Mutations

PSEN1 L232P

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659498 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTC to CCC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was identified in a Korean patient with early onset Alzheimer’s disease and a family history of dementia (Park et al., 2017). Memory decline was first noticed when the proband was 37 years old, and within a year he was unable to live independently.  He received a clinical diagnosis of dementia at age 41, and experienced his first tonic-clonic seizure at age 42. The proband has six siblings, three of whom also suffered from dementia, with symptom onset in their 40s or 50s; one brother was healthy at age 59, another brother died in his 20s, and the health status of the remaining brother is unknown. The mother of the proband was diagnosed with dementia in her 40s and the father died of cancer at age 54 with no reported symptoms of dementia. The family history is thus consistent with an autosomal-dominant pattern of inheritance, but DNA from family members was not available for segregation analysis.

The mutation was not found in the Korean Reference Genome Database, which contains whole-genome sequencing data on 622 healthy Korean individuals, nor was it seen in the ExAC or 1000 Genomes databases.

Neuropathology

Unknown. However, MRI of the proband revealed diffuse cortical atrophy, especially in the frontal and parietal lobes.

Biological Effect

Unknown. PolyPhen-2 and SIFT predicted that this mutation is likely to be damaging. Amino acid 233 is in the fifth transmembrane domain, and three-dimensional modeling using Raptor X showed that the leucine-to-proline substitution might introduce a kink in this region.

Last Updated: 18 May 2018

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References

Paper Citations

  1. . Identification of a novel PSEN1 mutation (Leu232Pro) in a Korean patient with early-onset Alzheimer's disease and a family history of dementia. Neurobiol Aging. 2017 Aug;56:212.e11-212.e17. Epub 2017 Apr 26 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Identification of a novel PSEN1 mutation (Leu232Pro) in a Korean patient with early-onset Alzheimer's disease and a family history of dementia. Neurobiol Aging. 2017 Aug;56:212.e11-212.e17. Epub 2017 Apr 26 PubMed.

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