AustralieFrV1, Main, Exploration, bibRecord, 008B41

Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket : a multi-modal approach

Identifieur interne : 008B41 ( Main/Exploration ); précédent : 008B40; suivant : 008B42

Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket : a multi-modal approach

Auteurs : Marc Tischkowitz [Canada] ; Nancy Hamel [Canada] ; Marcelo A. Carvalho [États-Unis, Brésil] ; Gabriel Birrane [États-Unis] ; Aditi Soni [États-Unis] ; Erik H. Van Beers [Pays-Bas] ; Simon A. Joosse [Pays-Bas] ; Nora Wong [Canada] ; David Novak [Canada] ; Louise A. Quenneville [Canada] ; Scott A. Grist [Australie] ; Kcon Fab [Australie] ; Petra M. Nederlof [Pays-Bas] ; David E. Goldgar [États-Unis] ; Sean V. Tavtigian [France] ; Alvaro N. Monteiro [États-Unis] ; John A. A. Ladias [États-Unis] ; William D. Foulkes [Canada]

Source :

European journal of human genetics [ 1018-4813 ] ; 2008.

RBID : Pascal:08-0308026

Descripteurs français

Pascal (Inist)
- Cancer du sein, Pouvoir pathogène, Gène suppresseur tumeur, Variant, Disruption, Phosphopeptide, Héréditaire, Génétique.
Wicri :
- topic : Génétique.

English descriptors

KwdEn :
- Breast cancer, Disruption, Genetics, Hereditary, Pathogenicity, Phosphopeptide, Tumor suppressor gene, Variant.

Abstract

A number of germ-line mutations in the BRCA1 gene confer susceptibility to breast and ovarian cancer. However, it remains difficult to determine whether many single amino-acid (missense) changes in the BRCA1 protein that are frequently detected in the clinical setting are pathologic or not. Here, we used a combination of functional, crystallographic, biophysical, molecular and evolutionary techniques, and classical genetic segregation analysis to demonstrate that the BRCA1 missense variant M1775K is pathogenic. Functional assays in yeast and mammalian cells showed that the BRCA1 BRCT domains carrying the amino-acid change M1775K displayed markedly reduced transcriptional activity, indicating that this variant represents a deleterious mutation. Importantly, the M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCA1 BRCT domains, thereby inhibiting the BRCA1 interaction with the proteins BRIP1 and CtIP, which are involved in DNA damage-induced checkpoint control. These results indicate that the integrity of the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Moreover, this study demonstrates that multiple lines of evidence obtained from a combination of functional, structural, molecular and evolutionary techniques, and classical genetic segregation analysis are required to confirm the pathogenicity of rare variants of disease-susceptibility genes and obtain important insights into the underlying pathogenetic mechanisms.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905962

Affiliations:

