Mutations

PSEN1 I143T

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genome Build: GRCh37 (105)
Position: Chr14:73640363 T>C
dbSNP ID: rs63750004
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: ATT to ACT

Findings

This mutation was first identified by linkage analysis in a large Belgian family affected by early onset Alzheimer’s disease (Cruts et al., 1995). The family, known as AD/A, included at least 31 affected individuals over six generations, many of whom had neuropathologically confirmed AD. The mean age at onset in this family was 35.1 ± 4.8 years.

This mutation was also found in three other individuals with early onset AD. Of these mutation carriers, two were sisters who also carried a second PSEN1 mutation in trans. They both inherited the I143T mutation from their father and the PSEN1 I439V mutation from their mother, who was asymptomatic at age 55. The sisters both developed symptoms before age 35 (Rogaeva et al., 2001).

A French family, known as ROU 001, was also shown to carry this mutation. The family included at least three individuals affected by early onset AD. Symptom onset occurred at age 34 or 35. Note, the mutation was erroneously reported as I143W (Raux et al., 2005).

Neuropathology

Autopsies were performed on at least 11 affected family members from the AD/A family. Neuropathology consistent with the diagnosis of AD was observed, including amyloid plaques and neurofibrillary tangles in the cortex. A few cerebellar plaques were also noted (Martin et al., 1991).

Biological Effect

When transfected into HEK293 cells stably expressing Swedish mtAPP695 and BACE1, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage activity of PSEN1. This resulted in reduced secreted Aβ40, increased Aβ42, and an increased Aβ42/Aβ40 ratio (Li et al., 2016).

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References

Mutations Citations

  1. PSEN1 I439V

Paper Citations

  1. . Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
  2. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  3. . 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.
  4. . Early-onset Alzheimer's disease in 2 large Belgian families. Neurology. 1991 Jan;41(1):62-8. PubMed.
  5. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.

Further Reading

Papers

  1. . Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Med Genet. 2001 Oct 1;103(2):138-43. PubMed.
  2. . Familial cases presenting very early onset autosomal dominant Alzheimer's disease with I143T in presenilin-1 gene: implication for genotype-phenotype correlation. Neurogenetics. 2008 Feb;9(1):65-7. Epub 2007 Oct 30 PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
  2. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

Other mutations at this position

Alzpedia