Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium.
Identifieur interne : 003678 ( PubMed/Corpus ); précédent : 003677; suivant : 003679Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium.
Auteurs : Mara Colombo ; Marinus J. Blok ; Phillip Whiley ; Marta Santamari A ; 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 Baralle ; Barbara Wappenschmidt ; Eduardo Díaz-Rubio ; Trinidad Caldés ; Logan Walker ; Orland Díez ; Ana Vega ; Amanda B. Spurdle ; Paolo Radice ; Miguel De La HoyaSource :
- Human molecular genetics [ 1460-2083 ] ; 2014.
English descriptors
- KwdEn :
- MESH :
- chemical , analysis : RNA, Messenger.
- chemical , blood : BRCA1 Protein.
- chemical , genetics : BRCA1 Protein, Protein Isoforms.
- metabolism : Breast.
- Alternative Splicing, Female, Humans, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, RNA.
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 (Δ1Aq, Δ5, Δ5q, Δ8p, Δ9, Δ(9,10), Δ9_11, Δ11q, Δ13p and Δ14p) 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.
DOI: 10.1093/hmg/ddu075
PubMed: 24569164
Links to Exploration step
pubmed:24569164Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium.</title><author><name sortKey="Colombo, Mara" sort="Colombo, Mara" uniqKey="Colombo M" first="Mara" last="Colombo">Mara Colombo</name><affiliation><nlm:affiliation>Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Blok, Marinus J" sort="Blok, Marinus J" uniqKey="Blok M" first="Marinus J" last="Blok">Marinus J. Blok</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Whiley, Phillip" sort="Whiley, Phillip" uniqKey="Whiley P" first="Phillip" last="Whiley">Phillip Whiley</name><affiliation><nlm:affiliation>Molecular Cancer Epidemiology Laboratory, Genetics and Computational Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Santamari A, Marta" sort="Santamari A, Marta" uniqKey="Santamari A M" first="Marta" last="Santamari A">Marta Santamari A</name><affiliation><nlm:affiliation>Grupo de Medicina Xenómica-USC, Universidad de Santiago de Compostela, CIBERER, IDIS, Santiago de Compostela, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Gutierrez Enriquez, Sara" sort="Gutierrez Enriquez, Sara" uniqKey="Gutierrez Enriquez S" first="Sara" last="Gutiérrez-Enríquez">Sara Gutiérrez-Enríquez</name><affiliation><nlm:affiliation>Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO) and.</nlm:affiliation></affiliation></author><author><name sortKey="Romero, Atocha" sort="Romero, Atocha" uniqKey="Romero A" first="Atocha" last="Romero">Atocha Romero</name><affiliation><nlm:affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Garre, Pilar" sort="Garre, Pilar" uniqKey="Garre P" first="Pilar" last="Garre">Pilar Garre</name><affiliation><nlm:affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Becker, Alexandra" sort="Becker, Alexandra" uniqKey="Becker A" first="Alexandra" last="Becker">Alexandra Becker</name><affiliation><nlm:affiliation>Center of Familial Breast and Ovarian Cancer, University Hospital Cologne, Cologne, Germany, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Smith, Lindsay Denise" sort="Smith, Lindsay Denise" uniqKey="Smith L" first="Lindsay Denise" last="Smith">Lindsay Denise Smith</name><affiliation><nlm:affiliation>Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.</nlm:affiliation></affiliation></author><author><name sortKey="De Vecchi, Giovanna" sort="De Vecchi, Giovanna" uniqKey="De Vecchi G" first="Giovanna" last="De Vecchi">Giovanna De Vecchi</name><affiliation><nlm:affiliation>Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Brandao, Rita D" sort="Brandao, Rita D" uniqKey="Brandao R" first="Rita D" last="Brandão">Rita D. Brandão</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Tserpelis, Demis" sort="Tserpelis, Demis" uniqKey="Tserpelis D" first="Demis" last="Tserpelis">Demis Tserpelis</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Brown, Melissa" sort="Brown, Melissa" uniqKey="Brown M" first="Melissa" last="Brown">Melissa Brown</name><affiliation><nlm:affiliation>School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Blanco, Ana" sort="Blanco, Ana" uniqKey="Blanco A" first="Ana" last="Blanco">Ana Blanco</name><affiliation><nlm:affiliation>Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Bonache, Sandra" sort="Bonache, Sandra" uniqKey="Bonache S" first="Sandra" last="Bonache">Sandra Bonache</name><affiliation><nlm:affiliation>Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO) and Oncogenetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Menendez, Mireia" sort="Menendez, Mireia" uniqKey="Menendez M" first="Mireia" last="Menéndez">Mireia Menéndez</name><affiliation><nlm:affiliation>Genetic Diagnosis Unit, Hereditary Cancer Program, Institut Català d'Oncologia, Barcelona, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Houdayer, Claude" sort="Houdayer, Claude" uniqKey="Houdayer C" first="Claude" last="Houdayer">Claude Houdayer</name><affiliation><nlm:affiliation>Service de Génétique and INSERM U830, Institut Curie and Université Paris Descartes, Sorbonne Paris Cité, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Foglia, Claudia" sort="Foglia, Claudia" uniqKey="Foglia C" first="Claudia" last="Foglia">Claudia Foglia</name><affiliation><nlm:affiliation>Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Fackenthal, James D" sort="Fackenthal, James D" uniqKey="Fackenthal J" first="James D" last="Fackenthal">James D. Fackenthal</name><affiliation><nlm:affiliation>Department of Medicine, The University of Chicago Medical Center, Chicago, IL, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Baralle, Diana" sort="Baralle, Diana" uniqKey="Baralle D" first="Diana" last="Baralle">Diana Baralle</name><affiliation><nlm:affiliation>Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Wappenschmidt, Barbara" sort="Wappenschmidt, Barbara" uniqKey="Wappenschmidt B" first="Barbara" last="Wappenschmidt">Barbara Wappenschmidt</name><affiliation><nlm:affiliation>Center of Familial Breast and Ovarian Cancer, University Hospital Cologne, Cologne, Germany, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Diaz Rubio, Eduardo" sort="Diaz Rubio, Eduardo" uniqKey="Diaz Rubio E" first="Eduardo" last="Díaz-Rubio">Eduardo Díaz-Rubio</name><affiliation><nlm:affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain, Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Caldes, Trinidad" sort="Caldes, Trinidad" uniqKey="Caldes T" first="Trinidad" last="Caldés">Trinidad Caldés</name><affiliation><nlm:affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Walker, Logan" sort="Walker, Logan" uniqKey="Walker L" first="Logan" last="Walker">Logan Walker</name><affiliation><nlm:affiliation>Department of Pathology, University of Otago, Christchurch, New Zealand.</nlm:affiliation></affiliation></author><author><name sortKey="Diez, Orland" sort="Diez, Orland" uniqKey="Diez O" first="Orland" last="Díez">Orland Díez</name><affiliation><nlm:affiliation>Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO) and Oncogenetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain, Oncogenetics Group, University Hospital of Vall d'Hebron, Barcelona, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Vega, Ana" sort="Vega, Ana" uniqKey="Vega A" first="Ana" last="Vega">Ana Vega</name><affiliation><nlm:affiliation>Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B" last="Spurdle">Amanda B. Spurdle</name><affiliation><nlm:affiliation>Molecular Cancer Epidemiology Laboratory, Genetics and Computational Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Radice, Paolo" sort="Radice, Paolo" uniqKey="Radice P" first="Paolo" last="Radice">Paolo Radice</name><affiliation><nlm:affiliation>Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="De La Hoya, Miguel" sort="De La Hoya, Miguel" uniqKey="De La Hoya M" first="Miguel" last="De La Hoya">Miguel De La Hoya</name><affiliation><nlm:affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain, mhoya@hotmail.com mdhoya@hotmail.com.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:24569164</idno><idno type="pmid">24569164</idno><idno type="doi">10.1093/hmg/ddu075</idno><idno type="wicri:Area/PubMed/Corpus">003678</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">003678</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium.</title><author><name sortKey="Colombo, Mara" sort="Colombo, Mara" uniqKey="Colombo M" first="Mara" last="Colombo">Mara Colombo</name><affiliation><nlm:affiliation>Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Blok, Marinus J" sort="Blok, Marinus J" uniqKey="Blok M" first="Marinus J" last="Blok">Marinus J. Blok</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Whiley, Phillip" sort="Whiley, Phillip" uniqKey="Whiley P" first="Phillip" last="Whiley">Phillip Whiley</name><affiliation><nlm:affiliation>Molecular Cancer Epidemiology Laboratory, Genetics and Computational Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Santamari A, Marta" sort="Santamari A, Marta" uniqKey="Santamari A M" first="Marta" last="Santamari A">Marta Santamari A</name><affiliation><nlm:affiliation>Grupo de Medicina Xenómica-USC, Universidad de Santiago de Compostela, CIBERER, IDIS, Santiago de Compostela, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Gutierrez Enriquez, Sara" sort="Gutierrez Enriquez, Sara" uniqKey="Gutierrez Enriquez S" first="Sara" last="Gutiérrez-Enríquez">Sara Gutiérrez-Enríquez</name><affiliation><nlm:affiliation>Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO) and.