Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Atypical Dementia
Reference Assembly: GRCh37/hg19
Position: Chr14:73685864 T>A
dbSNP ID: rs63751032
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to CAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was first reported in a French pedigree known as ALZ 161, which included three individuals affected by early onset dementia. Onset ranged from 38 to 42 years of age. Further clinical details were not reported (Raux et al., 2005).

This mutation was also found in an individual with early onset dementia presenting with a complex clinical phenotype, described as variant AD with features resembling frontotemporal dementia as well as dementia with Lewy bodies. The patient first developed symptoms at age 37, starting with depression, anxiety, personality changes, and social inhibition. Visual and auditory hallucinations followed, along with progressive cognitive deterioration affecting memory, attention, and executive function. She later developed extrapyramidal signs, notably bradykinesia and rigidity. At the time of the report, the patient was 41 years of age and required extensive medical care. Her family history was unknown and segregation with disease could not be analyzed. No mutations were detected in PSEN2 (exons 4, 5, and 7), MAPT, or APP. The L424H mutation was absent from 100 age-matched controls as well as 50 individuals with early onset AD and 100 with late-onset AD (Zekanowski et al., 2006). It was also absent from the gnomAD variant database (gnomAD v2.1.1, August 2021).

Neuropathology

Unknown. MRI showed generalized cerebral atrophy. SPECT imaging showed diffuse cerebral hypoperfusion (Zekanowski et al., 2006).

Biological Effect

A study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples. This variant also increased Aβ43 levels by approximately fourfold compared with wildtype PSEN1.

In silico modeling suggested little movement of the surrounding amino acids in mutant PSEN1 compared with the wild-type protein (Zekanowski et al., 2006). However, 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.

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: 01 Dec 2022

Comments

- Takaomi Saido
  RIKEN Center for Brain Science
- Posted: 25 Mar 2006
- Paper: Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment.
This study and others imply that some of the PS mutations may induce pathological gain-of-function phenotypes.

View all comments by Takaomi Saido

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References

News Citations

Paper Citations

Raux G, Guyant-Maréchal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D. Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
Zekanowski C, Golan MP, Krzyśko KA, Lipczyńska-Łojkowska W, Filipek S, Kowalska A, Rossa G, Pepłońska B, Styczyńska M, Maruszak A, Religa D, Wender M, Kulczycki J, Barcikowska M, Kuźnicki J. Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. Exp Neurol. 2006 Jul;200(1):82-8. PubMed.
Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; 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 L424H

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