Mutations

PSEN1 I143F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640362 A>T
dbSNP ID: rs63750322
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATT to TTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was found in a family from the UK with an autosomal dominant pattern of AD inheritance and a median age at onset of 55 years (Rossor et al., 1996; Palmer et al., 1999). The mutation was present in three members with AD, as well as in a member who was symptom-free at age 68, suggesting incomplete penetrance. The mutation was absent from 96 white controls. The affected mutation carriers had disease onset at 53, 55, and 59 years of age, with clinical features fulfilling the NINCDS criteria for probable AD. APOE genotyping revealed that all three mutation carriers were homozygous for the E3 allele. The mutation was also reported in an individual with age at onset of 51 years, and disease duration of six years (Gómez-Isla et al., 1999).

Neuropathology
In one case, widespread senile plaques and neurofibrillary tangles with amyloid staining of blood vessels were reported (Rossor et al., 1996). In another case, a few differences with sporadic AD were highlighted (Gómez-Isla et al., 1999). In particular, the percentage of the superior temporal sulcus region covered by plaques containing Aβ42/Aβ43 was found to be elevated, resulting in a lower ratio of Aβ40 to Aβ42/Aβ43, compared with average measurements of 51 cases of sporadic AD. Also, neurofibrillary tangle formation and neuronal loss were accelerated compared to sporadic AD.  

Biological Effect
The biological effect of this mutation is unknown, but it is a conservative substitution, which may explain the incomplete penetrance and relatively late age of onset. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, I143 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).

Last Updated: 03 Aug 2019

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References

News Citations

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

Paper Citations

  1. . Incomplete penetrance of familial Alzheimer's disease in a pedigree with a novel presenilin-1 gene mutation. Lancet. 1996 Jun 1;347(9014):1560. PubMed.
  2. . Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online. Hum Mutat. 1999;13(3):256. PubMed.
  3. . The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors. Brain. 1999 Sep;122 ( Pt 9):1709-19. PubMed.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Incomplete penetrance of familial Alzheimer's disease in a pedigree with a novel presenilin-1 gene mutation. Lancet. 1996 Jun 1;347(9014):1560. PubMed.
  2. . Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online. Hum Mutat. 1999;13(3):256. PubMed.

Other mutations at this position

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