ESPE Abstracts (2016) 86 P-P1-348

Exonic Splicing Mutations by Silent Nucleotide Variation in the Androgen Receptor Gene Causes Androgen Insensitivity Syndrome

Rafael Loch Batista, Andreza de Santi Rodrigues, Tathiana Evilen da Silva, Flavia Siqueira Cunha, Nathalia Lisboa Gomes, Daniela Rodrigues, Sorahia Domenice, Elaine Frade Costa & Berenice Bilharinho de Mendonca


Universidade de Sao Paulo, Sao Paulo SP, Brazil


Background: Androgen Insensitivity Syndrome is a common form of 46,XY DSD. In the literature, 85–90% of patients with complete form of Androgen Insensitivity (CAIS) and 30% of patients with parcial form (PAIS) have the AR gene mutation identified, In most cases are found a missense mutation with aminoacid change. Mutations without aminoacid changes (silent mutations) are rarely related to human diseases and have never been identified in patients with CAIS.

Objective and hypotheses: To describe two different silent mutations in the AR exonic region causing a splicing alteration and a premature stop codon in AIS patients without others mutations identified in the AR gene.

Method: We sequenced the whole coding region of the AR gene including all exon/intron boundaries after amplification by PCR in 14 segments using primers derived from published sequences. All mutations, included silent mutations identified were analysed by prediction tools: Netgene2 and Human Splicing Finder. For new mutations considered deleterious in predictive sites by splicing alteration we performed a sequencing of partial AR cDNA, flanking the mutation region.

Results: We found two silent mutations in two families with AIS. The first mutation (p.S889S) in exon 8 of AR was found in a patient with atypical genitalia raised in male social sex. The second mutation (p.S510S) was found in a family with three affected 46,XY patients with normal female external genitalia, primary amenorrhea and inguinal hernia. Both mutations were classified as deleterious by predictive tools. Silent mutations creating an alternative splicing was described in only one patient with PAIS but this mutation has not been described in the complete form of AIS. A sequencing of partial cDNA, flanking the mutation region, in patient’s AR mRNA (p.S510S) showed a lost around 90 bp at the end of exon 1 leading to a premature stop codon.

Conclusion: Silent mutations creating an alternative splicing and a premature stop codon can be associated with both partial and complete form of AIS. This is the first description of silent mutation in the AR causing splicing alteration in CAIS.