A new alternative splice variant of BRCA1 containing an additional in-frame exon

The breast/ovarian cancer susceptibility gene BRCA1 interact with multiple protein complexes involved in cellular mechanisms, such as DNA repair, transcription, homologous recombination and cell cycle regulation. Extensive analyses over the past decade led to the detection of several BRCA1 alternative splice variants. Here, we identify the first BRCA1 alternative splice variant containing an additional in-frame exon. This previously unknown exon 13A-containing transcript is generated by the insertion of 66 nucleotides between exons 13 and 14, due to alternative splicing in intron 13 (IVS13-2786-2720). Furthermore, exon 13A-containing transcript was detectable in total RNA samples from 12 normal tissues and several breast and other cancer cell lines. As revealed by real-time PCR analysis, this transcript corresponds to 20 to 25% of the total BRCA1 mRNA expression levels in leukocytes, brain and cerebellum tissues, whereas its relative level of expression is less than 5% in other tested tissues and cancer cell lines. This novel alternative transcript adds 22 amino acids after residue 1452, thus modifying the primary structure of the trans-activation domain 1 (AD1) and the protein-protein interacting domain of BRCA1 with BRCA2, AR and MSH2. No sequence variant has been detected by direct genomic sequencing of exon 13A in individuals originating from high-risk breast/ovarian cancer families.