</nlm:affiliation></affiliation></author><author><name sortKey="Romero, Atocha" sort="Romero, Atocha" uniqKey="Romero A" first="Atocha" last="Romero">Atocha Romero</name><affiliation><nlm:affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Garre, Pilar" sort="Garre, Pilar" uniqKey="Garre P" first="Pilar" last="Garre">Pilar Garre</name><affiliation><nlm:affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Becker, Alexandra" sort="Becker, Alexandra" uniqKey="Becker A" first="Alexandra" last="Becker">Alexandra Becker</name><affiliation><nlm:affiliation>Center of Familial Breast and Ovarian Cancer, University Hospital Cologne, Cologne, Germany, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Smith, Lindsay Denise" sort="Smith, Lindsay Denise" uniqKey="Smith L" first="Lindsay Denise" last="Smith">Lindsay Denise Smith</name><affiliation><nlm:affiliation>Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.</nlm:affiliation></affiliation></author><author><name sortKey="De Vecchi, Giovanna" sort="De Vecchi, Giovanna" uniqKey="De Vecchi G" first="Giovanna" last="De Vecchi">Giovanna De Vecchi</name><affiliation><nlm:affiliation>Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Brandao, Rita D" sort="Brandao, Rita D" uniqKey="Brandao R" first="Rita D" last="Brandão">Rita D. Brandão</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Tserpelis, Demis" sort="Tserpelis, Demis" uniqKey="Tserpelis D" first="Demis" last="Tserpelis">Demis Tserpelis</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Brown, Melissa" sort="Brown, Melissa" uniqKey="Brown M" first="Melissa" last="Brown">Melissa Brown</name><affiliation><nlm:affiliation>School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Blanco, Ana" sort="Blanco, Ana" uniqKey="Blanco A" first="Ana" last="Blanco">Ana Blanco</name><affiliation><nlm:affiliation>Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Bonache, Sandra" sort="Bonache, Sandra" uniqKey="Bonache S" first="Sandra" last="Bonache">Sandra Bonache</name><affiliation><nlm:affiliation>Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO) and Oncogenetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Menendez, Mireia" sort="Menendez, Mireia" uniqKey="Menendez M" first="Mireia" last="Menéndez">Mireia Menéndez</name><affiliation><nlm:affiliation>Genetic Diagnosis Unit, Hereditary Cancer Program, Institut Català d'Oncologia, Barcelona, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Houdayer, Claude" sort="Houdayer, Claude" uniqKey="Houdayer C" first="Claude" last="Houdayer">Claude Houdayer</name><affiliation><nlm:affiliation>Service de Génétique and INSERM U830, Institut Curie and Université Paris Descartes, Sorbonne Paris Cité, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Foglia, Claudia" sort="Foglia, Claudia" uniqKey="Foglia C" first="Claudia" last="Foglia">Claudia Foglia</name><affiliation><nlm:affiliation>Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Fackenthal, James D" sort="Fackenthal, James D" uniqKey="Fackenthal J" first="James D" last="Fackenthal">James D. Fackenthal</name><affiliation><nlm:affiliation>Department of Medicine, The University of Chicago Medical Center, Chicago, IL, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Baralle, Diana" sort="Baralle, Diana" uniqKey="Baralle D" first="Diana" last="Baralle">Diana Baralle</name><affiliation><nlm:affiliation>Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Wappenschmidt, Barbara" sort="Wappenschmidt, Barbara" uniqKey="Wappenschmidt B" first="Barbara" last="Wappenschmidt">Barbara Wappenschmidt</name><affiliation><nlm:affiliation>Center of Familial Breast and Ovarian Cancer, University Hospital Cologne, Cologne, Germany, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Diaz Rubio, Eduardo" sort="Diaz Rubio, Eduardo" uniqKey="Diaz Rubio E" first="Eduardo" last="Díaz-Rubio">Eduardo Díaz-Rubio</name><affiliation><nlm:affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain, Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Caldes, Trinidad" sort="Caldes, Trinidad" uniqKey="Caldes T" first="Trinidad" last="Caldés">Trinidad Caldés</name><affiliation><nlm:affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Walker, Logan" sort="Walker, Logan" uniqKey="Walker L" first="Logan" last="Walker">Logan Walker</name><affiliation><nlm:affiliation>Department of Pathology, University of Otago, Christchurch, New Zealand.