Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Ataxia
Reference Assembly: GRCh37/hg19
Position: Chr14:73640284 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to GCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was first reported in a family with three members affected by early onset progressive ataxia and dementia (Anheim et al., 2007). The clinical phenotype in this family was fairly homogenous, with onset before age 35 and death between 35 and 40 years. The proband developed balance, writing, and memory problems at age 34. Her father developed symptoms at age 29, including tremor and problems with gait. The proband’s paternal grandmother reportedly experienced onset at age 24, including gait ataxia and balance impairment, and died at age 35. The mutation was detected in the proband, but not in her unaffected mother. The other two affected individuals could not be genotyped as they were predeceased. The proband also carried a known polymorphism in PSEN1, E318G, which some have described as benign, but others have suggested increases the risk of late-onset AD.

Ataxia was not among the symptoms reported in a Colombian pedigree found to carry the P117A mutation. As reported, the  pedigree contained eight individuals over four generations who developed dementia during the fourth decade of life. The proband developed progressive memory impairment with gradual onset at 32 years of age and met NINCDS-ADRDA criteria for probable Alzheimer’s disease. Transmission of AD in this family is consistent with autosomal-dominant inheritance (Kauwe et al., 2008).

A French mutation carrier developed AD symptoms at 34 years of age and subsequently experienced seizures at age 41 (Zarea et al. 2016). 

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

Neuropathology

Unknown.

Biological Effect

P117 has been identified as key for PSEN1's γ-processivity, the carboxypeptidase activity that trims Aβ intermediates to form shorter, secreted species, and this mutant appears to reduce it (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. Interestingly, the authors 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.

Consistent with these findings, the Aβ42/Aβ total ratio was higher in HEK cells expressing P117A than in cells expressing wild-type PSEN1 (Kauwe et al., 2008) and a greater than 10-fold increase in the Aβ42/Aβ0 ratio was reported using purified proteins to test the mutant's ability to process the APP-C99 substrate in vitro (Sun et al., 2017). Liu et al reported a decrease in total secreted Aβ and Sun et al. found robust reductions in both Aβ42 and Aβ40 production, however, Kauwe et al. found no significant difference in total Aβ levels.

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. Anheim M, Hannequin D, Boulay C, Martin C, Campion D, Tranchant C. Ataxic variant of Alzheimer's disease caused by Pro117Ala PSEN1 mutation. J Neurol Neurosurg Psychiatry. 2007 Dec;78(12):1414-5. PubMed.
2. Kauwe JS, Wang J, Chakraverty S, Goate AM, Henao-Martinez AF. Novel presenilin 1 variant (P117A) causing Alzheimer's disease in the fourth decade of life. Neurosci Lett. 2008 Jun 20;438(2):257-9. Epub 2008 Apr 15 PubMed.
3. Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
4. 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.
5. 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.
6. 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. E318G

External Citations

1. gnomAD v2.1.1
2. Kauwe et al., 2008

Further Reading

No Available Further Reading