Mutations

PSEN1 E184D

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic, Dementia with Lewy Bodies : Not Classified, Primary Progressive Aphasia : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659355 A>C
dbSNP ID: rs63750311
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAA to GAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was first discovered in a family of Japanese origin with early onset AD affecting four individuals across three generations (Yasuda et al., 1997). The mutation was found in the proband and his affected mother, but not in the proband’s three healthy sisters, 64 patients with early onset AD, 100 unrelated patients with probable AD, nor 100 healthy volunteers (Yasuda et al., 1997; Yokota et al., 2002). All affected members developed dementia, with symptoms emerging in their early 40s, and a mean duration of disease of nine years. Symptoms in the proband included memory loss, disorientation, mild extrapyramidal signs, and seizures in the advanced stages of disease. In three cases, the first symptom was memory impairment, and in one, personality change. Two members experienced myoclonus, while the other two developed parkinsonism.

The mutation was subsequently found in several other unrelated individuals suffering from AD. For example, in the U.K. it was reported in a family with five individuals affected by AD spanning three generations with a mean age at onset of 42 years (Janssen et al., 2003). It was also found in a Brazilian family of Asian ancestry with autosomal dominant inheritance of AD and a mean age at onset of 48 years  (Llibre-Guerra et al., 2021).  

Of note, the mutation has also been found in individuals diagnosed with dementia with Lewy bodies (DLB) and primary progressive aphasia (PPA). In the original Japanese pedigree, one case developed symptoms consistent with DLB, including hallucinations, delusions, and parkinsonism in the middle stages of disease (Yokota et al., 2002). Moreover, a 44-year-old Czech woman who carried the mutation and had a family history of early onset dementia, presented with the logopenic variant of PPA, including a severe difficulty finding words, but preserved language comprehension (Picková et al., 2017). This patient developed episodic memory impairment, progressing to dementia with behavioral changes including irritability and compulsiveness.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

In three cases, neuropathology was consistent with AD (Yasuda et al., 1997; Yokota et al., 2002; Picková et al., 2017). However, unique features were also reported. In one case, there were heavy amyloid deposits in the walls of small meningeal arteries, as well as around small vessels within the brain parenchyma (Yasuda et al., 1997). Immunostaining showed that Aβ42 was predominant over Aβ40 in neuritic plaques of the temporal cortex, whereas Aβ40 was predominant in cerebral amyloid angiopathy lesions in the hippocampus (Yasuda 2000). In the patient who developed DLB symptoms, there was, additionally, robust α-synuclein pathology, including Lewy bodies and accumulation of the non-Aβ component of AD amyloid (NAC) in plaques and astrocytes (Yokota et al., 2002). Lewy body pathology was also found in the patient who developed PPA, meeting the diagnostic criteria for diffuse neocortical Lewy body disease (Picková et al., 2017).

In the original proband, MRI demonstrated mild atrophy of the left medial temporal lobe and moderate atrophy of the bilateral parietal lobes, whereas PET revealed mild temporoparietal and moderate parietal hypoperfusion bilaterally (Yasuda et al., 1997). In the patient diagnosed with PPA, MRI showed early left perisylvian and bitemporal atrophy (Picková et al., 2017).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased Aβ40 and Aβ42 production, and an elevated Aβ42/Aβ40 ratio (Sun et al., 2017).

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 : Likely Pathogenic*

*Carriers of this variant had heterogenous phenotypes.

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

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. E184D: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. E184D: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

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.

PP1-M

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. E184D: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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.

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

Last Updated: 22 Feb 2022

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References

Paper Citations

  1. . A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy. Neurosci Lett. 1997 Aug 22;232(1):29-32. PubMed.
  2. . NACP/alpha-synuclein, NAC, and beta-amyloid pathology of familial Alzheimer's disease with the E184D presenilin-1 mutation: a clinicopathological study of two autopsy cases. Acta Neuropathol. 2002 Dec;104(6):637-48. PubMed.
  3. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  4. . Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes. Alzheimers Dement. 2021 Apr;17(4):653-664. Epub 2020 Nov 23 PubMed.
  5. . Genetic Alzheimer Disease and Sporadic Dementia With Lewy Bodies: A Comorbidity Presenting as Primary Progressive Aphasia. Cogn Behav Neurol. 2017 Mar;30(1):23-29. PubMed.
  6. . Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry. 2000 Feb;68(2):220-3. PubMed.
  7. . 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.
  8. . 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

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. . A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy. Neurosci Lett. 1997 Aug 22;232(1):29-32. PubMed.

Other mutations at this position

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