Mutations

PSEN1 G183V

Overview

Pathogenicity: Other Tauopathy : Unclear Pathogenicity
Clinical Phenotype: Pick's disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653628 G>T
dbSNP ID: rs63751068
Coding/Non-Coding: Coding
Mutation Type: Point, 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: one suffering from Pick’s disease and the other from Alzheimer’s disease (AD). 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 whether this mutation is truly pathogenic has been 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).

In addition, a subsequent study identified the mutation in two Belgian siblings who suffered from AD, rather than Pick’s disease (Perrone et al., 2020). These individuals had memory impairment, without symptoms of frontotemporal dementia. Also, the neuropathology of one of them was typical of AD. Of note, this individual also carried the PSEN1 P49L mutation.

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.

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).

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).

Last Updated: 29 Sep 2020

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References

Webinar Citations

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

Mutations Citations

  1. PSEN1 P49L

Paper Citations

  1. . 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. . 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. . 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. . 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.
  5. . Tau is central in the genetic Alzheimer-frontotemporal dementia spectrum. Trends Genet. 2005 Dec;21(12):664-72. PubMed.
  6. . 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.

Further Reading

Papers

  1. . Frontotemporal dementia-like phenotypes associated with presenilin-1 mutations. Am J Alzheimers Dis Other Demen. 2006 Aug-Sep;21(4):281-6. PubMed.
  2. . Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest. 2007 May;117(5):1230-9. Epub 2007 Apr 12 PubMed.
  3. . 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.

Protein Diagram

Primary Papers

  1. . A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques. Ann Neurol. 2004 May;55(5):617-26. PubMed.

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