Novel point mutation in the splice donor site of exon-intron junction 6 ofthe androgen receptor gene in a patient with partial androgen insensitivity syndrome

Androgen receptor (AR) gene mutations have been shown to cause androgen ins ensitivity syndrome with altered sexual differentiation in XY individuals, ranging from a partial insensitivity with male phenotype and azoospermia to a complete insensitivity with female phenotype and the absence of pubic an d axillary sexual hair after puberty. In this study we present an 11-yr-old XY girl, with clinical manifestations peculiar for impaired androgen biological action, including female phenoty pe, blind-ending vagina, small degree of posterior labial fusion, and absen ce of uterus, fallopian tubes, and ovaries. At the time of the diagnosis th e patient had a FSH/LH ratio according to the puberal stage, undetectable 1 7 beta-estradiol, and high levels of testosterone (80.1 ng/mL). After bilat eral gonadectomy, performed at the age of 11 yr, histological examination s howed small embryonic seminiferous tubules containing prevalently Sertoli c ells and occasional spermatogonia together with abundant fibrous tissue. Mo lecular study of the patient showed a guanine to thymine transversion in po sition + 5 of the donor splice site in the junction between exon 6 and intr on 6 of the AR gene. The result of RT-PCR amplification of the AR messenger ribonucleic acid from cultured genital skin fibroblasts of the patient sug gests that splicing is defective, and intron 6 is retained in most of the r eceptor messenger ribonucleic acid molecules. We show by immunoblotting tha t most of the expressed protein lacks part of the C-terminal hormone-bindin g domain, and a small amount of normal receptor is observed. This is probab ly responsible for the reduced binding capacity in genital skin fibroblasts of the patient. The molecular basis of the alteration in this case is a novel, uncommon mut ation, leading to a phenotype indicative of a partial androgen insensitivit y syndrome, Quigley's grade 5.