Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73170984 G>C
Position: (GRCh37/hg19):Chr14:73637692 G>C
dbSNP ID: rs63751141
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TGC to TCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was first reported in two Italian families, both of whom had a history of familial dementia. Affected members of both families met NINCDS-ADRDA criteria for probable AD; however, the clinical presentation in one family included atypical features.

The three affected members of the family known as FLO57 are described as having a fairly typical presentation of early onset AD, and began to exhibit memory decline in their early 50s, with a mean age of onset of approximately 53.5 years. In contrast, depression, social isolation, and sporadic mutism were the first symptoms of the proband in the other family, known as “FLO28.” These symptoms, which began at age 49, were followed by memory decline and extrapyramidal signs, with rigidity and bradykinesia. Hallucinations and delusions followed, and the proband became progressively more mute and parkinsonian. The proband’s mother had dementia with aggressive behavior, but symptoms reportedly began considerably later, at age 70. No mutations in MAPT were detected in the proband of FLO28, suggesting that PSEN1 C92S may produce a variable clinical phenotype, presenting as either fairly typical early onset AD or with an atypical presentation characterized by extrapyramidal signs and early psychiatric features (Tedde et al., 2003).

This variant was absent from the gnomAD variant database (v2.1.1, Jan 2022).

Neuropathology

Unknown.

Biological Effect

In transfected cultured cells, as well as in patient fibroblasts, this mutation increased Aβ42 secretion (Lewis et al., 2000; Zhang et al., 2000; Assini et al., 2003; Liu et al., 2022). Moreover, a study that examined the full set of Aβ peptides generated by PSEN1 activity in transfected cells, revealed a robust increase in toxic Aβ43 and a decrease in Aβ37, an indicator of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Also, like known pathogenic mutations, this variant decreased the Aβ37/Aβ42 ratio, a measurement that outperformed the standard Aβ42/Aβ40 ratio for distinguishing between control and AD samples. An in vitro assay using purified proteins to test the ability of the mutant to cleave the APP-C99 substrate, however, yielded somewhat inconsistent results. Although it showed an elevation of the Aβ42/Aβ40 ratio, the underlying cause was a drastic reduction in both Aβ42 and Aβ40 production, with Aβ40 levels being undetectable (Sun et al., 2017).

Whether this variant also affects processing of the developmental protein Notch is uncertain. In C. elegans, the mutant interfered with Notch cleavage (Zhang et al., 2000), but in human cells, no effect was detected (Okochi et al., 2000). 

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

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022

Paper Citations

1. Tedde A, Nacmias B, Ciantelli M, Forleo P, Cellini E, Bagnoli S, Piccini C, Caffarra P, Ghidoni E, Paganini M, Bracco L, Sorbi S. Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.
2. Lewis PA, Perez-Tur J, Golde TE, Hardy J. The presenilin 1 C92S mutation increases abeta 42 production. Biochem Biophys Res Commun. 2000 Oct 14;277(1):261-3. PubMed.
3. Zhang DM, Levitan D, Yu G, Nishimura M, Chen F, Tandon A, Kawarai T, Arawaka S, Supala A, Song YQ, Rogaeva E, Liang Y, Holmes E, Milman P, Sato C, Zhang L, St George-Hyslop P. Mutation of the conserved N-terminal cysteine (Cys92) of human presenilin 1 causes increased A beta42 secretion in mammalian cells but impaired Notch/lin-12 signalling in C. elegans. Neuroreport. 2000 Sep 28;11(14):3227-30. PubMed.
4. Assini A, Terreni L, Borghi R, Giliberto L, Piccini A, Loqui D, Fogliarino S, Forloni G, Tabaton M. Pure spastic paraparesis associated with a novel presenilin 1 R278K mutation. Neurology. 2003 Jan 14;60(1):150. PubMed.
5. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
6. 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.
7. Okochi M, Eimer S, Bottcher A, Baumeister R, Romig H, Walter J, Capell A, Steiner H, Haass C. A loss of function mutant of the presenilin homologue SEL-12 undergoes aberrant endoproteolysis in Caenorhabditis elegans and increases abeta 42 generation in human cells. J Biol Chem. 2000 Dec 29;275(52):40925-32. PubMed.
8. 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.

Further Reading