Colombo, Mara ORCID: 0000-0001-5465-354X, Blok, Marinus J., Whiley, Phillip, Santamarina, Marta, Gutierrez-Enriquez, Sara ORCID: 0000-0002-1711-6101, Romero, Atocha, Garre, Pilar, Becker, Alexandra, Smith, Lindsay Denise, De Vecchi, Giovanna, Brandao, Rita D., Tserpelis, Demis, Brown, Melissa ORCID: 0000-0002-2830-9259, Blanco, Ana, Bonache, Sandra, Menendez, Mireia, Houdayer, Claude, Foglia, Claudia ORCID: 0000-0002-5505-7667, Fackenthal, James D., Baralle, Diana ORCID: 0000-0003-3217-4833, Wappenschmidt, Barbara, Diaz-Rubio, Eduardo ORCID: 0000-0003-2792-5348, Caldes, Trinidad, Walker, Logan ORCID: 0000-0003-0018-3719, Diez, Orland, Vega, Ana, Spurdle, Amanda B., Radice, Paolo ORCID: 0000-0001-6298-4111 and De La Hoya, Miguel (2014). Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium. Hum. Mol. Genet., 23 (14). S. 3666 - 3681. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

Loss-of-function germline mutations in BRCA1 (MIM #113705) confer markedly increased risk of breast and ovarian cancer. The full-length transcript codifies for a protein involved in DNA repair pathways and cell-cycle checkpoints. Several BRCA1 splicing isoforms have been described in public domain databases, but the physiological role (if any) of BRCA1 alternative splicing remains to be established. An accurate 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 relative semi-quantification to 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 (Delta 1Aq, Delta 5, Delta 5q, Delta 8p, Delta 9, Delta(9,10), Delta 9_11, Delta 11q, Delta 13p and Delta 14p) represent a substantial fraction of the full-length expression level (ranging from 5 to 100%). Remarkably, our data indicate that BRCA1 alternative splicing is similar in blood and breast, 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Colombo, MaraUNSPECIFIEDorcid.org/0000-0001-5465-354XUNSPECIFIED
Blok, Marinus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Whiley, PhillipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santamarina, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gutierrez-Enriquez, SaraUNSPECIFIEDorcid.org/0000-0002-1711-6101UNSPECIFIED
Romero, AtochaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garre, PilarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, Lindsay DeniseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Vecchi, GiovannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brandao, Rita D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tserpelis, DemisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brown, MelissaUNSPECIFIEDorcid.org/0000-0002-2830-9259UNSPECIFIED
Blanco, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonache, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menendez, MireiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houdayer, ClaudeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foglia, ClaudiaUNSPECIFIEDorcid.org/0000-0002-5505-7667UNSPECIFIED
Fackenthal, James D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baralle, DianaUNSPECIFIEDorcid.org/0000-0003-3217-4833UNSPECIFIED
Wappenschmidt, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diaz-Rubio, EduardoUNSPECIFIEDorcid.org/0000-0003-2792-5348UNSPECIFIED
Caldes, TrinidadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walker, LoganUNSPECIFIEDorcid.org/0000-0003-0018-3719UNSPECIFIED
Diez, OrlandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vega, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radice, PaoloUNSPECIFIEDorcid.org/0000-0001-6298-4111UNSPECIFIED
De La Hoya, MiguelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-433886
DOI: 10.1093/hmg/ddu075
Journal or Publication Title: Hum. Mol. Genet.
Volume: 23
Number: 14
Page Range: S. 3666 - 3681
Date: 2014
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
EARLY EMBRYONIC LETHALITY; MESSENGER-RNA; UNCLASSIFIED VARIANTS; INTRINSIC DISORDER; GENETIC-VARIANTS; MCF-7 CELLS; MUTATIONS; CANCER; TRANSCRIPTION; BREASTMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/43388

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