Larner AJ, Ray PS, Doran M.
The R269H mutation in presenilin-1 presenting as late-onset autosomal dominant Alzheimer's disease.
J Neurol Sci. 2007 Jan 31;252(2):173-6.
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There is a three-generation history of LOAD in the family reported in this study. Only the proband's DNA was sequenced, and as a result there is no evidence of segregation of disease with the mutation. However, this mutation has been reported in an early-onset AD family in the UK. It would be interesting to know whether the family in this paper is related to the original family but exhibiting a later age of onset. If this were the case, it would greatly strengthen the case for pathogenicity with reduced penetrance. The conclusion that screening autosomal-dominant AD cases with late-onset AD for PS1 mutations is worthwhile.
We first described the PSEN1-R269H mutation in a single case of early-onset AD (Gomez-Isla et al., 1997). There, the R269H PS1 mutation was associated with higher amounts of total cerebral Aβ and Aβ x-42, and increased NFT counts. Like the PSEN2 N141I mutation (Levy-Lahad et al., 1995), the PSEN-R269H mutation now appears to be associated with both early- and late-onset AD. For both mutations, the possibility of genetic modifiers influencing age-dependent penetrance may be worth pursuing.
Gómez-Isla T, Wasco W, Pettingell WP, Gurubhagavatula S, Schmidt SD, Jondro PD, McNamara M, Rodes LA, DiBlasi T, Growdon WB, Seubert P, Schenk D, Growdon JH, Hyman BT, Tanzi RE.
A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes.
Ann Neurol. 1997 Jun;41(6):809-13.
Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K.
Candidate gene for the chromosome 1 familial Alzheimer's disease locus.
Science. 1995 Aug 18;269(5226):973-7.