Stockholm. Perhaps the hottest buzz at the 8th International Conference on Alzheimer’s Disease and Related Disorders here in the City of Water revolved around a candidate gene rumored to have finally been found on chromosome 10, the genome area that several genetics labs have scoured ever since reports about a probable linkage to late-onset AD (LOAD) appeared about it in 2000. This morning, Nilufer Ertekin-Taner in Steven Younkin’s lab presented unpublished data suggesting that α-T catenin was at least one of the AD-linked genes in this region. The work is based on the analysis of 10 extended families of LOAD patients who had extremely high plasma Aβ42 levels.
α-T catenin is an effective binding partner of β-catenin, which is known to interact with presenilin-1, Ertekin-Taner said. It also resides at the 80 centimorgan address that the group had previously found to be most strongly linked to LOAD.
The Younkin team then looked for single nucleotide polymorphisms (SNPs) and found one, the T allele of 4360, that appeared to be associated with elevated Aβ42 levels. The 4360 SNP resides in an intron, raising the question how it could possibly affect Aβ42 levels. In her presentation, Ertekin-Taner said her data led her to suggest the working hypothesis that SNP causes a splicing change that leads to the translation of a truncated, dysfunctional protein.
The researchers also studied a large case-control series to see if they could find associations with the 4360 SNP, and apparently it came up positive only when linked to ApoE. As is usually the case when a research team proposes a new gene for AD, this work will surely be hotly debated while the other laboratories in the field try to reproduce the data. Ertekin-Taner said that she suspects the relevant region on chromosome 10 to contain additional AD genes, particularly upstream of α-T catenin.--Gabrielle Strobel.
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- Ertekin-Taner N, Ronald J, Asahara H, Younkin L, Hella M, Jain S, Gnida E, Younkin S, Fadale D, Ohyagi Y, Singleton A, Scanlin L, de Andrade M, Petersen R, Graff-Radford N, Hutton M. Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Hum Mol Genet. 2003 Dec 1;12(23):3133-43. PubMed.