Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659429 G>T
dbSNP ID: rs63750053
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGA to GTA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was among the first PSEN1 mutations identified. It was found in a large German pedigree, known as family L (Poorkaj et al., 1998). This family included at least 19 family members affected by early onset Alzheimer’s disease. Eight affected family members were confirmed to carry the mutation, strongly suggesting pathogenicity. The average age of onset in this family was 41.3 ± 4.5 years of age.  Disease in family L was characterized by onset of dementia before the age of 50, progressive aphasia, early myoclonus and generalized seizures, and paratonia (involuntary resistance to passive movement) (Lampe et al., 1994). 

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

The diagnosis of AD was confirmed in at least nine mutation carriers from the L family. Neuropathological findings included cortical atrophy, extensive amyloid plaques and neurofibrillary tangles, and prominent amyloid angiopathy (Lampe et al., 1994). A subsequent study reported a few differences with sporadic AD (Gómez-Isla et al., 1999). In particular, the percentage of the superior temporal sulcus region covered by plaques containing Aβ42/Aβ43 was found to be elevated, resulting in a lower ratio of Aβ40 to Aβ42/Aβ43, compared with average measurements of 51 cases of sporadic AD. Also, neurofibrillary tangle formation and neuronal loss were accelerated compared to sporadic AD.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it abrogates Aβ40 production and drastically reduces Aβ42 production (Sun et al., 2017). In addition, it causes incomplete endoproteolytic processing of PSEN1.

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggests mutations in G209 could alter the protein's local conformation and affect the positioning of residues that directly contribute to substrate binding (Zhou et al., 2019; Jan 2019 news).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

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References

News Citations

1. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Poorkaj P, Sharma V, Anderson L, Nemens E, Alonso ME, Orr H, White J, Heston L, Bird TD, Schellenberg GD. Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PubMed.
2. Lampe TH, Bird TD, Nochlin D, Nemens E, Risse SC, Sumi SM, Koerker R, Leaird B, Wier M, Raskind MA. Phenotype of chromosome 14-linked familial Alzheimer's disease in a large kindred. Ann Neurol. 1994 Sep;36(3):368-78. PubMed.
3. Gómez-Isla T, Growdon WB, McNamara MJ, Nochlin D, Bird TD, Arango JC, Lopera F, Kosik KS, Lantos PL, Cairns NJ, Hyman BT. The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors. Brain. 1999 Sep;122 ( Pt 9):1709-19. PubMed.
4. 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.
5. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
6. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading