Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173576 C>T
Position: (GRCh37/hg19):Chr14:73640284 C>T
dbSNP ID: rs63750550
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to TCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation has been reported in an American family with early onset Alzheimer’s disease (Dowjat et al., 2004). The family had three affected individuals over the three generations described in the pedigree. The first symptom in the proband was personality changes at age 33. By age 35 he had severe dementia and was unable to state the date, month, year, place, or name of the president. Myoclonus was also noted. He died at age 54. The proband’s younger sibling had onset of cognitive decline at age 31, which also started with personality problems. At age 36 years, she suffered a grand mal seizure and was subsequently noted to have myoclonus. Two years later, she was immobile, mute, and survived more than 13 years in a persistent vegetative state. The father of these two siblings experienced cognitive decline beginning at age 29, leading to his death four years later. Two years prior to his death he had “extreme forgetfulness,” anxiety, depression, unsteady gait, stooped posture, and hand tremor. The P117S mutation was detected in the two affected siblings, but was absent in their unaffected mother, presumably having been transmitted through their affected, predeceased father. No mutations were found in PSEN2 or APP.

The variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

Neuropathological data are available for one patient, the proband from the family described above, and a diagnosis of AD was confirmed by CERAD criteria. In brief, severe brain atrophy was noted, with neuronal loss estimated to be greater than 70 percent. There was also extensive loss of white matter and active gliosis throughout the brain. Lewy bodies were also noted (Dowjat et al., 2004).

Biological Effect

This mutant appears to reduce γ-processivity (Liu et al., 2021). Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant along with wildtype APP, revealed increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios compared with cells expressing wildtype PSEN1. The mutant was found to increase Aβ42 and Aβ43 production at the expense of Aβ37 and Aβ40, although Aβ38 was only moderately decreased. Consistently, the mutant was reported to increase the relative amount of secreted Aβ42 in both N2a cells expressing the mutant protein and skin fibroblasts from a mutation carrier (Dowjat et al., 2004). However, whereas this early study reported no change in total secreted Aβ, Liu and colleagues reported reduced levels. Interestingly, in the latter study Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios were found to correlate with reported ages of onset of clinical impairment across 16 PSEN1 mutations, including P117S. 

This mutation was also shown to affect neurite outgrowth in N2a cells. Compared with cells expressing wild-type PSEN1, cells expressing either the P117R or P117S mutation had reduced outgrowth (Dowjat et al., 2004).

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

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. Dowjat WK, Kuchna I, Wisniewski T, Wegiel J. A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 (Pro117Ser): Comparison of clinical, neuropathological and cell culture phenotypes of Pro117Leu and Pro117Ser mutations. J Alzheimers Dis. 2004 Feb;6(1):31-43. PubMed.
2. Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
3. 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

No Available Further Reading