Mutations

PSEN1 L174M

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Reference Assembly: GRCh37/hg19
Position: Chr14:73653600 C>A
dbSNP ID: rs63751144
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTG to ATG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation has been reported in a Cuban and an Italian family. The Cuban family included 281 individuals spanning six generations, with 22 reported patients, 18 for whom there was a disease description (Bertoli Avella et al., 2002). The proband descended from a Spanish founder. Mean age at onset was 59 and mean duration nine years. Memory impairment was the main symptom, with psychiatric symptoms (aggression, restlessness, anxiety, and depression) present in several cases. Four patients, all carrying the APOE ε4 allele, had ischemic episodes.

Segregation of the disease in this Cuban family was consistent with an autosomal dominant mode of inheritance with high penetrance. The mutation was present in all examined patients and in all relatives carrying the disease haplotype, although they had yet to reach the mean age at onset. The underlying C→A change was absent from 80 control chromosomes from the same population, as well as from 96 chromosomes from unaffected relatives that did not carry the disease haplotype.

The proband of the Italian family reported mild memory impairment at age 54 which progressed to severe impairment by age 58 (Tedde et al., 2003). The father and brother had similar symptoms and both died at age 64.

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

Neuropathology

Neuropathological examination of one individual from the Cuban family revealed neuronal loss, amyloid plaques, and neurofibrillary tangles consistent with Alzheimer’s disease. Cerebral amyloid angiopathy was also observed.

Biological Effect

An in vitro assay using purified proteins to test the ability of L174M PSEN1 to cleave the APP-C99 substrate revealed this mutation generates less Aβ40 than the wildtype protein, resulting in an elevated Aβ42/Aβ40 ratio (Sun et al., 2017). L174 M is a conservative amino acid substitution, but this position is highly conserved among different species and between homologous proteins, including presenilin 2 and sel-12. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggests mutations in L174 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).

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-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. L174M: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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.

PP1-S

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. L174M: At least one family with >=3 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: 22 Feb 2022

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References

News Citations

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

Paper Citations

  1. . A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease. Neurogenetics. 2002 Oct;4(2):97-104. PubMed.
  2. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.
  3. . 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.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  5. . 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

Protein Diagram

Primary Papers

  1. . A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease. Neurogenetics. 2002 Oct;4(2):97-104. PubMed.
  2. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.

Other mutations at this position

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