Sequence analysis of all identified open reading frames on the frontal temporal dementia haplotype on chromosome 3...

A segregating splice site mutation in the CHMP2B gene has been shown in the single Danish family which has been reported to show linkage between dementia and chromosome 3 markers. Despite extensive analysis, no other segregating mutations have been found in other kindreds, although some point variants have been found both in sporadic cases and in controls. We recently found a premature stop codon in a person without dementia and this led us to investigate whether the splice site mutation in the Danish kindred did not explain the disease, but rather was hitchhiking on the segregating disease haplotype. We determined to test this possibility by sequencing every other gene on the haplotype in a case from the kindred. We did not find any other unique variants. The implications of these findings for the likely mode of pathogenesis of frontal temporal dementia are discussed.