PSEN1 M233L (A>T)


Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659500 A>T
dbSNP ID: rs63751287
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to TTG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was found in a woman who experienced personality changes characteristic of fronto-temporal dementia starting at age 39 (Mendez et al., 2006). Symptoms included alterations in social behavior, abnormal personality regulation, emotional blunting, and poor insight. She also experienced a decline in personal hygiene, rigidity, compulsions, and changes in dietary/oral behaviors.

Several families carrying the related M233L (A>C) have been described. In these cases, symptoms and neuropathology have been reported as typical of AD, although one individual developed corticobasal syndrome.

Neuropathological data are unavailable, but SPECT imaging of this single case revealed hypoperfusion in posterior parietal areas, and a subsequent PET scan showed hypometabolism in prefrontal, parietal, and temporal cortices. MRI revealed global cerebral atrophy. 

Biological Effect
An in vitro assay using an M233L mutant (nucleotide change unspecified) and APP C99 as a substrate, revealed increased production of Aβ42, a moderate decrease in Aβ40 production, and a corresponding increase in the Aβ42:Aβ40 ratio (Bai et al., 2015; Sun et al., 2017). Five other pathogenic mutations have been described at codon 233, and a pathogenic mutation (M239V), has been documented at the homologous codon in PSEN2.

Last Updated: 11 Apr 2019


  1. This paper adds another example for the possible presence of a loss-of-function phenotype of PS mutations. In my view, (relative) elevation of Aβ42 is a gain-of-function phenotype commonly shared by most of the mutations, although the mechanism behind it may be a kind of loss-of-function type, that is, downregulation of Aβ40 generation. The PS mutations described in this paper and elsewhere, some of which do not even produce all the AD pathologies, seem to belong to a subclass of the entire set of pathogenic PS mutations.

    View all comments by Takaomi Saido

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Paper Citations

  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. . An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 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.

Other Citations

  1. M233L (A>C)

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary 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.

Other mutations at this position


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