Molecular basis of androgen insensitivity

Area of Science:

• Endocrinology
• Genetics
• Reproductive Biology

Background:

• Androgens, like testosterone, are crucial for male sexual differentiation and development.
• The androgen receptor (AR) mediates androgen actions; its gene is on the X-chromosome.
• Defects in the AR gene lead to androgen insensitivity syndrome (AIS), a form of male pseudohermaphroditism.

Purpose of the Study:

• To review the roles of androgens and the androgen receptor in male sexual development.
• To detail the genetic basis and diverse clinical manifestations of androgen insensitivity syndrome (AIS).
• To discuss the molecular mechanisms and diagnostic considerations for AIS and related disorders.

Main Methods:

• Literature review of studies on androgens, androgen receptor function, and AIS.
• Analysis of documented AR gene mutations and their associated phenotypes.
• Comparison of AIS with other disorders of sex development.

Main Results:

• Androgen receptor defects cause AIS, characterized by resistance to androgens.
• Over 150 distinct AR gene mutations have been identified, leading to varied phenotypes.
• Complete AIS (CAIS) presents with female external genitalia, while partial AIS (PAIS) shows a spectrum of virilization.
• AIS is distinct from other male pseudohermaphroditism causes and associated with conditions like spinal and bulbar muscular atrophy and prostate cancer.

Conclusions:

• Androgen receptor gene mutations are the primary cause of AIS, presenting a wide range of phenotypes.
• Accurate diagnosis of AIS relies on understanding AR gene mutations and clinical presentation.
• Differential diagnosis is crucial to distinguish AIS from other conditions with similar phenotypes but different molecular etiologies.