Serum biomarker for progranulin‐associated frontotemporal lobar degeneration
Identifieur interne : 000961 ( Main/Exploration ); précédent : 000960; suivant : 000962Serum biomarker for progranulin‐associated frontotemporal lobar degeneration
Auteurs : Kristel Sleegers [Belgique] ; Nathalie Brouwers [Belgique] ; Philip Van Damme [Belgique] ; Sebastiaan Engelborghs [Belgique] ; Ilse Gijselinck [Belgique] ; Julie Van Der Zee [Belgique] ; Karin Peeters [Belgique] ; Maria Mattheijssens [Belgique] ; Marc Cruts [Belgique] ; Rik Vandenberghe [Belgique] ; Peter P. De Deyn [Belgique] ; Wim Robberecht [Belgique] ; Christine Van Broeckhoven [Belgique]Source :
- Annals of Neurology [ 0364-5134 ] ; 2009-05.
Abstract
Objective: Mutations that lead to a loss of progranulin (PGRN) explain a considerable portion of the occurrence of frontotemporal lobar degeneration. We tested a biomarker allowing rapid detection of a loss of PGRN. Methods: We used an enzyme‐linked immunosorbent assay to measure in serum the PGRN protein levels of six affected and eight unaffected carriers from within an extended Belgian founder family segregating the null mutation IVS1+5G>C. Further, we measured serum PGRN levels in 2 patients with another null mutation (a Met1 and a frameshift mutation), in 4 patients carrying a predicted pathogenic missense mutation and in 5 patients carrying a benign missense polymorphism, in 9 unaffected noncarrier relatives, and in 22 community controls. Results: Serum PGRN levels were reduced in both affected and unaffected null mutation carriers compared with noncarrier relatives (pexact < 0.0001), and allowed perfect discrimination between carriers and noncarriers (sensitivity: 1.0; 1 − specificity: 0.0). Serum PGRN levels in Cys139Arg and Arg564Cys mutation carriers were significantly lower than in controls, but greater than in null mutation carriers, fitting the hypothesis of partial loss of function caused by these missense mutations. As expected, levels for carriers of benign missense polymorphisms were not significantly different from controls. Interpretation: Our results indicate that the serum PGRN level is a reliable biomarker for diagnosing and early detection of frontotemporal lobar degeneration caused by PGRN null mutations, and provided the first in vivo evidence that at least some missense mutations in PGRN may lead to a (partial) loss of PGRN. Ann Neurol 2009
Url:
DOI: 10.1002/ana.21621
Affiliations:
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d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Neurogenetics, Institute Born‐Bunge</wicri:regionArea><wicri:noRegion>Institute Born‐Bunge</wicri:noRegion></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>University of Antwerp, Antwerpen</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation></author><author><name sortKey="Mattheijssens, Maria" sort="Mattheijssens, Maria" uniqKey="Mattheijssens M" first="Maria" last="Mattheijssens">Maria Mattheijssens</name><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB (Flanders Institute for Biotechnology), University of Antwerp, Antwerpen</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Neurogenetics, Institute Born‐Bunge</wicri:regionArea><wicri:noRegion>Institute Born‐Bunge</wicri:noRegion></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>University of Antwerp, Antwerpen</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation></author><author><name sortKey="Cruts, Marc" sort="Cruts, Marc" uniqKey="Cruts M" first="Marc" last="Cruts">Marc Cruts</name><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB (Flanders Institute for Biotechnology), University of Antwerp, Antwerpen</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Neurogenetics, Institute Born‐Bunge</wicri:regionArea><wicri:noRegion>Institute Born‐Bunge</wicri:noRegion></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>University of Antwerp, Antwerpen</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation></author><author><name sortKey="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Neurology, University Hospital Gasthuisberg</wicri:regionArea><wicri:noRegion>University Hospital Gasthuisberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>University of Leuven, Leuven</wicri:regionArea><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="De