</nlm:affiliation></affiliation></author><author><name sortKey="Diez, Orland" sort="Diez, Orland" uniqKey="Diez O" first="Orland" last="Díez">Orland Díez</name><affiliation><nlm:affiliation>Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO) and Oncogenetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain, Oncogenetics Group, University Hospital of Vall d'Hebron, Barcelona, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Vega, Ana" sort="Vega, Ana" uniqKey="Vega A" first="Ana" last="Vega">Ana Vega</name><affiliation><nlm:affiliation>Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B" last="Spurdle">Amanda B. Spurdle</name><affiliation><nlm:affiliation>Molecular Cancer Epidemiology Laboratory, Genetics and Computational Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Radice, Paolo" sort="Radice, Paolo" uniqKey="Radice P" first="Paolo" last="Radice">Paolo Radice</name><affiliation><nlm:affiliation>Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="De La Hoya, Miguel" sort="De La Hoya, Miguel" uniqKey="De La Hoya M" first="Miguel" last="De La Hoya">Miguel De La Hoya</name><affiliation><nlm:affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain, mhoya@hotmail.com mdhoya@hotmail.com.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Human molecular genetics</title><idno type="eISSN">1460-2083</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Alternative Splicing</term><term>BRCA1 Protein (blood)</term><term>BRCA1 Protein (genetics)</term><term>Breast (metabolism)</term><term>Female</term><term>Humans</term><term>Protein Isoforms (genetics)</term><term>RNA, Messenger (analysis)</term><term>Reverse Transcriptase Polymerase Chain Reaction</term><term>Sequence Analysis, RNA</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>RNA, Messenger</term></keywords><keywords scheme="MESH" type="chemical" qualifier="blood" xml:lang="en"><term>BRCA1 Protein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>BRCA1 Protein</term><term>Protein Isoforms</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Breast</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Alternative Splicing</term><term>Female</term><term>Humans</term><term>Reverse Transcriptase Polymerase Chain Reaction</term><term>Sequence Analysis, RNA</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 (Δ1Aq, Δ5, Δ5q, Δ8p, Δ9, Δ(9,10), Δ9_11, Δ11q, Δ13p and Δ14p) 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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">24569164</PMID><DateCreated><Year>2014</Year><Month>06</Month><Day>21</Day></DateCreated><DateCompleted><Year>2015</Year><Month>02</Month><Day>09</Day></DateCompleted><DateRevised><Year>2014</Year><Month>06</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1460-2083</ISSN><JournalIssue CitedMedium="Internet"><Volume>23</Volume><Issue>14</Issue><PubDate><Year>2014</Year><Month>Jul</Month><Day>15</Day></PubDate></JournalIssue><Title>Human molecular genetics</Title><ISOAbbreviation>Hum. Mol. Genet.</ISOAbbreviation></Journal><ArticleTitle>Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium.</ArticleTitle><Pagination><MedlinePgn>3666-80</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1093/hmg/ddu075</ELocationID><Abstract><AbstractText>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 (Δ1Aq, Δ5, Δ5q, Δ8p, Δ9, Δ(9,10), Δ9_11, Δ11q, Δ13p and Δ14p) 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.</AbstractText><CopyrightInformation>© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Colombo</LastName><ForeName>Mara</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Blok</LastName><ForeName>Marinus J</ForeName><Initials>MJ</Initials><AffiliationInfo><Affiliation>Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Whiley</LastName><ForeName>Phillip</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Molecular Cancer Epidemiology Laboratory, Genetics and Computational Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Santamariña</LastName><ForeName>Marta</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Grupo de Medicina Xenómica-USC, Universidad de Santiago de Compostela, CIBERER, IDIS, Santiago de Compostela, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gutiérrez-Enríquez</LastName><ForeName>Sara</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO) and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Romero</LastName><ForeName>Atocha</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Garre</LastName><ForeName>Pilar</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Becker</LastName><ForeName>Alexandra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Center of Familial Breast and Ovarian Cancer, University Hospital Cologne, Cologne, Germany, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Smith</LastName><ForeName>Lindsay Denise</ForeName><Initials>LD</Initials><AffiliationInfo><Affiliation>Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>De Vecchi</LastName><ForeName>Giovanna</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brandão</LastName><ForeName>Rita