Mutations

PSEN1 L173F (G>C)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653599 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTG to TTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was detected in two siblings from a family affected by early onset Alzheimer's disease (Kasuga et al., 2009). The reported pedigree shows six affected individuals over three generations. The proband and her affected sister were heterozygous carriers, suggesting segregation with disease. In this family, depression and psychiatric symptoms preceded cognitive decline. The proband was treated for depression at age 29. By age 48 she had developed personality changes and visual and auditory hallucinations. She also developed parkinsonian symptoms, including rigidity and postural instability. Her sister experienced a similar disease course, starting with depression and bipolar symptoms as an adolescent. By age 40 she had developed cognitive decline as well as parkinsonism.

The variant was also reported in two Chinese families with familial Alzheimer's disease (Jia et al., 2020). One family had six affected members, spanning two generations, including two affected carriers and one unaffected non-carrier who was 52 years old, past the family's mean age at onset of 42. The two carriers were APOE3 homozygotes. The other family included four affected members, spanning two generations. The variant was identified in three of the affected carriers. Mean age at onset in this family was 39. Of note, the proband's APOE genotype was E4/E4.

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

Neuropathology

Unknown. MRI in both sisters showed atrophy of the medial temporal lobe. SPECT showed hypoperfusion of the posterior cingulate gyri and other cortical areas.

Biological Effect

N2a cells transfected with mutant PSEN1 secreted significantly more Aβ42 than cells expressing wild-type PSEN1. The Aβ42:Aβ40 ratio was also increased (Kasuga et al., 2009). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, PANTHER, Mutpred2, and Reve in the VarCards database) predicted this variant is damaging (Jia et al., 2020Xiao et al., 2021). Jia and colleageues reported a PHRED-CADD score of 24.3.

Last Updated: 30 Aug 2021

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

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

Paper Citations

  1. . Depression and psychiatric symptoms preceding onset of dementia in a family with early-onset Alzheimer disease with a novel PSEN1 mutation. J Neurol. 2009 Aug;256(8):1351-3. PubMed.
  2. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  4. . 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. . Depression and psychiatric symptoms preceding onset of dementia in a family with early-onset Alzheimer disease with a novel PSEN1 mutation. J Neurol. 2009 Aug;256(8):1351-3. PubMed.

Other mutations at this position

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.