CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro
Identifieur interne : 001346 ( Main/Exploration ); précédent : 001345; suivant : 001347CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro
Auteurs : Julie Van Der Zee [Belgique] ; Hazel Urwin ; Sebastiaan Engelborghs [Belgique] ; Marc Bruyland [Belgique] ; Rik Vandenberghe [Belgique] ; Bart Dermaut [Belgique] ; Tim De Pooter [Belgique] ; Karin Peeters [Belgique] ; Patrick Santens [Belgique] ; Peter P. De Deyn [Belgique] ; Elizabeth M. Fisher [Royaume-Uni] ; John Collinge ; Adrian M. Isaacs ; Christine Van Broeckhoven [Belgique]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2008-01-15.
Abstract
The charged multivesicular body protein 2B gene (CHMP2B) was recently associated with frontotemporal lobar degeneration (FTLD) linked to chromosome 3 in a Danish FTLD family (FTD-3). In this family, a mutation in the acceptor splice site of exon 6 produced two aberrant transcripts predicting two C-truncated CHMP2B proteins due to a read through of intron 5 (p.Met178ValfsX2) and a cryptic splicing event within exon 6 (p.Met178LeufsX30). Extensive mutation analysis of CHMP2B in Belgian patients (N 146) identified one nonsense mutation in exon 5 (c.493C>T) in a familial FTLD patient, predicting a C-truncated protein p.Gln165X analogous to the Danish mutant proteins. Overexpression of Belgian p.Gln165X in human neuroblastoma SK-N-SH cells showed the formation of large, aberrant endosomal structures that were highly similar to those observed for Danish p.Met178ValfsX2. Together, these data suggest that C-truncating mutations in CHMP2B might underlie the pathogenic mechanism in FTLD by disturbing endosome function. We also describe a missense mutation in exon 5 of CHMP2B (p.Asn143Ser) in a familial patient with cortical basal degeneration. However, the pathogenic character of this mutation remains elusive.
Url:
DOI: 10.1093/hmg/ddm309
Affiliations:
- Belgique, Royaume-Uni
- Angleterre, Grand Londres, Province d'Anvers
- Anvers, Londres
- University College de Londres, Université d'Anvers
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Isaacs</name><affiliation><wicri:noCountry code="no comma">MRC Prion Unit</wicri:noCountry></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></affiliation><affiliation></affiliation><affiliation wicri:level="4"><country>Belgique</country><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName><orgName type="university">Université d'Anvers</orgName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Belgique</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2008-01-15">2008-01-15</date><biblScope unit="volume">17</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="313">313</biblScope><biblScope unit="page" to="322">322</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">D3956E5DC59E5ABD8D91029F4F5BA33C331F6B94</idno><idno type="DOI">10.1093/hmg/ddm309</idno><idno type="ArticleID">ddm309</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">The charged multivesicular body protein 2B gene (CHMP2B) was recently associated with frontotemporal lobar degeneration (FTLD) linked to chromosome 3 in a Danish FTLD family (FTD-3). In this family, a mutation in the acceptor splice site of exon 6 produced two aberrant transcripts predicting two C-truncated CHMP2B proteins due to a read through of intron 5 (p.Met178ValfsX2) and a cryptic splicing event within exon 6 (p.Met178LeufsX30). Extensive mutation analysis of CHMP2B in Belgian patients (N 146) identified one nonsense mutation in exon 5 (c.493C>T) in a familial FTLD patient, predicting a C-truncated protein p.Gln165X analogous to the Danish mutant proteins. Overexpression of Belgian p.Gln165X in human neuroblastoma SK-N-SH cells showed the formation of large, aberrant endosomal structures that were highly similar to those observed for Danish p.Met178ValfsX2. Together, these data suggest that C-truncating mutations in CHMP2B might underlie the pathogenic mechanism in FTLD by disturbing endosome function. We also describe a missense mutation in exon 5 of CHMP2B (p.Asn143Ser) in a familial patient with cortical basal degeneration. However, the pathogenic character of this mutation remains elusive.</div></front></TEI><affiliations><list><country><li>Belgique</li><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Grand Londres</li><li>Province d'Anvers</li></region><settlement><li>Anvers</li><li>Londres</li></settlement><orgName><li>University College de Londres</li><li>Université d'Anvers</li></orgName></list><tree><noCountry><name sortKey="Collinge, John" sort="Collinge, John" uniqKey="Collinge J" first="John" last="Collinge">John Collinge</name><name sortKey="Isaacs, Adrian M" sort="Isaacs, Adrian M" uniqKey="Isaacs A" first="Adrian M." last="Isaacs">Adrian M. Isaacs</name><name sortKey="Urwin, Hazel" sort="Urwin, Hazel" uniqKey="Urwin H" first="Hazel" last="Urwin">Hazel Urwin</name></noCountry><country name="Belgique"><region name="Province d'Anvers"><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></region><name sortKey="Bruyland, Marc" sort="Bruyland, Marc" uniqKey="Bruyland M" first="Marc" last="Bruyland">Marc Bruyland</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 Pooter, Tim" sort="De Pooter, Tim" uniqKey="De Pooter T" first="Tim" last="De Pooter">Tim De Pooter</name><name sortKey="Dermaut, Bart" sort="Dermaut, Bart" uniqKey="Dermaut B" first="Bart" last="Dermaut">Bart Dermaut</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="Peeters, Karin" sort="Peeters, Karin" uniqKey="Peeters K" first="Karin" last="Peeters">Karin Peeters</name><name sortKey="Santens, Patrick" sort="Santens, Patrick" uniqKey="Santens P" first="Patrick" last="Santens">Patrick Santens</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="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Fisher, Elizabeth M" sort="Fisher, Elizabeth M" uniqKey="Fisher E" first="Elizabeth M." last="Fisher">Elizabeth M. Fisher</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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