D</ForeName><Initials>RD</Initials><AffiliationInfo><Affiliation>Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tserpelis</LastName><ForeName>Demis</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brown</LastName><ForeName>Melissa</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Blanco</LastName><ForeName>Ana</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bonache</LastName><ForeName>Sandra</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO) and Oncogenetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Menéndez</LastName><ForeName>Mireia</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Genetic Diagnosis Unit, Hereditary Cancer Program, Institut Català d'Oncologia, Barcelona, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Houdayer</LastName><ForeName>Claude</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Service de Génétique and INSERM U830, Institut Curie and Université Paris Descartes, Sorbonne Paris Cité, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Foglia</LastName><ForeName>Claudia</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fackenthal</LastName><ForeName>James D</ForeName><Initials>JD</Initials><AffiliationInfo><Affiliation>Department of Medicine, The University of Chicago Medical Center, Chicago, IL, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Baralle</LastName><ForeName>Diana</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wappenschmidt</LastName><ForeName>Barbara</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Center of Familial Breast and Ovarian Cancer, University Hospital Cologne, Cologne, Germany, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><CollectiveName>kConFaB Investigators</CollectiveName></Author><Author ValidYN="Y"><LastName>Díaz-Rubio</LastName><ForeName>Eduardo</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain, Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Caldés</LastName><ForeName>Trinidad</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Walker</LastName><ForeName>Logan</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Department of Pathology, University of Otago, Christchurch, New Zealand.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Díez</LastName><ForeName>Orland</ForeName><Initials>O</Initials><AffiliationInfo><Affiliation>Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO) and Oncogenetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain, Oncogenetics Group, University Hospital of Vall d'Hebron, Barcelona, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vega</LastName><ForeName>Ana</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Spurdle</LastName><ForeName>Amanda B</ForeName><Initials>AB</Initials><AffiliationInfo><Affiliation>Molecular Cancer Epidemiology Laboratory, Genetics and Computational Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Radice</LastName><ForeName>Paolo</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>De La Hoya</LastName><ForeName>Miguel</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Laboratorio de Oncología Molecular, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain, mhoya@hotmail.com mdhoya@hotmail.com.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016448">Multicenter Study</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D013486">Research Support, U.S. Gov't, Non-P.H.S.</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>02</Month><Day>25</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Hum Mol Genet</MedlineTA><NlmUniqueID>9208958</NlmUniqueID><ISSNLinking>0964-6906</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019313">BRCA1 Protein</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D020033">Protein Isoforms</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D012333">RNA, Messenger</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D017398" MajorTopicYN="Y">Alternative Splicing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019313" MajorTopicYN="N">BRCA1 Protein</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="Y">blood</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001940" MajorTopicYN="N">Breast</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020033" MajorTopicYN="N">Protein Isoforms</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012333" MajorTopicYN="N">RNA, Messenger</DescriptorName><QualifierName UI="Q000032" MajorTopicYN="N">analysis</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020133" MajorTopicYN="N">Reverse Transcriptase Polymerase Chain Reaction</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017423" MajorTopicYN="N">Sequence Analysis, RNA</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate 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