Abstract
We have previously reported a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). Here we identify a mutation in CHMP2B, encoding a component of the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of this family. We also describe an additional missense mutation in an unrelated individual with FTD. Aberration in the endosomal ESCRTIII complex may result in FTD and neurodegenerative disease.
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Acknowledgements
We thank all members of the Danish family for their support of this research; J. Hardy for his early contribution to research on this kindred; G. Schiavo, G. Banting, J. Linehan, C. Powel, P. Jat, A. Clarke and E. Englund for their assistance with these studies; and R. Young for graphics. This work was funded by the UK Medical Research Council.
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Supplementary information
Supplementary Fig. 1
The Danish pedigree showing generations 1 to 3. (PDF 337 kb)
Supplementary Fig. 2
Inheritance of the disease haplotype in the Danish pedigree in branches taken from generations 1 to 3. (PDF 64 kb)
Supplementary Fig. 3
Electropherograms of the mutations identified in CHMP2b. (PDF 327 kb)
Supplementary Fig. 4
Multiple protein alignment of human CHMP2b, mutant isoforms and orthologs. (PDF 128 kb)
Supplementary Fig. 5
Overexpression of CHMP2bΔ10 displays an aberrant phenotype in undifferentiated PC12 cells. (PDF 393 kb)
Supplementary Table 1
Primer sequences for CHMP2b. (PDF 27 kb)
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Skibinski, G., Parkinson, N., Brown, J. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet 37, 806–808 (2005). https://doi.org/10.1038/ng1609
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DOI: https://doi.org/10.1038/ng1609
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