Mutations

PSEN1 E120K

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Nasu-Hakola Disease, Spastic Paraparesis, 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 three families. 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 was also found in a Korean woman with progressive memory impairment beginning at 33 years of age (Li et al., 2018). By 38, this patient 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 proband for mutations linked to spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, Friedereich's ataxia, and Huntington's disease were negative.

Neuropathology

Neuropathology consistent with AD was reported (Hutton et al., 1996). In the case of the Korean patient, brain MRI revealed generalized cortical atrophy with atrophy in the bilateral medial temporal lobes and cerebellum (Li et al., 2018). Moreover, PiB-PET imaging showed Aβ accumulation in the striatum, as well as in the bilateral frontal lobes, posterior cingulate cortices, and precuneus, but not the cerebelum.

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.

Last Updated: 18 Sep 2019

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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. . 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.
  5. . 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

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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

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