Mutations

APP V717I (London)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.275341G>A
Genomic Mutation Name (NT1): g.284037G>A
dbSNP ID: rs63750264
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Point, Missense
Codon Change: GTC to ATC
Research Models: 11

Findings

This mutation was one of the first described in APP. It was originally identified in 1991 in an English kindred with early onset Alzheimer's disease, identified as family F23. The average age of onset in this family was 57 ± 5 years and the diagnosis was confirmed by autopsy. In the same publication,  an American family known as family 372 was also reported to carry this mutation (Goate et al., 1991; Hardy et al., 1991).

This mutation appears to be one of the most common APP mutations worldwide, with approximately 30 families identified from various countries of origin, including the United States, England, Japan, Thailand, Germany, France, Italy, Australia, Belgium, Iran, and China.

Neuropathology

The neuropathological phenotype associated with the London mutation is variable. For the original English family, neuropathological findings were available for one individual who had severe AD pathology along with mild amyloid angiopathy and cortical and brainstem Lewy bodies. In the American family, numerous β-amyloid plaques and neurofibrillary tangles were observed ,but no amyoid angiopathy or Lewy bodies (Hardy et al., 1991).

Biological Effect

The effects of this mutation have been well-characterized. In many cells types, including primary mouse neurons, this mutation increases the Aβ42/Aβ40 ratio by increasing Aβ42 levels with little effect on Aβ40 levels (e.g. Eckman et al., 1997; De Jonghe et al., 2001; Theuns et al., 2006; Herl et al., 2009). This finding has also been observed in neurons generated from inducible pluripotent stem cells (iPSCs) derived from the skin fibroblasts of mutation carriers. The transcriptions factors Oct4, SOX2, cMYC, and KLF4 created the iPSCs, which were then directed to differentiate into forebrain neurons. In addition to increasing Aβ42 levels, the V717I mutation in these neurons altered APP subcellular localization, Aβ38 and sAPPβ generation, and tau expression and phosphorylation (Muratore et al., 2014).

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References

Paper Citations

  1. . Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991 Feb 21;349(6311):704-6. PubMed.
  2. Molecular classification of Alzheimer's disease. Lancet. 1991 Jun 1;337(8753):1342-3. PubMed.
  3. . A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). Hum Mol Genet. 1997 Nov;6(12):2087-9. PubMed.
  4. . Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability. Hum Mol Genet. 2001 Aug 1;10(16):1665-71. PubMed.
  5. . Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment. Hum Mutat. 2006 Sep;27(9):888-96. PubMed.
  6. . Mutations in amyloid precursor protein affect its interactions with presenilin/gamma-secretase. Mol Cell Neurosci. 2009 Jun;41(2):166-74. Epub 2009 Mar 9 PubMed.
  7. . The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet. 2014 Jul 1;23(13):3523-36. Epub 2014 Feb 12 PubMed.

Further Reading

Papers

  1. . The 717Val----Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups. Biochem Biophys Res Commun. 1991 Aug 15;178(3):1141-6. PubMed.
  2. . Mis-sense mutation Val----Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease. Lancet. 1991 Apr 20;337(8747):978-9. PubMed.
  3. . Screening for mutations in the open reading frame and promoter of the beta-amyloid precursor protein gene in familial Alzheimer's disease: identification of a further family with APP717 Val-->Ile. Hum Mol Genet. 1992 Jun;1(3):165-8. PubMed.
  4. . APP717 and Alzheimer's disease in Italy. Nat Genet. 1993 May;4(1):10. PubMed.
  5. . Screening of the mis-sense mutation producing the 717Val-->Ile substitution in the amyloid precursor protein in Japanese familial and sporadic Alzheimer's disease. J Neurol Sci. 1993 Jul;117(1-2):12-5. PubMed.
  6. . Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer's disease. Ann Neurol. 1995 Jul;38(1):124-7. PubMed.
  7. . A mutation in codon 717 of the amyloid precursor protein gene in an Australian family with Alzheimer's disease. Neurosci Lett. 1995 Oct 27;199(3):183-6. PubMed.
  8. . Japanese siblings with missense mutation (717Val --> Ile) in amyloid precursor protein of early-onset Alzheimer's disease. Neurology. 1996 Jun;46(6):1721-3. PubMed.
  9. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  10. . No founder effect in three novel Alzheimer's disease families with APP 717 Val-->Ile mutation. Clerget-darpoux. French Alzheimer's Disease Study Group. J Med Genet. 1996 Aug;33(8):661-4. PubMed.
  11. . High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000 Jan;66(1):110-7. PubMed.
  12. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  13. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
  14. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
  15. . Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease. Brain. 2006 Nov;129(Pt 11):2984-91. PubMed.
  16. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.
  17. . Mutational analysis in early-onset familial Alzheimer's disease in Mainland China. Neurobiol Aging. 2014 Aug;35(8):1957.e1-6. Epub 2014 Feb 20 PubMed.
  18. Molecular classification of Alzheimer's disease. Lancet. 1991 Jun 1;337(8753):1342-3. PubMed.
  19. . Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability. Hum Mol Genet. 2001 Aug 1;10(16):1665-71. PubMed.
  20. . Early-Onset Alzheimer's Disease in Two Iranian Families: A Genetic Study. Dement Geriatr Cogn Disord. 2014 Aug 14;38(5-6):330-336. PubMed.

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Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991 Feb 21;349(6311):704-6. PubMed.

Other mutations at this position

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