster, C Ris-Stalpers
1Department of Endocrinology, Erasmus University, Rotterdam, The Netherlands.
Abstract:
Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. At least three pathological situations are associated with abnormal androgen receptor structure and function: androgen insensitivity syndrome (AIS), spinal and bulbar muscular atrophy (SBMA) and prostate cancer. In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. Complete or gross deletions of the androgen receptor gene have not been found frequently in persons with complete androgen insensitivity syndrome. Point mutations at several different sites in exons 2-8 encoding the DNA- and androgen-binding domain, have been reported for partial and complete forms of androgen insensitivity. A relatively high number of mutations were reported in two different clusters in exon 5 and in exon 7. The number of mutations in exon 1 is extremely low and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain and which is encoded by the first half of exon 4. Androgen receptor gene mutations in prostate cancer are very rare and are reported only in exons 4-8. The X-linked spinal and bulbar muscle atrophy (SBMA; Kennedy's disease) is associated with an expanded length (> 40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.
Insights
Androgen receptor gene mutations cause disorders like androgen insensitivity syndrome (AIS) and spinal and bulbar muscular atrophy (SBMA). Most mutations occur in specific DNA-binding regions, affecting male development and function.
Area of Science:
- Molecular Endocrinology
- Genetics
- Reproductive Biology
Background:
- Androgens are crucial for male sexual development, acting via the androgen receptor (AR), a transcription factor.
- Abnormalities in AR structure and function are linked to androgen insensitivity syndrome (AIS), spinal and bulbar muscular atrophy (SBMA), and prostate cancer.
Purpose of the Study:
- To review the pathological situations associated with androgen receptor gene mutations.
- To identify mutation hotspots and patterns in different androgen receptor-related disorders.
Main Methods:
- Literature review of reported androgen receptor gene mutations.
- Analysis of mutation distribution across AR gene exons and functional domains.
Main Results:
- Point mutations in AR exons 2-8 are common in AIS, with hotspots in exons 5 and 7.
- Exon 1 and the hinge region (part of exon 4) show very few mutations.
- SBMA is associated with polyglutamine tract expansions in the AR N-terminal domain.
- AR mutations are rare in prostate cancer, primarily found in exons 4-8.
Conclusions:
- Androgen receptor gene mutations are implicated in various disorders affecting male development and health.
- Specific mutation patterns and locations within the AR gene correlate with distinct clinical phenotypes.
- Understanding AR mutation sites aids in diagnosing and potentially treating AR-related conditions.