Overview

Pathogenicity: Alzheimer's Disease : Not Classified, Other Tauopathy : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP2, PP3
Clinical Phenotype: Pick's disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653628 G>T
dbSNP ID: rs63751068
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Deletion; Missense
Codon Change: GGG to GTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation has been identified in two families with Alzheimer’s disease (AD) and one suffering from Pick’s disease. Because of the families’ different clinical phenotypes and neuropathology, as well as the presence of affected non-carriers in the family with Pick’s disease, its pathogenicity remains unclear.

The mutation was first reported in a Belgian individual who had autopsy-confirmed Pick's disease and a positive family history of a slowly progressive frontotemporal dementia-like disorder (Dermaut et al., 2004). At the age of 52 the proband developed insidious and progressive changes in behavior and personality, including apathy, emotional blunting, and over-eating. Signs of frontal disinhibition, such as inappropriate laughing, were also apparent. He died at age 62 with severe dementia. The proband’s father had died at the age of 77 with symptoms consistent with a retrospective diagnosis of FTD. The proband’s brother committed suicide at age 55 following a nine-year history of progressive personality and behavioral changes that were also consistent with a diagnosis of FTD. All together, DNA from eight siblings, including the proband and his deceased brother, revealed five mutation carriers. The remaining three mutation carriers showed signs of moderate or mild cognitive decline at ages of 60, 58, 56. Of note, three siblings who did not carry the mutation also showed similar alterations. No mutations in APP, PSEN2, MAPT, or PRNP were found in the study, but its pathogenicity was called into question based on the phenotypes of the non-carriers, and following the identification of additional FTD genes, such as progranulin (see Jul 2012 webinar).

Two subsequent, AD-focused studies also reported the mutation, but the relationship of the mutation to disease was uncertain. In one study, two Belgian siblings presented with memory impairment, without symptoms of frontotemporal dementia (Perrone et al., 2020). The neuropathology of one of them was typical of AD, but this individual also carried the PSEN1 P49L mutation. The other report described a 30-year-old Turkish man who had a family history of AD, but only mild to moderate cognitive decline and no detectable atrophy as assessed by MRI at the time of the study (Eryilmaz et al., 2021). 

G183V is absent from both the gnomAD and ExAC variant databases.

Neuropathology

Postmortem examination of the originally described proband’s brain showed severe frontotemporal atrophy. In the neocortex, Pick bodies, tau-positive cytoplasmic neuronal inclusions, were observed. A striking absence of extracellular Aβ deposits was noted. Overall, the neuropathology was consistent with Pick’s disease (Dermaut et al., 2004). In contrast, the double mutation carrier with memory loss (carrying G183V and P49L) had neuropathology consistent with AD, with classic AD neurofibrillary tangles and no signs of Pick’s disease (Perrone et al., 2020). A mild atrophy of the frontotemporal gyri was noted. In addition, brain imaging using SPECT showed moderate hypoperfusion of the bilateral parietal, temporal, and frontal lobes, compatible with AD, and MRI revealed age-related atrophy and multiple supratentorial lacunary infarcts. As noted above, an MRI brain scan of the Turkish carrier failed to reveal detectable atrophy (Eryilmaz et al., 2021).

Biological Effect

When transfected into HEK293 cells or mouse embryonic fibroblasts lacking endogenous presenilins, the G183V mutation only mildly increased the Aβ42/Aβ40 ratio (Dermaut et al., 2004) and had no effect on Notch cleavage (Watanabe et al., 2012). In an in vitro assay using purified proteins to test the mutant’s ability to cleave the APP-C99 substrate, it generated less Aβ40 and Aβ42 than wild-type PSEN1, and increased the Aβ42/Aβ40 ratio by approximately two-fold (Sun et al., 2017).

This mutation is unusual in that in addition to producing full-length PSEN1 G183V protein, it also generates alternative transcripts that either lack exon 6 or exons 6 and 7 (Dermaut et al., 2004; Perrone et al., 2020) and possibly to decreased overall levels of presenilin and loss of function (Dermaut et al., 2005, see Jan 2007 webinar). It has also been reported that the truncated proteins interact with full-length PSEN1 forming very stable, high molecular weight complexes that may result in a dominant-negative suppression of APP cleavage (Newman et al., 2014). A study using patient lymphoblasts, however, reported low levels of truncated transcripts (less than 6 percent) due to loss via nonsense-mediated mRNA decay, and were thus considered unlikely to interfere with the function of the wild-type protein (Perrone et al., 2020).

Although some in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because the reported carriers had heterogenous phenotypes and the variant's relationship to AD was unclear.

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

Research Models

A knock-in mouse model carrying this mutation has been generated; it produces aberrantly spliced transcripts lacking either exon 6 or both exons 6 and 7 (Watanabe et al., 2012). As expected due to nonsense-mediated RNA decay, it has low levels of PSEN1 mRNA and protein, specifically in the brain. Consistent with this, the mice have decreased γ-secretase activity in the cerebral cortex. When crossed with mice lacking PSEN2, homozygous knock-in mice display mild spatial-memory deficits leading to the suggestion that decreased presenilin function may underlie the observed cognitive deficit (Watanabe et al., 2012).

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References

Webinar Citations

1. Weeding Mendel’s Garden: Can We Hoe Dubious Genetic Associations? 3 Aug 2012
2. Presenilin Loss of Function—Plan B for AD? 9 Mar 2007

Mutations Citations

1. PSEN1 P49L

Paper Citations

1. Watanabe H, Xia D, Kanekiyo T, Kelleher RJ, Shen J. Familial frontotemporal dementia-associated presenilin-1 c.548G>T mutation causes decreased mRNA expression and reduced presenilin function in knock-in mice. J Neurosci. 2012 Apr 11;32(15):5085-96. PubMed.
2. Dermaut B, Kumar-Singh S, Engelborghs S, Theuns J, Rademakers R, Saerens J, Pickut BA, Peeters K, van den Broeck M, Vennekens K, Claes S, Cruts M, Cras P, Martin JJ, Van Broeckhoven C, De Deyn PP. A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques. Ann Neurol. 2004 May;55(5):617-26. PubMed.
3. Perrone F, Bjerke M, Hens E, Sieben A, Timmers M, De Roeck A, Vandenberghe R, Sleegers K, Martin JJ, De Deyn PP, Engelborghs S, van der Zee J, Van Broeckhoven C, Cacace R, BELNEU Consortium. Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
4. Eryilmaz IE, Bakar M, Egeli U, Cecener G, Yurdacan B, Colak DK, Tunca B. Evaluation of the Clinical Features Accompanied by the Gene Mutations: The 2 Novel PSEN1 Variants in a Turkish Early-onset Alzheimer Disease Cohort. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):214-222. 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. Dermaut B, Kumar-Singh S, Rademakers R, Theuns J, Cruts M, Van Broeckhoven C. Tau is central in the genetic Alzheimer-frontotemporal dementia spectrum. Trends Genet. 2005 Dec;21(12):664-72. PubMed.
7. Newman M, Wilson L, Verdile G, Lim A, Khan I, Moussavi Nik SH, Pursglove S, Chapman G, Martins RN, Lardelli M. Differential, dominant activation and inhibition of Notch signalling and APP cleavage by truncations of PSEN1 in human disease. Hum Mol Genet. 2013 Oct 6; 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.

External Citations

1. CADD v.1.6

Further Reading