Molecular basis of androgen insensitivity

Area of Science:

• Genetics
• Molecular Biology
• Endocrinology

Background:

• Androgen insensitivity syndrome (AIS) in 46,XY individuals arises from androgen receptor (AR) gene mutations.
• Phenotypes range from female to undervirilized or infertile male presentations.
• Understanding AR mutations is crucial for diagnosing and managing AIS.

Purpose of the Study:

• To investigate AR gene mutations in AIS patients.
• To identify specific amino acid residues or regions critical for DNA binding and transcriptional activation.
• To correlate genotype with phenotype in AIS.

Main Methods:

• Genomic DNA analysis using Polymerase Chain Reaction - Single Strand Conformation Polymorphism (PCR-SSCP) under varied conditions.
• Sequencing of the androgen receptor gene.
• Phenotypic assessment of patients.

Main Results:

• Three novel mutations were identified in exon 1 of the AR gene in patients with a female phenotype.
• A cytosine insertion (codon 42) caused a frameshift and premature stop codon (171), leading to undetectable receptor protein.
• An adenine deletion (codon 263) resulted in a premature stop codon (292), also causing undetectable receptor protein and hormone binding.
• A guanine-to-adenine transition (codon 493) created a premature stop codon.
• A cytosine-to-adenine transition in exon 2 (Ala564Asp) impaired DNA binding and transactivation in a receptor-positive AIS patient.

Conclusions:

• Specific AR mutations can lead to complete or partial androgen insensitivity.
• Mutations affecting critical regions like DNA binding domains significantly impact receptor function.
• PCR-SSCP is effective in detecting novel mutations in the AR gene associated with AIS.