Androgen Insensitivity Syndrome: Clinical and Molecular Insights

Androgen Insensitivity Syndrome (AIS) encompasses a spectrum of X-linked disorders arising from impaired androgen receptor (AR) function in 46,XY individuals. Phenotypes range from Complete AIS (CAIS), characterised by female external genitalia and undescended testes, to Partial AIS (PAIS) and mild forms with varying degrees of undervirilisation. Pathogenic variants in the AR gene, including missense, nonsense and splice-site mutations, disrupt ligand binding, receptor dimerisation or DNA interaction, leading to tissue resistance to testosterone and dihydrotestosterone. Molecular studies have unveiled deep intronic mutations and pseudoexon activation as non-coding mechanisms of AR inactivation, while emerging evidence points to alternative regulatory factors influencing receptor activity. Clinically, AIS is suspected in individuals with female or ambiguous genitalia, elevated luteinising hormone and testosterone levels, and no Müllerian structures on imaging. Definitive diagnosis relies on genetic testing, often via next-generation sequencing panels. Management requires a tailored, multidisciplinary approach addressing timing of gonadectomy, hormone replacement, fertility potential and psychosocial support. Long-term considerations include bone health, metabolic risk and patient autonomy in sex assignment, emphasising the global significance of early diagnosis and personalised care.

Research from Nature Portfolio

Foundational studies have expanded understanding of non-coding AR variants in both CAIS and PAIS. One investigation identified a deep intronic mutation in intron 6 that creates a cryptic splice acceptor site, triggering pseudoexon inclusion and premature stop codons. Affected fibroblasts exhibited complete loss of AR protein, underscoring the need to screen beyond coding regions for elusive causative variants. In a related report, a deep intronic change in the same intron generated an alternative splice acceptor, yielding aberrant mRNAs subject to nonsense-mediated decay. This mechanism explained PAIS cases lacking exonic AR mutations and highlighted the clinical relevance of intronic regulatory elements in androgen signalling during sexual differentiation.

Androgen Insensitivity Syndrome: Clinical and Molecular Insights publication trend

The graph below shows the total number of articles in androgen insensitivity syndrome: clinical and molecular insights across all publications each year (not limited to Nature Index journals).

Technical terms

Androgen Receptor (AR): A nuclear transcription factor activated by testosterone or dihydrotestosterone.

Androgen Insensitivity Syndrome (AIS): A disorder where body tissues fail to respond to androgens, despite normal or elevated hormone levels.

Pseudoexon: A cryptic exon within an intron that is erroneously included in mRNA due to aberrant splicing signals.

Splice Acceptor Site: A sequence motif at the 3′ end of an intron essential for correct removal of intronic RNA during mRNA processing.

Next-Generation Sequencing (NGS): High-throughput DNA sequencing technology enabling rapid analysis of multiple genes simultaneously.

References

1. A Very Early Diagnosis of Complete Androgen Insensitivity Syndrome Due to a Novel Variant in the AR Gene: A Neonatal Case Study. Biomedicines (2024).
2. Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene. Scientific Reports (2016).
3. Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene. Scientific Reports (2018).
4. Complete Androgen Insensitivity Syndrome: From Bench to Bed. International Journal of Molecular Sciences (2021).
5. Androgen insensitivity syndrome: a review. Archives of Endocrinology and Metabolism (2018).