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. 2008 Jan 15;17(2):313-22.
doi: 10.1093/hmg/ddm309. Epub 2007 Oct 22.

CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro

Julie van der Zee  1 , Hazel Urwin, Sebastiaan Engelborghs, Marc Bruyland, Rik Vandenberghe, Bart Dermaut, Tim De Pooter, Karin Peeters, Patrick Santens, Peter P De Deyn, Elizabeth M Fisher, John Collinge, Adrian M Isaacs, Christine Van Broeckhoven
Affiliations

CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro

Julie van der Zee et al. Hum Mol Genet. .

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.

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