Mutations

APP V715M (French)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.275335G>A
Genomic Mutation Name (NT1): g.284031G>A
dbSNP ID: rs63750734
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Point, Missense
Codon Change: GTG to ATG

Findings

This mutation was first reported in a two-generation family of Italian origin with three affected siblings fullfilling NINCDS-ADRDA criteria for probable AD. Affected individuals displayed memory problems with an age of onset ranging from 41 to 60 years. Other clinical features included apraxia, aphasia, and agnosia (Ancolio et al., 1999). 

This mutation was also found in one Korean individual with early onset Alzheimer's disease and a family history of dementia. Age of onset in this individual was 41 years, beginning with progressive memory and visuospatial impairment associated with apraxia, bradykinesia, and epilepsy (Park et al., 2008).

Neuropathology

Progressive cortical atrophy was seen by MRI and hypometabolism by PET in one affected individual (Park et al., 2008).

Biological Effect

This mutation is unusual in that it was found to reduce total Aβ production. In HEK-293 cells, this mutation caused a significant reduction in Aβ40 with no change in Aβ42. There was a marked increase in N-terminally truncated Aβ42 (Aβx-42) but N-terminally truncated Aβ40 (Aβx-40) was not affected. An increase in secreted APPα was also observed (Ancolio et al., 1999).

However, a study using NMR spectroscopy found that this mutation, along with V715A at the same position, alters the structure and dynamics of the transmembrane domain of APP, making it more accesible to γ-secretase for ε-cleavage, and consequently shifting production toward Aβ42 (Chen et al., 2014).

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References

Mutations Citations

  1. APP V715A (German)

Paper Citations

  1. . Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4119-24. PubMed.
  2. . Identification of PSEN1 and APP gene mutations in Korean patients with early-onset Alzheimer's disease. J Korean Med Sci. 2008 Apr;23(2):213-7. PubMed.
  3. . Familial Alzheimer's mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site. Nat Commun. 2014;5:3037. PubMed.

Further Reading

Papers

  1. . Blepharospasm in familial AD secondary to an APP mutation (V715M). Acta Neurol Belg. 2014 Mar 28; PubMed.
  2. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  3. . 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.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4119-24. PubMed.

Other mutations at this position

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