Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664793 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCT to GTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was detected in a 50-year-old male with a four-year history of progressive memory impairment. He was diagnosed with Alzheimer’s disease based on clinical examination, MRI imaging, and CSF biomarkers, which showed a typical AD pattern (i.e., decreased Aβ42, increased total tau, increased phosphorylated tau). His affected father experienced onset at age 42 and died at 46 with advanced dementia and neuropathology consistent with AD. The patient’s paternal grandmother was also thought to have suffered from dementia in middle age (Luedecke et al., 2014).

In addition to the proband, the mutation was also detected in DNA retrieved from the archived brain of the proband's father. The mutation was absent in the patient’s unaffected mother, and therefore segregates with disease in this family. No other mutations were detected in PSEN1 or PSEN2, or in exons 16 or 17 of APP. According to the algorithm proposed by Guerreiro et al., 2010 the A275V mutation can be classified as definitely pathogenic.

Neuropathology

Neuropathological examination of the proband's father revealed enlarged cerebral ventricles, atrophy of the frontal cortex, and the presence of neurofibrillary tangles and amyloid plaques consistent with a postmortem diagnosis of AD (Luedecke et al., 2014).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it generates less Aβ40 than the wildtype protein, resulting in a slight increase in the Aβ42/Aβ40 ratio (Sun et al., 2017).

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References

Paper Citations

1. Luedecke D, Becktepe JS, Lehmbeck JT, Finckh U, Yamamoto R, Jahn H, Boelmans K. A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease. Neurosci Lett. 2014 Apr 30;566:115-9. Epub 2014 Feb 26 PubMed.
2. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
3. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

Further Reading

No Available Further Reading