SINGLE-STRAND CONFORMATION POLYMORPHISM ANALYSIS OF ANDROGEN RECEPTORGENE-MUTATIONS IN PATIENTS WITH ANDROGEN INSENSITIVITY SYNDROMES - APPLICATION FOR DIAGNOSIS, GENETIC-COUNSELING, AND THERAPY

Recent studies indicate that mutations in the androgen receptor gene a re associated with androgen insensitivity syndromes, a heterogeneous g roup of related disorders involving defective sexual differentiation i n karyotypic males. In this report, we address the possibility of rapi d mutational analysis of the androgen receptor gene for initial diagno sis, genetic counseling, and molecular subclassification of affected p atients and their families. DNA from peripheral blood leukocytes of si x patients from five families with various degrees of androgen insensi tivity was studied. Exons 2 to 8 of the androgen receptor gene were an alyzed using a combination of single strand conformation polymorphism analysis and direct DNA sequencing. Female family members were also st udied to identify heterozygote carriers. Point mutations in the AR gen e were identified in all six patients, and all mutations caused amino acid substitutions. One patient with incomplete androgen insensitivity was a mosaic for the mutation. Four of the five mothers, as well as a young sister of one patient, were carriers of the mutation present in the affected child. Our data show that new mutations may occur in the androgen receptor gene leading to sporadic androgen insensitivity syn drome. Molecular genetic characterization of the variant allele can se rve as a primary tool for diagnosis and subsequent therapy, and can pr ovide a basis for distinguishing heterozygous carriers in familial and rogen resistance. The identification of carriers is of substantial cli nical importance for genetic counseling.