AR – Androgen Insensitivity Syndrome

Androgen insensitivity syndrome (AIS) is an X-linked recessive disorder caused by loss-of-function mutations in the androgen receptor gene (AR) leading to end-organ resistance to androgenic steroids in 46,XY individuals. A broad spectrum of external genital phenotypes is observed, from complete female external appearance (CAIS) to varying degrees of undervirilization (PAIS). The association between AR and AIS is supported by extensive genetic and functional studies demonstrating that AR mutations underlie defective virilization.

Genetic evidence includes mutations detected in over 180 unrelated AIS patients across more than 60 families, with a variant spectrum comprising predominantly missense substitutions in the ligand-binding and DNA-binding domains, as well as frameshift and nonsense alleles. RFLP and SSCP analyses in 52 AIS patients revealed no large deletions but pointed to point mutations and microdeletions (PMID:1356901). In a cohort of 27 CAIS/PAIS subjects, 14 distinct AR mutations were identified by SSCP and sequencing, including both missense and frameshift changes (PMID:1307250). Segregation has been demonstrated in multiple pedigrees, including a Brazilian family with five affected 46,XY relatives and two carrier mothers, all hemizygous or heterozygous for the novel c.3015C>T (p.Leu830Phe) variant (PMID:21645389).

The inheritance pattern is X-linked recessive; carrier testing using exon 1 CAG/HindIII polymorphisms identifies mothers in ~50% of families and enables prenatal diagnosis where the causative mutation is unknown (PMID:1356901). Recurrent hotspot mutations at CpG dinucleotides, such as p.Arg855Cys, have been identified in multiple independent CAIS kindreds (PMID:9001799). The overall variant spectrum includes over 200 missense changes, 15 frameshifts, and several splice defects, with no clear genotype–phenotype correlations beyond truncating alleles causing CAIS.

Functional assays have elucidated the mechanism of pathogenicity: ligand-binding domain mutations (e.g., p.Arg772Cys) reduce androgen affinity and mRNA levels, impairing transcriptional activation in cell models (PMID:1856263). DNA-binding domain substitutions abolish target gene activation while preserving ligand binding, some of which respond to high androgen concentrations (PMID:10971094). Molecular modeling and COS cell studies confirm disrupted N-terminal/C-terminal interactions and altered receptor dimerization. An AR FxxLF motif mutation preventing N/C interaction delays disease onset in SBMA mouse models, underscoring the importance of receptor conformation (PMID:26673324).

No large-scale studies have refuted the AR–AIS link; RFLP analyses found no gross deletions, reinforcing that point mutations predominate. There is no credible evidence of non-AR loci causing AIS phenotypes in 46,XY individuals with intact AR coding regions.

In summary, AR mutations demonstrate a definitive causal relationship with AIS, supported by extensive case series, segregation in multi-generation families, and concordant functional data. Molecular diagnosis allows accurate genetic counseling, carrier detection, and informed decisions on gonadectomy, hormone therapy, and potential androgen responsiveness in PAIS.

Key Take-home: AR genotyping is clinically essential for confirming AIS diagnosis, guiding personalized management, and enabling carrier and prenatal testing.

References

• BMC research notes • 2011 • Severe forms of partial androgen insensitivity syndrome due to p.L830F novel mutation in androgen receptor gene in a Brazilian family. PMID:21645389
• Hormone research • 1992 • Molecular analysis of the androgen receptor gene in 52 patients with complete or partial androgen insensitivity syndrome: a collaborative study. PMID:1356901
• Human molecular genetics • 1992 • Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome. PMID:1307250
• The Journal of clinical endocrinology and metabolism • 2003 • Clinical, hormonal, behavioral, and genetic characteristics of androgen insensitivity syndrome in a Brazilian cohort: five novel mutations in the androgen receptor gene. PMID:12843171
• Gene • 2018 • Mutational analysis of the androgen receptor (NR3C4) gene in patients with 46,XY DSD. PMID:29051026
• Human molecular genetics • 1996 • Functional analysis of six androgen receptor mutations identified in patients with partial androgen insensitivity syndrome. PMID:8824883
• 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

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