EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Skibinski, Gaia

Frontotemporal dementia (FTD) is a common cause of early onset progressive dementia. FTD is genetically heterogeneous with loci identified at several genomic regions including chromosome 17 and chromosome 9, An autosomal dominant form of FTD had previously been linked to the pericentromeric region of chromosome 3 (FTD3) in a large Danish family. The dementia starts with subtle personality and behaviour changes. The work presented in this thesis aimed to identify the mutant gene causing FTD3. Haplotype analysis was used to narrow the disease locus to between flanking markers, D3S3581 and D3S3690, which span a physical distance of 15.5Mb. Sequence analysis of candidate genes within the disease haplotype identified a mutation in the 3' acceptor splice site of exon 6 of charged multi vesicular body protein 2B (CHMP2B) that segregated with affected FTD3 family members only. This mutation was shown to disrupt RNA processing of CHMP2B resulting in the formation of two aberrant splice variants: Intron5 and CHMP2B?10. The former was the inclusion of the whole of intron 5 into the mRNA whilst the latter was the loss of 10 base pairs at the start of exon 6. Overexpression of the aberrant CHMP2B isoforms in an in vitro cell model showed disruption of the cellular localisation of CHMP2B and the endosomal pathway. Previous work carried out on Vps2, the yeast ortholog of CHMP2B, identified it as one of four proteins that make up the endosomal sorting complex required for transport III (ESCRTIII) complex. The ESCRTIII complex assembles on the endosomal membrane and functions in the formation of multivesicular bodies (MVBs) and the sorting of proteins for degradation, recycling or storage. The identification of mutations in CHMP2B in FTD adds to the growing body of evidence in the literature that supports endosomal dysfunction as an underlying mechanism of neurodegeneration. The work in this study allows diagnostic testing for FTD3 family members and has provided new clues for the understanding of neurodegeneration in FTD and other neurodegenerative diseases

UCL Discovery

Mutations in the ESCRTIII endosomal complex protein Chmp2b associate with frontotemporal dementia

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Mutations in the ESCRTIII endosomal complex protein CHMP2B associate with frontotemporal dementia

http://discovery.ucl.ac.uk/1446676/1/Whiting.Bryony.Anneke_thesis.pdf

Mutations in the ESCRTIII endosomal complex protein CHMP2B associate with frontotemporal dementia

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UCL Discovery

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