Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37 (105)
Position: Chr14:73683938 G>A
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTA to ATA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11


This variant was found in four members, spanning two generations, of a family in Southern Italy with autosomal dominant, early onset frontotemporal dementia (Bernardi et al., 2009). Three of the affected individuals, who were siblings, developed similar symptoms, fulfilling the clinical criteria for FTD. The fourth, their mother, had already died at the time of the study, but clinical records suggest she had a similar phenotype.

Although the mutation was absent from 100 previously screened familial AD patients and from 100 cognitively healthy controls (Bernardi et al., 2009), its allele count and frequency were relatively high in the gnomAD database (one and 0.0033 percent, respectively; Koriath et al., 2018). Thus, the latter study predicted the variant’s penetrance at less than 10 percent, and described it as "most likely benign" or causing an "only small increase in risk."


Although neuropathological data are unavailable, in one case, 18FDG-PET showed hypometabolism in the parietal and frontal cortices, as well as in the putamen and caudate. In another case, SPECT showed widespread cortical hypoperfusion.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed a severe decrease in Aβ42 production and undetectable levels of Aβ40 (Sun et al., 2017).

Last Updated: 20 Feb 2019


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Paper Citations

  1. . Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia. Neurobiol Aging. 2009 Nov;30(11):1825-33. PubMed.
  2. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  3. . 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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia. Neurobiol Aging. 2009 Nov;30(11):1825-33. PubMed.


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