Deyn, Peter P" sort="De Deyn, Peter P" uniqKey="De Deyn P" first="Peter P." last="De Deyn">Peter P. De Deyn</name><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>University of Antwerp, Antwerpen</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Neurochemistry and Behavior, Institute Born‐Bunge</wicri:regionArea><wicri:noRegion>Institute Born‐Bunge</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Memory Clinic and Division of Neurology, ZNA Middelheim, Antwerpen</wicri:regionArea><wicri:noRegion>Antwerpen</wicri:noRegion></affiliation></author><author><name sortKey="Robberecht, Wim" sort="Robberecht, Wim" uniqKey="Robberecht W" first="Wim" last="Robberecht">Wim Robberecht</name><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory for Neurobiology and Vesalius Research Center, VIB</wicri:regionArea><wicri:noRegion>VIB</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Neurology, University Hospital Gasthuisberg</wicri:regionArea><wicri:noRegion>University Hospital Gasthuisberg</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>University of Leuven, Leuven</wicri:regionArea><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB (Flanders Institute for Biotechnology), University of Antwerp, Antwerpen</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Neurogenetics, Institute Born‐Bunge</wicri:regionArea><wicri:noRegion>Institute Born‐Bunge</wicri:noRegion></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>University of Antwerp, Antwerpen</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="sub">Official Journal of the American Neurological Association and the Child Neurology Society</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-05">2009-05</date><biblScope unit="volume">65</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="603">603</biblScope><biblScope unit="page" to="609">609</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">B8399E4CB0B3C52969DC2D116DC63E7CA16BBE90</idno><idno type="DOI">10.1002/ana.21621</idno><idno type="ArticleID">ANA21621</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Objective: Mutations that lead to a loss of progranulin (PGRN) explain a considerable portion of the occurrence of frontotemporal lobar degeneration. We tested a biomarker allowing rapid detection of a loss of PGRN. Methods: We used an enzyme‐linked immunosorbent assay to measure in serum the PGRN protein levels of six affected and eight unaffected carriers from within an extended Belgian founder family segregating the null mutation IVS1+5G>C. Further, we measured serum PGRN levels in 2 patients with another null mutation (a Met1 and a frameshift mutation), in 4 patients carrying a predicted pathogenic missense mutation and in 5 patients carrying a benign missense polymorphism, in 9 unaffected noncarrier relatives, and in 22 community controls. Results: Serum PGRN levels were reduced in both affected and unaffected null mutation carriers compared with noncarrier relatives (pexact < 0.0001), and allowed perfect discrimination between carriers and noncarriers (sensitivity: 1.0; 1 − specificity: 0.0). Serum PGRN levels in Cys139Arg and Arg564Cys mutation carriers were significantly lower than in controls, but greater than in null mutation carriers, fitting the hypothesis of partial loss of function caused by these missense mutations. As expected, levels for carriers of benign missense polymorphisms were not significantly different from controls. Interpretation: Our results indicate that the serum PGRN level is a reliable biomarker for diagnosing and early detection of frontotemporal lobar degeneration caused by PGRN null mutations, and provided the first in vivo evidence that at least some missense mutations in PGRN may lead to a (partial) loss of PGRN. Ann Neurol 2009</div></front></TEI><affiliations><list><country><li>Belgique</li></country><region><li>Province d'Anvers</li></region><settlement><li>Anvers</li></settlement><orgName><li>Université d'Anvers</li></orgName></list><tree><country name="Belgique"><region name="Province d'Anvers"><name sortKey="Sleegers, Kristel" sort="Sleegers, Kristel" uniqKey="Sleegers K" first="Kristel" last="Sleegers">Kristel Sleegers</name></region><name sortKey="Brouwers, Nathalie" sort="Brouwers, Nathalie" uniqKey="Brouwers