Eight novel mutations of the androgen receptor gene in patients with androgen insensitivity syndrome

Androgen insensitivity syndrome (AIS) is an X-linked genetic disorder of ma le sexual differentiation caused by mutations in the androgen receptor (AR) gene. A reliable genotype-phenotype correlation in these patients does not exist as yet. Here we report the molecular studies performed on eight indi viduals with AIS. Exon-specific polymerase chain reaction (PCR), single-str and conformation polymorphism, and sequencing analyses, were performed in e xons 2 to 8 of the AR gene. In one case, total cellular RNA was extracted f rom genital skin fibroblasts and reverse transcriptase-PCR was performed. S ix different point mutations leading to amino acid substitutions (P682T, Q7 11E, G743E, F827V, H874R, D879Y), one splice-junction mutation (g -->c at 5, exon 6/intron 6), and a missense mutation without amino acid substitutio n (S888S) were identified. All mutations, including a de novo mutation, wer e previously undescribed on the steroid binding domain. Of the eight mutati ons identified, four led to a complete female phenotype (codons 743. 827, 8 74 and the donor splice site +5), two were detected in phenotypic females w ith partial virilization (codons 682 and 711), and two were present in phen otypic male subjects with undervirilized external genitalia, thus indicatin g that all of these sites determine AR functional activity.