Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173630 A>G
Position: (GRCh37/hg19):Chr14:73640338 A>G
dbSNP ID: rs63750353
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAT to GAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in a Mexican-American family with a history of early onset dementia spanning at least four generations (Crook et al., 1997). The pedigree contained nine affected individuals and revealed a pattern consistent with autosomal dominant inheritance.

The proband had a history of developmental delay. She was evaluated for symptoms of apathy and depression in her early 30s. Cognitive changes were evident at age 35 and myoclonic jerking began soon after. Ages of onset were known for four additional family members: 34, 34, 36, and 37 years.

Genetic testing was performed in two affected siblings and one unaffected sibling and found to segregate with disease. The N135D mutation in PSEN1 corresponds to the Volga German mutation in PSEN2 (N141I), a highly pathogenic mutation that is the most common PSEN2 mutation worldwide.

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

Neuropathology

Biopsy of the proband’s frontal lobe showed mild loss of neurons and secondary gliosis with multiple neuritic plaques and abundant neurofibrillary tangles. It was noted that nearly every neuron contained a tangle. Microglia were increased diffusely and particularly in association with neuritic plaques (Crook et al., 1997).

Biological Effect

A study that examined the full set of Aβ peptides generated by this variant transfected into human embryonic kidney cells lacking endogenous PSEN1 and PSEN2, revealed an increase in toxic Aβ43 and a decrease in Aβ37, an indicator of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Importantly, like known pathogenic mutations, the variant decreased the Aβ37/Aβ42 ratio, a measurement that outperformed the Aβ42/Aβ40 ratio as a biomarker for distinguishing between control and AD samples.

Consistently, earlier studies had shown that, when expressed in CHO cells stably transfected with human APP751, the N135D mutation increased intracellular Aβ42 levels and decreased intracellular Aβ40 levels. Similar effects on secreted Aβ40 and Aβ42 were measured in conditioned media (Qi et al., 2003). However, an in vitro assay using purified proteins to test the mutant's ability to cleave the APP-C99 substrate indicated a decreases in both peptides compared with wild-type PSEN1, but Aβ40 production was more dramatically affected, resulting in an apporoximately 10-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017).

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).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP1-M

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. N135D: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 21 Apr 2022

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References

News Citations

Paper Citations

Crook R, Ellis R, Shanks M, Thal LJ, Perez-Tur J, Baker M, Hutton M, Haltia T, Hardy J, Galasko D. Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation. Ann Neurol. 1997 Jul;42(1):124-8. PubMed.
Qi Y, Morishima-Kawashima M, Sato T, Mitsumori R, Ihara Y. Distinct mechanisms by mutant presenilin 1 and 2 leading to increased intracellular levels of amyloid beta-protein 42 in Chinese hamster ovary cells. Biochemistry. 2003 Feb 4;42(4):1042-52. PubMed.
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.
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.

Mutations

PSEN1 N135D

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