title: CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro.
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.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.forename: Hazel
authors.initials: H
authors.lastname: Urwin
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Marc
authors.initials: M
authors.lastname: Bruyland
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.forename: Bart
authors.initials: B
authors.lastname: Dermaut
authors.forename: Tim
authors.initials: T
authors.lastname: De Pooter
authors.forename: Karin
authors.initials: K
authors.lastname: Peeters
authors.forename: Patrick
authors.initials: P
authors.lastname: Santens
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Fisher
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Isaacs
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D010375:Pedigree; D014162:Transfection
chemical_list: C503812:CHMP2B protein, human; D056827:Endosomal Sorting Complexes Required for Transport; D009419:Nerve Tissue Proteins