CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro.
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.
van der Zee
Julie
J
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
Urwin
Hazel
H
Engelborghs
Sebastiaan
S
Bruyland
Marc
M
Vandenberghe
Rik
R
Dermaut
Bart
B
De Pooter
Tim
T
Peeters
Karin
K
Santens
Patrick
P
De Deyn
Peter P
PP
Fisher
Elizabeth M
EM
Collinge
John
J
Isaacs
Adrian M
AM
Van Broeckhoven
Christine
C
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
C503812:CHMP2B protein, human; D056827:Endosomal Sorting Complexes Required for Transport; D009419:Nerve Tissue Proteins