Mutations

PSEN1 E120K

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Spastic Paraparesis, Parkinsonism, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640293 G>A
dbSNP ID: rs63750800
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAA to AAA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation has been reported in several families with a history of AD or dementia. One family of British/Irish decent, known as F121, had six affected family members over three generations. Onset of symptoms ranged from 32 to 39 years in this family, and a diagnosis of AD was confirmed by pathology in some family members (Hutton et al., 1996).

The details of the second family are limited, but the index patient was of Danish origin and developed symptoms at age 43 and had AD with spastic paraparesis. The mean age of onset in this family was reported as 44 years, ranging from 43 to 45 years; however, it was unclear how many individuals were affected. Segregation with disease could not be assessed due to lack of DNA from individuals other than the index patient (Lindquist et al., 2009).

The mutation has also been reported in two Korean women. In one case, the patient had progressive memory impairment beginning at 33 years of age (Li et al., 2018). By 38, she had global cognitive deficits, including impairments in verbal and visual memory, language, and visuospatial functions, with relative sparing of attention and frontal-executive function. She also had cerebellar dysfunction and was diagnosed with early onset dementia with spastic paraparesis. Of note, her grandmother developed dementia in her 70s and a cousin was diagnosed with late-onset cerebellar ataxia at age 54. Genetic testing of the patient for mutations linked to spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, Friedereich's ataxia, and Huntington's disease were negative. A second Korean woman carrying this mutation had AD and a family history of the disease (Kim et al., 2020). Her symptoms, which began at age 34, included memory impairment, visuospatial dysfunction, anomia, depression, apathy, abulia, and delusion. Motor symptoms also developed in this patient, including cerebellar ataxia, parkinsonism, and dystonia.

Neuropathology

Neuropathology consistent with AD was reported (Hutton et al., 1996). In the Korean patients, brain MRI revealed generalized cortical atrophy with atrophy in the bilateral medial temporal lobes and cerebellum in one case (Li et al., 2018), and mild, diffuse cortical atrophy with left hippocampal atrophy in the other (Kim et al., 2020). In this second patient, SPECT showed bilateral hypometabolism in the temporal lobes. Moreover, Aβ accumulation was found in the brains of both Korean patients using PiB PET imaging. In the first patient, the striatum, bilateral frontal lobes, posterior cingulate cortices, and precuneus, but not the cerebellum, were affected (Li et al., 2018).

Biological Effect

 When expressed in COS-1 cells co-transfected with APP695, this mutation increased the Aβ42/Aβ total ratio (Murayama et al., 1999). Moreover, in an vitro assay using purified proteins, the mutation reduced the production of Aβ42, and nearly abrogated production of Aβ40, resulting in an approximately ten-fold increase in the Aβ42/Aβ40 ratio compared with wild-type PSEN1 (Sun et al., 2017). A study using induced pluripotent stem cells from a middle-aged mutation carrier, however, revealed increased extracellular accumulation of Aβ compared with control cells (Li et al., 2018). This study also reported increased levels of phosphorylated tau, mitochondrial abnormalities, and disrupted autophagy.

The E120 site is evolutionarily conserved (GERP score = 4.74) and in silico algorithms predicted the mutation is probably damaging (Polyphen2), and not tolerable (SIFT). Moreover, it has a CADD score of 27.0, suggesting it is in the top one percent of deleterious variants (Kim et al., 2020).

Last Updated: 05 Mar 2020

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.
  2. . Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort. Clin Genet. 2009 Aug;76(2):205-9. Epub 2009 Jul 29 PubMed.
  3. . iPSC Modeling of Presenilin1 Mutation in Alzheimer's Disease with Cerebellar Ataxia. Exp Neurobiol. 2018 Oct;27(5):350-364. Epub 2018 Oct 31 PubMed.
  4. . PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. PubMed.
  5. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
  6. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.

Other mutations at this position

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.