Le document en format XML

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<author><name sortKey="Birrane, Gabriel" sort="Birrane, Gabriel" uniqKey="Birrane G" first="Gabriel" last="Birrane">Gabriel Birrane</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Department of Medicine, Molecular Medicine Laboratory and Macromolecular Crystallography Unit, Division of Experimental Medicine, Harvard Institutes of Medicine, Harvard Medical School</s1>
<s2>Boston, MA</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
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<author><name sortKey="Soni, Aditi" sort="Soni, Aditi" uniqKey="Soni A" first="Aditi" last="Soni">Aditi Soni</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Department of Medicine, Molecular Medicine Laboratory and Macromolecular Crystallography Unit, Division of Experimental Medicine, Harvard Institutes of Medicine, Harvard Medical School</s1>
<s2>Boston, MA</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Boston, MA</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Van Beers, Erik H" sort="Van Beers, Erik H" uniqKey="Van Beers E" first="Erik H." last="Van Beers">Erik H. Van Beers</name>
<affiliation wicri:level="3"><inist:fA14 i1="07"><s1>Division of Experimental Therapy and Department of Pathology, Netherlands Cancer Institute</s1>
<s2>Amsterdam</s2>
<s3>NLD</s3>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>13 aut.</sZ>
</inist:fA14>
<country>Pays-Bas</country>
<placeName><settlement type="city">Amsterdam</settlement>
<region nuts="2" type="province">Hollande-Septentrionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Joosse, Simon A" sort="Joosse, Simon A" uniqKey="Joosse S" first="Simon A." last="Joosse">Simon A. Joosse</name>
<affiliation wicri:level="3"><inist:fA14 i1="07"><s1>Division of Experimental Therapy and Department of Pathology, Netherlands Cancer Institute</s1>
<s2>Amsterdam</s2>
<s3>NLD</s3>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>13 aut.</sZ>
</inist:fA14>
<country>Pays-Bas</country>
<placeName><settlement type="city">Amsterdam</settlement>
<region nuts="2" type="province">Hollande-Septentrionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wong, Nora" sort="Wong, Nora" uniqKey="Wong N" first="Nora" last="Wong">Nora Wong</name>
<affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Program in Cancer Genetics, Departments of Oncology, Human Genetics and Medicine, McGill University</s1>
<s2>Montréal, Quebec</s2>
<s3>CAN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>18 aut.</sZ>
</inist:fA14>
<country>Canada</country>
<placeName><settlement type="city">Montréal</settlement>
<region type="state">Québec</region>
</placeName>
<orgName type="university">Université McGill</orgName>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Oncology, Segal Cancer Centre, Sir M.B. Davis-Jewish General Hospital</s1>
<s2>Montréal, Quebec</s2>
<s3>CAN</s3>
<sZ>1 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>18 aut.</sZ>
</inist:fA14>
<country>Canada</country>
<wicri:noRegion>Montréal, Quebec</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Novak, David" sort="Novak, David" uniqKey="Novak D" first="David" last="Novak">David Novak</name>
<affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Program in Cancer Genetics, Departments of Oncology, Human Genetics and Medicine, McGill University</s1>
<s2>Montréal, Quebec</s2>
<s3>CAN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>18 aut.</sZ>
</inist:fA14>
<country>Canada</country>
<placeName><settlement type="city">Montréal</settlement>
<region type="state">Québec</region>
</placeName>
<orgName type="university">Université McGill</orgName>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Medicine, The Research Institute, McGill University Health Centre</s1>
<s2>Montréal, Quebec</s2>
<s3>CAN</s3>
<sZ>2 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>18 aut.</sZ>
</inist:fA14>
<country>Canada</country>
<wicri:noRegion>Montréal, Quebec</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Quenneville, Louise A" sort="Quenneville, Louise A" uniqKey="Quenneville L" first="Louise A." last="Quenneville">Louise A. Quenneville</name>
<affiliation wicri:level="4"><inist:fA14 i1="08"><s1>Department of Pathology, Sir M.B. Davis-Jewish General Hospital, McGill University</s1>
<s2>Montréal, Quebec</s2>
<s3>CAN</s3>
<sZ>10 aut.</sZ>
</inist:fA14>
<country>Canada</country>
<placeName><settlement type="city">Montréal</settlement>
<region type="state">Québec</region>
</placeName>
<orgName type="university">Université McGill</orgName>
</affiliation>
</author>
<author><name sortKey="Grist, Scott A" sort="Grist, Scott A" uniqKey="Grist S" first="Scott A." last="Grist">Scott A. Grist</name>
<affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Department of Hematology & Genetic Pathology, Flinders Medical Centre, Flinders University of South Australia</s1>
<s2>Adelaide, South Australia</s2>
<s3>AUS</s3>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>Australie</country>
<wicri:noRegion>Adelaide, South Australia</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Fab, Kcon" sort="Fab, Kcon" uniqKey="Fab K" first="Kcon" last="Fab">Kcon Fab</name>
<affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Institute</s1>
<s2>East Melbourne, Victoria</s2>
