ESPE Abstracts

Background: Androgen insensitivity syndrome (AIS) is a genetic disease X-linked, caused by functional abnormalities of the androgen receptor (AR). Mutations in the AR are associated with broad phenotypic spectrum from partial insensibility (PAIS) to complete insensitivity (CAIS).

Objective and hypotheses: To characterize the mutations (MUT) identified in the AR in 38 Brazilian families with AIS. The MUT were analyzed considering their type, location in the gene, functional domain and associated phenotype.

Method: PCR amplification of the coding and promoter regions of the AR gene, followed by direct sequencing. The identified MUT were searched in the literature, genomic sites and the novel MUT were evaluated by prediction sites. We classify MUT according to the type (missense and nonsense), exomic location, the affected functional domain (NTD, LDB, DBD, and Hinge) and phenotype (CAIS and PAIS).

Results: We identified 17 different AR MUT in 22 families with PAIS (n=37) and 13 in 16 families with CAIS (n=23). Of these, six (CAIS) and eight (PAIS) have not been described. These novel variants are not found in either 1000 Genome and ESP-6500 database and the all of them were considered deleterious. Missense MUT were identified in 90.5% of PAIS and in 83% of CAIS and nonsense MUT in 9.5% of PAIS and 17% in CAIS. The frequency of MUT by exon differ between CAIS and PAIS patients, being more frequent in exons 5 and 7 (18 and 17%) in PAIS and in exons 1 and 4 (27 and 21%) in CAIS. In functional domains, there was a lower frequency of MUT in the DBD (12.5% in CAIS and 20% in PAIS) followed by the NTD (25% in CAIS and 20% in PAIS) and LBD (62.5% in CAIS and 60% in PAIS). We describe for the first time, a large deletion in the promoter region of the AR gene in a family with PAIS, whose exonic region was normal. Mutations in AR were not identified in 18.2% of families with PAIS (4/22) and 6.25% of the families with CAIS (1/16).

Conclusion: The identification of MUT related to different phenotypes of AIS in Brazilian families allows for greater insight into genetic defects. The strategy of seeking MUT in the promoter region, when there is clinical suspicion of AIS without MUT in exonic region of the AR may allow the identification of genetic alteration in patients without exomic mutations.