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

Julie van der Zee1, Hazel Urwin, Sebastiaan Engelborghs

  • 1Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.

Human Molecular Genetics
|October 25, 2007
PubMed

Insights

C-truncating mutations in the charged multivesicular body protein 2B gene (CHMP2B) are linked to frontotemporal lobar degeneration (FTLD). These mutations disrupt endosome function, suggesting a pathogenic mechanism for FTLD.

Area of Science:

  • Genetics
  • Neuroscience
  • Cell Biology

Background:

  • The charged multivesicular body protein 2B (CHMP2B) gene has been linked to frontotemporal lobar degeneration (FTLD).
  • A Danish FTLD family (FTD-3) exhibited mutations in CHMP2B, leading to C-truncated proteins and aberrant endosomal structures.

Purpose of the Study:

  • To investigate the role of CHMP2B mutations in frontotemporal lobar degeneration (FTLD).
  • To analyze CHMP2B mutation carriers in Belgian FTLD patients and characterize the functional impact of identified mutations.

Main Methods:

  • Mutation analysis of the CHMP2B gene in 146 Belgian FTLD patients.
  • In vitro overexpression of a novel CHMP2B mutant protein (p.Gln165X) in human neuroblastoma SK-N-SH cells.
  • Microscopic analysis of endosomal structures in cells expressing mutant CHMP2B.

Main Results:

  • A nonsense mutation (c.493C>T) in CHMP2B exon 5 was identified in a familial FTLD patient, predicting a C-truncated protein (p.Gln165X).
  • Overexpression of p.Gln165X induced large, aberrant endosomal structures similar to those caused by Danish CHMP2B mutants.
  • A missense mutation (p.Asn143Ser) was found in a familial patient with cortical basal degeneration, but its pathogenicity is undetermined.

Conclusions:

  • C-truncating CHMP2B mutations may cause FTLD by disrupting endosome function.
  • The findings support CHMP2B as a potential FTLD-associated gene.
  • Further research is needed to elucidate the pathogenicity of the identified missense mutation.

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