<s3>AUS</s3>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>Australie</country>
<wicri:noRegion>East Melbourne, Victoria</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Nederlof, Petra M" sort="Nederlof, Petra M" uniqKey="Nederlof P" first="Petra M." last="Nederlof">Petra M. Nederlof</name>
<affiliation wicri:level="3"><inist:fA14 i1="07"><s1>Division of Experimental Therapy and Department of Pathology, Netherlands Cancer Institute</s1>
<s2>Amsterdam</s2>
<s3>NLD</s3>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>13 aut.</sZ>
</inist:fA14>
<country>Pays-Bas</country>
<placeName><settlement type="city">Amsterdam</settlement>
<region nuts="2" type="province">Hollande-Septentrionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Goldgar, David E" sort="Goldgar, David E" uniqKey="Goldgar D" first="David E." last="Goldgar">David E. Goldgar</name>
<affiliation wicri:level="1"><inist:fA14 i1="11"><s1>Department of Dermatology, University of Utah School of Medicine</s1>
<s2>Salt Lake City, UT</s2>
<s3>USA</s3>
<sZ>14 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Salt Lake City, UT</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V." last="Tavtigian">Sean V. Tavtigian</name>
<affiliation wicri:level="3"><inist:fA14 i1="12"><s1>Intemational Agency for Research on Cancer, World Health Organization</s1>
<s2>Lyon</s2>
<s3>FRA</s3>
<sZ>15 aut.</sZ>
</inist:fA14>
<country>France</country>
<placeName><region type="region">Auvergne-Rhône-Alpes</region>
<region type="old region">Rhône-Alpes</region>
<settlement type="city">Lyon</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Monteiro, Alvaro N" sort="Monteiro, Alvaro N" uniqKey="Monteiro A" first="Alvaro N." last="Monteiro">Alvaro N. Monteiro</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Risk Assessment, Detection, and Intervention Program, H. Lee Moffitt Cancer Center & Research Institute</s1>
<s2>Tampa, FL</s2>
<s3>USA</s3>
<sZ>3 aut.</sZ>
<sZ>16 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Tampa, FL</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ladias, John A A" sort="Ladias, John A A" uniqKey="Ladias J" first="John A. A." last="Ladias">John A. A. Ladias</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Department of Medicine, Molecular Medicine Laboratory and Macromolecular Crystallography Unit, Division of Experimental Medicine, Harvard Institutes of Medicine, Harvard Medical School</s1>
<s2>Boston, MA</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Boston, MA</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Foulkes, William D" sort="Foulkes, William D" uniqKey="Foulkes W" first="William D." last="Foulkes">William D. Foulkes</name>
<affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Program in Cancer Genetics, Departments of Oncology, Human Genetics and Medicine, McGill University</s1>
<s2>Montréal, Quebec</s2>
<s3>CAN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>18 aut.</sZ>
</inist:fA14>
<country>Canada</country>
<placeName><settlement type="city">Montréal</settlement>
<region type="state">Québec</region>
</placeName>
<orgName type="university">Université McGill</orgName>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Oncology, Segal Cancer Centre, Sir M.B. Davis-Jewish General Hospital</s1>
<s2>Montréal, Quebec</s2>
<s3>CAN</s3>
<sZ>1 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>18 aut.</sZ>
</inist:fA14>
<country>Canada</country>
<wicri:noRegion>Montréal, Quebec</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Medicine, The Research Institute, McGill University Health Centre</s1>
<s2>Montréal, Quebec</s2>
<s3>CAN</s3>
<sZ>2 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>18 aut.</sZ>
</inist:fA14>
<country>Canada</country>
<wicri:noRegion>Montréal, Quebec</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">European journal of human genetics</title>
<title level="j" type="abbreviated">Eur. j. hum. genet.</title>
<idno type="ISSN">1018-4813</idno>
<imprint><date when="2008">2008</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><title level="j" type="main">European journal of human genetics</title>
<title level="j" type="abbreviated">Eur. j. hum. genet.</title>
<idno type="ISSN">1018-4813</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Breast cancer</term>
<term>Disruption</term>
<term>Genetics</term>
<term>Hereditary</term>
<term>Pathogenicity</term>
<term>Phosphopeptide</term>
<term>Tumor suppressor gene</term>
<term>Variant</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Cancer du sein</term>
<term>Pouvoir pathogène</term>
<term>Gène suppresseur tumeur</term>
<term>Variant</term>
<term>Disruption</term>
<term>Phosphopeptide</term>
<term>Héréditaire</term>
<term>Génétique</term>
</keywords>
<keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">A number of germ-line mutations in the BRCA1 gene confer susceptibility to breast and ovarian cancer. However, it remains difficult to determine whether many single amino-acid (missense) changes in the BRCA1 protein that are frequently detected in the clinical setting are pathologic or not. Here, we used a combination of functional, crystallographic, biophysical, molecular and evolutionary techniques, and classical genetic segregation analysis to demonstrate that the BRCA1 missense variant M1775K is pathogenic. Functional assays in yeast and mammalian cells showed that the BRCA1 BRCT domains carrying the amino-acid change M1775K displayed markedly reduced transcriptional activity, indicating that this variant represents a deleterious mutation. Importantly, the M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCA1 BRCT domains, thereby inhibiting the BRCA1 interaction with the proteins BRIP1 and CtIP, which are involved in DNA damage-induced checkpoint control. These results indicate that the integrity of the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Moreover, this study demonstrates that multiple lines of evidence obtained from a combination of functional, structural, molecular and evolutionary techniques, and classical genetic segregation analysis are required to confirm the pathogenicity of rare variants of disease-susceptibility genes and obtain important insights into the underlying pathogenetic mechanisms.</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>Brésil</li>
<li>Canada</li>
<li>France</li>
<li>Pays-Bas</li>
<li>États-Unis</li>
</country>
<region><li>Auvergne-Rhône-Alpes</li>
<li>Hollande-Septentrionale</li>
<li>Québec</li>
<li>Rhône-Alpes</li>
<li>État de Rio de Janeiro</li>
</region>
<settlement><li>Amsterdam</li>
<li>Lyon</li>
<li>Montréal</li>
<li>Rio de Janeiro</li>
</settlement>
<orgName><li>Université McGill</li>
</orgName>
</list>
<tree><country name="Canada"><region name="Québec"><name sortKey="Tischkowitz, Marc" sort="Tischkowitz, Marc" uniqKey="Tischkowitz M" first="Marc" last="Tischkowitz">Marc Tischkowitz</name>
</region>
<name sortKey="Foulkes, William D" sort="Foulkes, William D" uniqKey="Foulkes W" first="William D." last="Foulkes">William D. Foulkes</name>
<name sortKey="Foulkes, William D" sort="Foulkes, William D" uniqKey="Foulkes W" first="William D." last="Foulkes">William D. Foulkes</name>
<name sortKey="Foulkes, William D" sort="Foulkes, William D" uniqKey="Foulkes W" first="William D." last="Foulkes">William D. Foulkes</name>
<name sortKey="Hamel, Nancy" sort="Hamel, Nancy" uniqKey="Hamel N" first="Nancy" last="Hamel">Nancy Hamel</name>
<name sortKey="Hamel, Nancy" sort="Hamel, Nancy" uniqKey="Hamel N" first="Nancy" last="Hamel">Nancy Hamel</name>
<name sortKey="Novak, David" sort="Novak, David" uniqKey="Novak D" first="David" last="Novak">David Novak</name>
<name sortKey="Novak, David" sort="Novak, David" uniqKey="Novak D" first="David" last="Novak">David Novak</name>
<name sortKey="Quenneville, Louise A" sort="Quenneville, Louise A" uniqKey="Quenneville L" first="Louise A." last="Quenneville">Louise A. Quenneville</name>
<name sortKey="Tischkowitz, Marc" sort="Tischkowitz, Marc" uniqKey="Tischkowitz M" first="Marc" last="Tischkowitz">Marc Tischkowitz</name>
<name sortKey="Wong, Nora" sort="Wong, Nora" uniqKey="Wong N" first="Nora" last="Wong">Nora Wong</name>
<name sortKey="Wong, Nora" sort="Wong, Nora" uniqKey="Wong N" first="Nora" last="Wong">Nora Wong</name>
</country>
<country name="États-Unis"><noRegion><name sortKey="Carvalho, Marcelo A" sort="Carvalho, Marcelo A" uniqKey="Carvalho M" first="Marcelo A." last="Carvalho">Marcelo A. Carvalho</name>
</noRegion>
<name sortKey="Birrane, Gabriel" sort="Birrane, Gabriel" uniqKey="Birrane G" first="Gabriel" last="Birrane">Gabriel Birrane</name>
<name sortKey="Goldgar, David E" sort="Goldgar, David E" uniqKey="Goldgar D" first="David E." last="Goldgar">David E. Goldgar</name>
<name sortKey="Ladias, John A A" sort="Ladias, John A A" uniqKey="Ladias J" first="John A. A." last="Ladias">John A. A. Ladias</name>
<name sortKey="Monteiro, Alvaro N" sort="Monteiro, Alvaro N" uniqKey="Monteiro A" first="Alvaro N." last="Monteiro">Alvaro N. Monteiro</name>
<name sortKey="Soni, Aditi" sort="Soni, Aditi" uniqKey="Soni A" first="Aditi" last="Soni">Aditi Soni</name>
</country>
<country name="Brésil"><region name="État de Rio de Janeiro"><name sortKey="Carvalho, Marcelo A" sort="Carvalho, Marcelo A" uniqKey="Carvalho M" first="Marcelo A." last="Carvalho">Marcelo A. Carvalho</name>
</region>
</country>
<country name="Pays-Bas"><region name="Hollande-Septentrionale"><name sortKey="Van Beers, Erik H" sort="Van Beers, Erik H" uniqKey="Van Beers E" first="Erik H." last="Van Beers">Erik H. Van Beers</name>
</region>
<name sortKey="Joosse, Simon A" sort="Joosse, Simon A" uniqKey="Joosse S" first="Simon A." last="Joosse">Simon A. Joosse</name>
<name sortKey="Nederlof, Petra M" sort="Nederlof, Petra M" uniqKey="Nederlof P" first="Petra M." last="Nederlof">Petra M. Nederlof</name>
</country>
<country name="Australie"><noRegion><name sortKey="Grist, Scott A" sort="Grist, Scott A" uniqKey="Grist S" first="Scott A." last="Grist">Scott A. Grist</name>
</noRegion>
<name sortKey="Fab, Kcon" sort="Fab, Kcon" uniqKey="Fab K" first="Kcon" last="Fab">Kcon Fab</name>
</country>
<country name="France"><region name="Auvergne-Rhône-Alpes"><name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V." last="Tavtigian">Sean V. Tavtigian</name>
</region>
</country>
</tree>
</affiliations>
</record>

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Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket : a multi-modal approach

Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket : a multi-modal approach

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