Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659501 T>C
dbSNP ID: rs63751024
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to ACG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7
Research Models: 1


This mutation was first reported in a pedigree known as PERTH1, which had familial early onset AD. As reported, the family had four affected individuals over three generations. The mutation segregated with disease in this family; it was present in all three living affected family members and absent in three unaffected members. Affected family members developed symptoms at 33, 34, and 38 years; age at onset was unknown in one individual. AD pathology was confirmed in at least one case at autopsy (Kwok et al., 1997).

M233T was also found in two French kindreds, the first with five affected individuals over three generations. Age of onset in this family ranged from 38 to 45 years and segregation with disease was confirmed (Campion et al., 1999). A second French kindred, known as ALZ 202, consisted of three affected individuals who met NINCDS-ADRDA criteria for probable or definite AD. Age at onset in this family was 38 to 40 years. Segregation with disease could not be assessed (Raux et al., 2005).

This mutation has also been found in a Korean individual with early onset AD. The patient did not have a family history of dementia. She experienced symptom onset at age 34. Her disease progressed rapidly; at age 36 she scored 20/30 on the Korean Mini-Mental State Examination; two years later she scored 4/30. Symptoms included memory and visuospatial impairments, apraxia, aphasia, and optic ataxia. PET showed diffuse cerebral hypometabolism (Park et al., 2008).

The M233T mutation was found in a Caucasian man of Spanish or Portuguese ancestry. He first presented with clinical symptoms at age 35 and died at the age of 42. Presenting symptoms were atypical for AD, including prominent behavioral symptoms (depression/apathy and aggressiveness) and extrapyramidal signs such as dysarthria, left hand apraxia, face and foot dystonia, and pyramidal signs (Babinski). He later developed myoclonus and tonic-clonic seizures. Neuroimaging studies revealed hippocampal and bilateral parietotemporal atrophy. The family history was unclear (Guerreiro et al., 2010).


Neuropathology consistent with AD in at least one case (Kwok et al., 1997).

Biological Effect

This residue is conserved between PSEN1 and PSEN2 (see PSEN2 M239). Pathogenic mutations have been reported in the homologous PSEN2 residue (M239I and M239V).

In vitro, CHO cells co-expressing APP and mutant PSEN1 have increased Aβ42 (Qi et al., 2003). They also have increased Aβ48 and Aβ39, whereas levels of Aβ40, Aβ43, and Aβ46 are decreased (Qi-Takahara et al., 2005). Increased Aβ42 and decreased Aβ40 were also detected in the cell membrane fraction of CHO cells co-expressing APP and mutant PSEN1 (Sato et al., 2003). Consistent with these findings, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed increased Aβ42 and decreased Aβ40 production, yielding an approximately 10-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017).

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Research Models

This mutation has been introduced into mouse models of disease, including the APP751SL/PS1 KI double mutant, which also expresses APP with the London (V717I) and Swedish (K670N/M671L) mutations.

Last Updated: 01 Aug 2019


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Research Models Citations

  1. APP751SL/PS1 KI

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PubMed.
  2. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  3. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
  4. . Identification of PSEN1 and APP gene mutations in Korean patients with early-onset Alzheimer's disease. J Korean Med Sci. 2008 Apr;23(2):213-7. PubMed.
  5. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  6. . Distinct mechanisms by mutant presenilin 1 and 2 leading to increased intracellular levels of amyloid beta-protein 42 in Chinese hamster ovary cells. Biochemistry. 2003 Feb 4;42(4):1042-52. PubMed.
  7. . Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci. 2005 Jan 12;25(2):436-45. PubMed.
  8. . Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49-99 of beta-amyloid precursor protein. J Biol Chem. 2003 Jul 4;278(27):24294-301. PubMed.
  9. . 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.
  10. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Other Citations

  1. PSEN2 M239

Further Reading


  1. . Redox proteomics identification of oxidatively modified brain proteins in inherited Alzheimer's disease: an initial assessment. J Alzheimers Dis. 2006 Dec;10(4):391-7. PubMed.
  2. . Equimolar production of amyloid beta-protein and amyloid precursor protein intracellular domain from beta-carboxyl-terminal fragment by gamma-secretase. J Biol Chem. 2006 May 26;281(21):14776-86. PubMed.
  3. . DAPT-induced intracellular accumulations of longer amyloid beta-proteins: further implications for the mechanism of intramembrane cleavage by gamma-secretase. Biochemistry. 2006 Mar 28;45(12):3952-60. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PubMed.

Other mutations at this position


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