Human Molecular Genetics Advance Access originally published online on October 22, 2007
Human Molecular Genetics 2008 17(2):313-322; doi:10.1093/hmg/ddm309
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CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro
1 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB 2 Laboratory of Neurogenetics 3 Laboratory of Neurochemistry and Behavior, Institute Born-Bunge 4 University of Antwerp 5 Memory Clinic, Department of Neurology, ZNA Middelheim General Hospital, Antwerpen, Belgium 6 MRC Prion Unit 7 Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK 8 Department of Neurology, AZ Zusters van Barmhartigheid, Ronse, Belgium 9 Department of Neurology, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium 10 Department of Neurology, University Hospital Ghent, University of Ghent, Gent, Belgium
* To whom correspondence should be addressed at: Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, VIB University of Antwerp—CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium. Tel: +32 32651001; Fax: +32 32651012; Email: christine.vanbroeckhoven{at}ua.ac.be
Received July 11, 2007; Accepted October 16, 2007
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.