AR – Complete Androgen Insensitivity Syndrome

The androgen receptor (AR) plays a critical role in male sexual differentiation by mediating androgen signaling. Complete androgen insensitivity syndrome (CAIS) results from loss-of-function variants in AR, leading to a female external phenotype in 46,XY individuals despite normal or elevated androgen levels. This gene–disease relationship is well established through numerous case reports, large family studies, and extensive functional analyses.

1. Clinical Validity

AR–CAIS association is classified as Definitive. Over 50 unrelated probands have been reported with AR mutations causing CAIS ([PMID:1307250], [PMID:8096390]). Segregation has been demonstrated in a 700-member Brazilian kindred with 19 affected relatives segregating an AR missense variant ([PMID:14756668]). Functional assays in patient cells and heterologous systems consistently show absent androgen binding and impaired transactivation.

2. Genetic Evidence

CAIS follows an X-linked recessive inheritance pattern. More than 30 distinct AR coding variants have been identified in unrelated CAIS patients, including de novo and familial de novo events. Reported variant classes include missense, frameshift, splice, and large gene disruptions. A representative de novo missense variant is c.2231G>T (p.Gly744Val) detected by SSCP and sequencing in exon 5 of AR ([PMID:8096390]). The recurrent hotspot p.Arg855Cys has been identified in multiple independent families via allele-specific assays ([PMID:9001799]).

3. Functional Evidence

Mechanistically, AR mutations lead to haploinsufficiency or dominant-negative effects. In vitro studies of p.Arg772Cys demonstrate markedly reduced ligand binding affinity (Kd ~3 nM vs. 0.5 nM) and thermal instability, accompanied by a 10-fold decrease in transcriptional activity ([PMID:1856263]). Site-directed mutagenesis and molecular modeling of DNA-binding domain mutants (e.g., p.Leu617Pro) confirm loss of DNA recognition and transactivation ([PMID:8647313]). Frameshift and truncating variants abrogate receptor expression and fail to bind androgen or activate reporter genes ([PMID:7649349]).

4. Conflicting Evidence

No significant conflicting data have been reported for AR variants in CAIS. All studies consistently demonstrate loss of AR function correlating with the CAIS phenotype.

5. Integration and Conclusion

Extensive genetic and experimental evidence conclusively links AR defects with CAIS. Diagnostic sequencing of AR is essential for confirming CAIS, guiding gonadectomy timing, hormonal management, and genetic counseling. Functional assays support pathogenicity of novel AR variants.

Key Take-home: AR mutation analysis provides a reliable molecular diagnosis for CAIS, enabling informed clinical management and family counseling.

References

• Human molecular genetics • 1992 • Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome. PMID:1307250
• The Journal of steroid biochemistry and molecular biology • 1993 • Complete androgen insensitivity syndrome associated with a de novo mutation of the androgen receptor gene detected by single strand conformation polymorphism. PMID:8096390
• Clinical genetics • 2004 • Concordance of phenotypic expression and gender identity in a large kindred with a mutation in the androgen receptor. PMID:14756668
• The Journal of clinical endocrinology and metabolism • 1991 • Androgen resistance associated with a mutation of the androgen receptor at amino acid 772 (Arg----Cys) results from a combination of decreased messenger ribonucleic acid levels and impairment of receptor function. PMID:1856263
• Clinical genetics • 1996 • Rapid detection of a mutation hot-spot in the human androgen receptor. PMID:9001799
• Molecular and cellular endocrinology • 1995 • Complete androgen insensitivity syndrome due to a new frameshift deletion in exon 4 of the androgen receptor gene: functional analysis of the mutant receptor. PMID:7649349
• Molecular and cellular endocrinology • 1996 • Molecular modeling and in vitro investigations of the human androgen receptor DNA-binding domain: application for the study of two mutations. PMID:8647313

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