Mutations

PSEN1 I143F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3, BS2
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
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).

This variant is absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

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

Although the substitution underlying this variant is a conservative one, two in-depth studies of the Aβ peptides produced by cells transfected with this variant revealed a deleterious effect, decreasing both the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios compared with cells expressing wildtype PSEN1 (Apr 2022 news; Petit et al., 2022; Liu et al., 2022). Both ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at 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).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic*

*This variant may have reduced penetrance, a condition outside the scope of the ACMG-AMP guidelines.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. I143F: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 26 Apr 2022

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  2. 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. . Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
  5. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  6. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  7. . 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. . 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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