COMPLETE ANDROGEN INSENSITIVITY SYNDROME DUE TO A NEW FRAMESHIFT DELETION IN EXON-4 OF THE ANDROGEN RECEPTOR GENE - FUNCTIONAL-ANALYSIS OF THE MUTANT RECEPTOR

We studied the androgen receptor gene in a large kindred with complete androgen insensitivity syndrome and negative receptor-binding activit y. single-strand conformation polymorphism (SSCP) analysis and sequenc ing identified a 13 base pair deletion within exon 4. This was respons ible for a predictive frameshift in the open reading frame and introdu ction of a premature stop codon at position 783 instead of 919. The de letion was reproduced in androgen receptor wildtype cDNA and transfect ed into mammalian cells. Western blot showed a smaller androgen recept or of 94 kDa for the transfected mutated cDNA instead of 110 kDa. Andr ogen-binding assay of the mutated transfected cells assessed the lack of androgen-binding. Gel retardation assay demonstrated the ability of the mutant to bind target DNA; however, the mutant was unable to tran sactivate a reporter gene. Although the role of the partial deletion i n the lack of androgen action was expected, in vitro analyses highligh t the role of the abnormal C-terminal portion in the inhibition of the receptor transregulatory activity of the protein causing androgen res istance in this family.