Complete androgen insensitivity caused by a splice donor site mutation in intron 2 of the human androgen receptor gene resulting in an exon 2-lackingtranscript with premature stop-codon and reduced expression

Various mutations within the human androgen receptor gene have been documen ted to cause defective sexual differentiation in karyotypic male individual s. In this study, we report a previously undescribed point mutation at the donor splice-site of the second intron of the androgen receptor gene in a p atient with a completely female phenotype. The sequence alteration was dete cted by single-strand-conformation-analysis-PCR and genomic sequencing. App lying competitive re reverse transcribed PCR, cDNA sequencing and Western b lotting, we could demonstrate considerable aberrations of structure and con centration of the transcript and its translation product in the patient's f ibroblasts from the genital region. (1) In the transcript, exon 1 and 3 are directly linked to each other, the complete second exon is skipped. The mR NA predictively suffers a codon frame-shift in exon 3 associated with a pre mature termination between codons 598 and 599, leading to a truncated andro gen receptor protein lacking any in vivo function. (2) Steady-state concent ration levels of transcript and protein are abnormally low. Our observation s highlight the influence of exon-flanking intron sequences on proper expre ssion and function of gene products. (C) 1999 Elsevier Science Ltd. All rig hts reserved.