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. Epub 2006 Dec 26
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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 U.K. 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.
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