Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73219144 T>G
Position: (GRCh37/hg19):Chr14:73685852 T>G
dbSNP ID: rs63750802
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to CGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was first identified in a family affected by early onset Alzheimer’s disease (Shrimpton et al., 2007). Disease in this family was characterized by seizures and cotton-wool plaques, but not spastic paraparesis. The proband, who also had rheumatoid arthritis, began to develop short-term memory loss in his late 30s. He became disoriented and developed irrational behavior. As the disease progressed, seizures developed, and he died at age 48, about a decade after onset. The reported pedigree shows that his mother and sister were also affected. The mutation was detected in both the proband and his affected sister.

The mutation was later identified in a member of a Japanese family affected by familial Alzheimer’s disease with parkinsonism (Niwa et al., 2013). The proband developed cognitive impairment at age 31 after a motorcycle accident. By 39 she had also developed a parkinsonism gait and posture. She died at age 43, 12 years after symptom onset. Six other family members were affected by severe dementia and parkinsonism, including the proband’s father, her three siblings, and two daughters. Onset for all began in their 30s or 40s. Segregation with disease could not be determined, as DNA was available only from one of the proband’s affected daughters. A subsequent study described a Japanese woman carrying the mutation with AD onset at 40 years of age (Islam et al., 2022). 

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

Neuropathology

Autopsy showed amyloid pathology in the neocortex and hippocampus. The majority of plaques were large, round, non-cored plaques (i.e., cotton-wool plaques), although some rare cored plaques were also observed. Tau pathology was most pronounced in the hippocampus and entorhinal cortex, and included neurofibrillary tangles and neuropil threads. Some amyloid angiopathy was also noted (Shrimpton et al., 2007).

Similarly, autopsy of the Japanese proband showed extensive amyloid pathology throughout the neocortex and hippocampus. Large cotton-wool plaques were abundant. Neurofibrillary tangles, neuropil threads, neuronal loss, and gliosis were also observed. The substantia nigra was atrophic, but α-synuclein staining was negative and Lewy bodies were not observed. Cerebral amyloid angiopathy affected arterioles in the neocortex, and capillaries in the neocortex and subcortical nuclei (Niwa et al., 2013).

Biological Effect

In an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, L420R produced less of both Aβ42 and Aβ40 than wildtype PSEN1. Because the decrease in Aβ40 production was greater than that of Aβ42, the Aβ42/Aβ40 ratio was increased (Sun et al., 2017).

Of note, in one carrier with an APOE2/3 genotype, blood ApoE levels were reduced compared with those of non-carriers (Islam et al., 2022). This may be due to the disruption of PSEN1’s proposed role in ApoE secretion.

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

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

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References

Paper Citations

1. Shrimpton AE, Schelper RL, Linke RP, Hardy J, Crook R, Dickson DW, Ishizawa T, Davis RL. A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease, seizures and cotton wool plaques, but not spastic paraparesis. Neuropathology. 2007 Jun;27(3):228-32. PubMed.
2. Niwa A, Matsuo K, Shindo A, Yata K, Shiraishi T, Tomimoto H. Clinical and neuropathological findings in a patient with familial Alzheimer disease showing a mutation in the PSEN1 gene. Neuropathology. 2012 Aug 12; PubMed.
3. Islam S, Sun Y, Gao Y, Nakamura T, Noorani AA, Li T, Wong PC, Kimura N, Matsubara E, Kasuga K, Ikeuchi T, Tomita T, Zou K, Michikawa M. Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis. J Neurosci. 2022 Feb 23;42(8):1574-1586. Epub 2022 Jan 5 PubMed.
4. Sun L, Zhou R, Yang G, Shi Y. 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.
5. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. 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