N" first="Nathalie" last="Brouwers">Nathalie Brouwers</name><name sortKey="Brouwers, Nathalie" sort="Brouwers, Nathalie" uniqKey="Brouwers N" first="Nathalie" last="Brouwers">Nathalie Brouwers</name><name sortKey="Brouwers, Nathalie" sort="Brouwers, Nathalie" uniqKey="Brouwers N" first="Nathalie" last="Brouwers">Nathalie Brouwers</name><name sortKey="Cruts, Marc" sort="Cruts, Marc" uniqKey="Cruts M" first="Marc" last="Cruts">Marc Cruts</name><name sortKey="Cruts, Marc" sort="Cruts, Marc" uniqKey="Cruts M" first="Marc" last="Cruts">Marc Cruts</name><name sortKey="Cruts, Marc" sort="Cruts, Marc" uniqKey="Cruts M" first="Marc" last="Cruts">Marc Cruts</name><name sortKey="De Deyn, Peter P" sort="De Deyn, Peter P" uniqKey="De Deyn P" first="Peter P." last="De Deyn">Peter P. De Deyn</name><name sortKey="De Deyn, Peter P" sort="De Deyn, Peter P" uniqKey="De Deyn P" first="Peter P." last="De Deyn">Peter P. De Deyn</name><name sortKey="De Deyn, Peter P" sort="De Deyn, Peter P" uniqKey="De Deyn P" first="Peter P." last="De Deyn">Peter P. De Deyn</name><name sortKey="Engelborghs, Sebastiaan" sort="Engelborghs, Sebastiaan" uniqKey="Engelborghs S" first="Sebastiaan" last="Engelborghs">Sebastiaan Engelborghs</name><name sortKey="Engelborghs, Sebastiaan" sort="Engelborghs, Sebastiaan" uniqKey="Engelborghs S" first="Sebastiaan" last="Engelborghs">Sebastiaan Engelborghs</name><name sortKey="Engelborghs, Sebastiaan" sort="Engelborghs, Sebastiaan" uniqKey="Engelborghs S" first="Sebastiaan" last="Engelborghs">Sebastiaan Engelborghs</name><name sortKey="Gijselinck, Ilse" sort="Gijselinck, Ilse" uniqKey="Gijselinck I" first="Ilse" last="Gijselinck">Ilse Gijselinck</name><name sortKey="Gijselinck, Ilse" sort="Gijselinck, Ilse" uniqKey="Gijselinck I" first="Ilse" last="Gijselinck">Ilse Gijselinck</name><name sortKey="Gijselinck, Ilse" sort="Gijselinck, Ilse" uniqKey="Gijselinck I" first="Ilse" last="Gijselinck">Ilse Gijselinck</name><name sortKey="Mattheijssens, Maria" sort="Mattheijssens, Maria" uniqKey="Mattheijssens M" first="Maria" last="Mattheijssens">Maria Mattheijssens</name><name sortKey="Mattheijssens, Maria" sort="Mattheijssens, Maria" uniqKey="Mattheijssens M" first="Maria" last="Mattheijssens">Maria Mattheijssens</name><name sortKey="Mattheijssens, Maria" sort="Mattheijssens, Maria" uniqKey="Mattheijssens M" first="Maria" last="Mattheijssens">Maria Mattheijssens</name><name sortKey="Peeters, Karin" sort="Peeters, Karin" uniqKey="Peeters K" first="Karin" last="Peeters">Karin Peeters</name><name sortKey="Peeters, Karin" sort="Peeters, Karin" uniqKey="Peeters K" first="Karin" last="Peeters">Karin Peeters</name><name sortKey="Peeters, Karin" sort="Peeters, Karin" uniqKey="Peeters K" first="Karin" last="Peeters">Karin Peeters</name><name sortKey="Robberecht, Wim" sort="Robberecht, Wim" uniqKey="Robberecht W" first="Wim" last="Robberecht">Wim Robberecht</name><name sortKey="Robberecht, Wim" sort="Robberecht, Wim" uniqKey="Robberecht W" first="Wim" last="Robberecht">Wim Robberecht</name><name sortKey="Robberecht, Wim" sort="Robberecht, Wim" uniqKey="Robberecht W" first="Wim" last="Robberecht">Wim Robberecht</name><name sortKey="Sleegers, Kristel" sort="Sleegers, Kristel" uniqKey="Sleegers K" first="Kristel" last="Sleegers">Kristel Sleegers</name><name sortKey="Sleegers, Kristel" sort="Sleegers, Kristel" uniqKey="Sleegers K" first="Kristel" last="Sleegers">Kristel Sleegers</name><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name><name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name><name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name><name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name><name sortKey="Van Der Zee, Julie" sort="Van Der Zee, Julie" uniqKey="Van Der Zee J" first="Julie" last="Van Der Zee">Julie Van Der Zee</name><name sortKey="Van Der Zee, Julie" sort="Van Der Zee, Julie" uniqKey="Van Der Zee J" first="Julie" last="Van Der Zee">Julie Van Der Zee</name><name sortKey="Van Der Zee, Julie" sort="Van Der Zee, Julie" uniqKey="Van Der Zee J" first="Julie" last="Van Der Zee">Julie Van Der Zee</name><name sortKey="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name><name sortKey="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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