Endocrine Abstracts (2002) 3 P156

Seven novel mutations in the androgen receptor gene associated with complete androgen insensitivity syndrome

JES Jääskeläinen, NP Mongan, H Martin & IA Hughes


Department of Paediatrics, University of Cambridge, Cambridge, UK.


Complete androgen insensitivity syndrome (CAIS), is generally caused by a mutation in the androgen receptor (AR) gene. In sequencing genomic DNA from patients with CAIS, we identified 7 novel mutations in the AR. Their effects on AR function are speculated in relation to AR functional domains and crystal structure. Local Ethical Committee approval was obtained for the use of patient samples.

Exon 1 mutations, Q86X and Y480X, are located in the transactivation domain containing AF-1 and are important for coregulator binding. Both truncated ARs disturb transactivation and abolish DNA and ligand binding. Exon 2 mutation C562Y encoding for the second zinc finger, results in a mutant AR unable to activate AR target genes. A mutation at the intron 2/exon 3 junction is predicted to skip exon 3 and leave the LBD intact; androgen binding was normal. Exon 5 mutation G724V is located between helices 3 and 4 and exon 6 mutation L812P at the C-terminal end of helix 8. Both G724 and L812 are highly conserved and critical for ligand binding. Finally, exon 8 mutation P892T is located in the N-terminus of helix 12, proximal to the AF-2 and is predicted to affect N/C-terminal interactions.

Recent knowledge of the AR crystal structure and functional domains now enables a more rationale interpretation of the varied AR mutants which cause AIS.

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