Frontotemporal dementia caused by CHMP2B mutations

Abstract

CHMP2B mutations are a rare cause of autosomal dominant frontotemporal dementia (FTD). The best studied example is frontotemporal dementia linked to chromosome 3 (FTD-3) which occurs in a large Danish family, with a further CHMP2B mutation identified in an unrelated Belgian familial FTD patient. These mutations lead to C-terminal truncations of the CHMP2B protein and we will review recent advances in our understanding of the molecular effects of these mutant truncated proteins on vesicular fusion events within the endosome-lysosome and autophagy degradation pathways. We will also review the clinical features of FTD caused by CHMP2B truncation mutations as well as new brain imaging and neuropathological findings. Finally, we collate the current data on CHMP2B missense mutations, which have been reported in FTD and motor neuron disease.

Fig. (1)

Multiple alignment of CHMP2B proteins. Wildtype CHMP2B and C-terminal truncations CHMP2B^Intron5, CHMP2B^Delta10 and CHMP2B^Q165X were aligned with CHMP2B homologues from other species. The novel C-termini of CHMP2B^Intron5 and CHMP2B^Delta10 are highlighted in yellow. CHMP2B missense mutations identified in FTD-MND spectrum disorders are arrowed.

Fig. (2)

Representative brain scans in FTD-3 patients. Upper row: structural scans in FTD-3 with MRI for patients A and B, and a CT-scan for patient C. Lower row shows cerebral blood flow as measured by with H₂¹⁵O -PET scanning for the same 3 patients.