Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: A report from the ENIGMA consortium

Mara Colombo, Marinus J. Blok, Phillip Whiley, Marta Santamariña, Sara Gutiérrez-Enríquez, Atocha Romero, Pilar Garre, Alexandra Becker, Lindsay Denise Smith, Giovanna De Vecchi, Rita D. Brandão, Demis Tserpelis, Melissa Brown, Ana Blanco, Sandra Bonache, Mireia Menéndez, Claude Houdayer, Claudia Foglia, James D. Fackenthal, Diana BaralleBarbara Wappenschmidt, Eduardo Díaz-Rubio, Trinidad Caldés, Logan Walker, Orland Díez, Ana Vega, Amanda B. Spurdle, Paolo Radice, Miguel de la Hoya

Research output: Contribution to journalArticlepeer-review


Loss-of-function germline mutationsin BRCA1(MIM#113705) confer markedly increased risk of breastandovarian cancer. The full-lengthtranscript codifies for a protein involved in DNA repair pathways and cell-cycle checkpoints. Several BRCA1 splicing isoformshavebeendescribed in publicdomaindatabases, but thephysiological role (if any) of BRCA1 alternative splicing remains to be established.Anaccurate description of 'naturally occurring' alternative splicing at this locus is a prerequisite to understand its biological significance. However, a systematic analysis of alternative splicing at the BRCA1 locus is yet to be conducted. Here, the Evidence-Based Network for the Interpretation of Germ-Line Mutant Alleles consortium combines RT-PCR, exon scanning, cloning, sequencing and relativesemi-quantificationto describe naturally occurring BRCA1 alternative splicing with unprecedented resolution. The study has been conducted in blood-related RNA sources, commonly used for clinical splicing assays, as well as in one healthy breast tissue. We have characterized a total of 63 BRCA1 alternative splicing events, including 35 novel findings. A minimum of 10 splicing events (D1Aq, D5, D5q, D8p, D9, D(9, 10), D9_11, D11q, D13p and D14p) represent a substantial fraction of the full-length expression level (rangingfrom5to100%). Remarkably,ourdata indicate that BRCA1 alternative splicing is similar inbloodandbreast, a finding supporting the clinical relevance of blood-based in vitro splicing assays. Overall, our data suggest an alternative splicing model in which most non-mutually exclusive alternative splicing events are randomly combined into individual mRNA molecules to produce hundreds of different BRCA1 isoforms.

Original languageEnglish
Article numberddu075
Pages (from-to)3666-3680
Number of pages15
JournalHuman Molecular Genetics
Issue number14
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology
  • Medicine(all)


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