AR – Partial Androgen Insensitivity Syndrome

The AR gene encodes the androgen receptor, a nuclear transcription factor essential for male sexual differentiation. Partial androgen insensitivity syndrome (PAIS) is an X-linked recessive 46,XY disorder of sex development characterized by variable undervirilization, ranging from perineoscrotal hypospadias with micropenis and cryptorchidism to clitoromegaly with partial labial fusion. The disease displays intrafamilial phenotypic variability despite identical receptor mutations, underscoring the role of modifier factors in PAIS pathogenesis(PMID:8099270).

Genetic evidence includes a cohort study of 14 PAIS patients in which AR mutations were identified in five affected individuals, all harboring ligand-binding domain missense changes(PMID:1307250). Overall, at least 11 unrelated PAIS probands have been reported with AR variants spanning missense, small insertions, deletions, and frameshifts. Segregation analysis in a large kindred demonstrated two affected cousins and asymptomatic carrier status in female relatives, confirming X-linked recessive inheritance(PMID:8099270).

The variant spectrum in PAIS is dominated by missense substitutions within the ligand-binding domain, with rare frameshift and splice variants reported. A recurrent ligand-binding change, c.2395C>G (p.Gln799Glu), has been observed in multiple PAIS subjects and disrupts both androgen binding and receptor activation(PMID:8824883).

Functional assays of six PAIS-associated ligand-binding mutations revealed marked reductions in receptor transactivation and ligand affinity, consistent across cellular models. Some mutants retained partial activity at supraphysiologic androgen levels, suggesting potential responsiveness to androgen therapy in select patients(PMID:8824883).

Integrating genetic and experimental findings supports a loss-of-function mechanism due to impaired ligand binding and transactivation, modulated by additional genetic or environmental factors. The extensive number of unrelated cases, clear segregation in families, and concordant functional impairments establish a definitive gene-disease relationship.

Key Take-home: AR mutation testing is clinically informative for PAIS diagnosis, prognosis, and tailored androgen therapy decisions.

References

• Archives of disease in childhood • 1993 • Phenotypic variation and detection of carrier status in the partial androgen insensitivity syndrome. PMID:8099270
• Human molecular genetics • 1992 • Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome. PMID:1307250
• Human molecular genetics • 1996 • Functional analysis of six androgen receptor mutations identified in patients with partial androgen insensitivity syndrome. PMID:8824883

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