Journal Article

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

Julie van der Zee, 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 and Christine Van Broeckhoven

in Human Molecular Genetics

Volume 17, issue 2, pages 313-322
Published in print January 2008 | ISSN: 0964-6906
Published online October 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm309
CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro

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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.

Journal Article.  5551 words.  Illustrated.

Subjects: Genetics and Genomics

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