Pathogenicity: Other Tauopathy : Pathogenic
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


This mutation in PSEN1 has been 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.

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 following the identification of additional FTD genes, such as progranulin (see Jul 2012 webinar).


Postmortem examination of the 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).

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). 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, leading to truncated proteins (Dermaut et al., 2004) and possibly to decreased overall levels of presenilin and loss of function (Dermaut et al., 2005, see Jan 2007 webinar).

Research Models

A knock-in mouse model carrying this mutation has been generated; it produces aberrantly spliced transcripts lacking either exon 6 or exons 6 and 7 (Watanabe et al., 2012). The alternative transcripts are subject to nonsense-mediated decay, leading to low levels of PSEN1 mRNA and protein, specifically in the brain. Consistent with low levels of PSEN1, the mice also 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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Webinar Citations

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

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

Further Reading


  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.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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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