Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640285 C>G
dbSNP ID: rs63749805
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to CGA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was first reported in a Polish woman who developed memory complaints at age 36 (Zekanowski et al., 2003). Other symptoms included apathy, stereotyped behavior, and seizures. She met NINCDS-ADRDA criteria for Alzheimer’s disease. Family history was unavailable, therefore pathogenicity could not be assessed, but the authors noted that other pathogenic mutations have been detected at the this codon in other Polish families (see P117S and P117L; Dowjat et al., 2004; Wisniewski et al., 1998).

This mutation was also identified in a 35-year-old woman originally from Colombia who experienced memory problems beginning at age 33 (Gómez-Tortosa et al. , 2010). Although motor disturbances were not part of her initial presentation, she developed myoclonus, seizures, and gait impairment within two years of onset. She died at age 37. She had a family history of dementia including an affected father and three older siblings. Her father experienced onset at age 37 and died at age 42. Her brother had onset at 38 and died at 41. Two older sisters had onset at ages 36 and 37, and at the time of the report were living with severe dementia at ages 39 and 40 years.

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

Neuropathology

Unknown.

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 (HEK) 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. Also, total secreted Aβ levels were decreased. Similarly, an earlier study showed an increased Aβ42/40 ratio in HEK cells co-expressing P117R PSEN1 and APP with the Swedish mutation (Bialopiotrowicz et al., 2012). In this case, increased secretion of both Aβ40 and Aβ42 was observed. Interestingly, Liu and colleagues also reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations (Liu et al., 2021). 

This mutation was also found to affect cell-cycle progression in immortalized B-lymphocytes from mutation carriers. Specifically, G1 phase was prolonged and 5 phase shortened in conjunction with increased levels of p53 and p21 (Bialopiotrowicz et al., 2012).

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.

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References

Paper Citations

1. Zekanowski C, Styczyńska M, Pepłońska B, Gabryelewicz T, Religa D, Ilkowski J, Kijanowska-Haładyna B, Kotapka-Minc S, Mikkelsen S, Pfeffer A, Barczak A, Łuczywek E, Wasiak B, Chodakowska-Zebrowska M, Gustaw K, Łaczkowski J, Sobów T, Kuźnicki J, Barcikowska M. Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol. 2003 Dec;184(2):991-6. PubMed.
2. 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.
3. Wisniewski T, Dowjat WK, Buxbaum JD, Khorkova O, Efthimiopoulos S, Kulczycki J, Lojkowska W, Wegiel J, Wisniewski HM, Frangione B. A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years. Neuroreport. 1998 Jan 26;9(2):217-21. PubMed.
4. Gómez-Tortosa E, Barquero S, Barón M, Gil-Neciga E, Castellanos F, Zurdo M, Manzano S, Muñoz DG, Jiménez-Huete A, Rábano A, Sainz MJ, Guerrero R, Gobernado I, Pérez-Pérez J, Jiménez-Escrig A. Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
5. 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.
6. Bialopiotrowicz E, Szybinska A, Kuzniewska B, Buizza L, Uberti D, Kuznicki J, Wojda U. Highly Pathogenic Alzheimer's Disease Presenilin 1 P117R Mutation Causes a specific Increase in p53 and p21 Protein Levels and Cell Cycle Dysregulation in Human Lymphocytes. J Alzheimers Dis. 2012 Jan 1;32(2):397-415. PubMed.
7. 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.

Other Citations

1. P117S

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading