Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73637755 T>A
dbSNP ID: rs63751399
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTA to CAA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation, located in the first hydrophilic loop of the presenilin-1 protein, was detected in a Greek patient identified as p.62. She experienced symptom onset at age 33 and died three years later. Prominent symptoms included rapidly progressing dementia, drop attacks, myoclonic seizures, and bilateral spasticity. The patient had a family history of very early onset dementia. The patient’s brother and mother died at ages 35 and 36, respectively, and the family indicated that her maternal grandfather and uncle had had similar disease courses (Finckh et al., 2005).

Neuropathology

Autopsy confirmed the diagnosis of Alzheimer’s disease, reporting neuritic plaques (Braak stage C), neurofibrillary tangles (stage VI), and severe amyloid angiopathy (Finckh et al., 2005).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased Aβ40 production resulting in an approximately 5-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017).

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References

Paper Citations

1. 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.
2. 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

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database