Mutations

PSEN1 L219P

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659459 T>C
dbSNP ID: rs63750761
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTT to CCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was initially found in an Australian woman of British ancestry with a family history of dementia, including nine affected relatives spanning five generations (Smith et al., 1999). At 47 years of age, the proband began experiencing memory loss and cognitive impairment, which progressed in a manner consistent with AD, with deficits in orientation, recall, and language. The mutation was also detected in an affected sister and an affected cousin of the proband, but not in 50 unrelated subjects.

A subsequent study reported this mutation in a Turkish woman with an AD age at onset of 52 years and a family history of the disease (Eryilmaz et al., 2021). Of note, this mutation carrier also had the PSEN1 E318G variant, which has been described as an AD risk modifier. 

The L219P variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Neuropathological examination of the brain of the proband’s sister, who carried the mutation and died in a demented state at age 54, confirmed an AD diagnosis according to CERAD criteria. Amyloid plaques and neurofibrillary tangles were widespread, but most concentrated in the hippocampus where they were associated with moderate to severe neuronal loss. In addition, meningeal congophilic amyloid angiopathy was detected in the cortex and cerebellum, with moderate intracortical angiopathy. In the proband, PET and SPECT scans showed hypoperfusion and hypometabolism of the temporal lobes and the right parietal lobe.

Biological Effect
The biological effect of this variant is unknown, but several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging, and 3D modeling predicted conformational changes (Eryilmaz et al., 2021Xiao et al., 2021).

 

Last Updated: 13 Sep 2021

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References

Mutations Citations

  1. PSEN1 E318G

Paper Citations

  1. . Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene. Neuroreport. 1999 Feb 25;10(3):503-7. PubMed.
  2. . Evaluation of the Clinical Features Accompanied by the Gene Mutations: The 2 Novel PSEN1 Variants in a Turkish Early-onset Alzheimer Disease Cohort. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):214-222. PubMed.
  3. . 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. . Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene. Neuroreport. 1999 Feb 25;10(3):503-7. PubMed.

Other mutations at this position

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