Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr21:27264096 G>T
dbSNP ID: rs63750264
Genomic Region: Exon 17
Mutation Type: Point, Missense
Codon Change: GTC to TTC
Research Models: 10
This mutation was originally found in three generations of a family of Romanian origin by a research group at Indiana University School of Medicine. The average age of onset was 45.7 years (Murrell et al., 1991). It was later found in an Austrian individual (known as P. 31) of Romanian ancestry with a disease onset of approximately 38 years, as well as in two German siblings (known as P.32 and P.65) with onset at 40 and 37 years, respectively (Finckh et al., 2005).
Studies in cell culture have shown that the V717F mutation generally increases the Aβ42/Aβ40 ratio in conditioned media. COS cells expressing mutant APP695 secreted approximately equal levels of Aβ40 and Aβ42/43. This represented an increase in the Aβ42(43)/Aβ40 ratio, as cells expressing wild-type APP secreted predominantly Aβ40 (Tamaoka et al., 1994). A similar result was reported in M17 human neuroblastoma cells. Compared with cells expressing wild-type APP, cells transfected with APP V717F secreted relatively more Aβ42/43 than Aβ40 (Suzuki et al., 1994). A study focused primarily on the E693G “Arctic” APP mutation showed that HEK293 cells transfected with APP V717F produced an elevated Aβ42/Aβ40 ratio due to both an increase in secreted Aβ42 and a decrease in Aβ40 (Nilsberth et al., 2001).
- Murrell J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science. 1991 Oct 4;254(5028):97-9. PubMed.
- Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, Kapaki E, Davaki P, Lamszus K, Stavrou D, Gal A. Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
- Tamaoka A, Odaka A, Ishibashi Y, Usami M, Sahara N, Suzuki N, Nukina N, Mizusawa H, Shoji S, Kanazawa I. APP717 missense mutation affects the ratio of amyloid beta protein species (A beta 1-42/43 and a beta 1-40) in familial Alzheimer's disease brain. J Biol Chem. 1994 Dec 30;269(52):32721-4. PubMed.
- Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L, Eckman C, Golde TE, Younkin SG. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science. 1994 May 27;264(5163):1336-40. PubMed.
- Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Näslund J, Lannfelt L. The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001 Sep;4(9):887-93. PubMed.