Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659500 A>G
dbSNP ID: rs63751287
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to GTG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was detected in a woman with very early onset Alzheimer’s disease (at age 28) whose pedigree showed five affected family members over four generations (Houlden et al., 2001). Disease in the proband progressed rapidly, and she died at age 34. Her clinical presentation involved extrapyramidal features and early seizures. The clinical course in the proband was typical of her family, with affected members experiencing onset between the ages of 28 and 34 years, followed by rapid deterioration leading to death between 34 and 37. The clinical and neuropathological characteristics of this pedigree were described prior to the identification of the mutation (Revesz et al., 1997).

Although lack of DNA from family members precluded segregation analysis, the inheritance pattern is consistent with an autosomal-dominant trait. The mutation was not present in 150 control chromosomes.

Subsequently, this mutation was found in three members of a Canadian-Vietnamese family, who displayed a variety of atypical motor and psychiatric symptoms (Appel-Cresswell et al., 2018). The proband had a history of drug abuse in her teens. In her 20s, she exhibited memory and cognitive dysfunction, ataxia, dystonia, and verbal aggression, and experienced auditory hallucinations and seizures. By age 30, she was dysphagic, immobile, incontinent, and mute. An MRI at age 28 revealed generalized cerebral atrophy. The proband’s brother and father each began exhibiting symptoms at age 15—unsteady gait and cognitive difficulties in the former, and hallucinations in the latter—and by their 30s, they too displayed ataxia, dementia, neuropsychiatric symptoms, and evidence of seizures. The mother of the two affected siblings was neurologically normal and did not carry the M233V mutation.

The mutation was also identified in a Chinese individual who experienced memory loss starting at age 25, followed by bilateral parkinsonism responsive to L-DOPA at age 28 (Liu et al., 2019). The patient had two tonic-clonic seizures as a child. The mutation appears to have arisen de novo, as the parents did not carry the mutation.


Neuropathological examination of the proband of the first family showed abundant neurofibrillary tangles and amyloid plaques throughout the cerebral cortex. Occasional plaques in the spinal cord were also noted. Lewy bodies were observed in the substantia nigra and cortex. Moderate to severe amyloid angiopathy was also present in leptomeningeal, cerebral, and cerebellar vessels (Revesz et al., 1997; Houlden et al., 2001).

In the Chinese patient, FDG-PET revealed mild, bilateral hypermetabolism in the posterior putamen three years after onset, and hypometabolism in the posterior parietal cortex and right medial temporal lobe five years after onset (Liu et al., 2019). In addition, PiB-PET and florbetapir-PET indicated amyloid deposition in the frontal lobe, posterior cingulate, caudate, putament, and thalamus, and DAT-PET suggested reduced levels of dopamine transporters in the left putamen three years after onset. 

Biological Effect

When transfected into HEK293 cells stably expressing Swedish mtAPP 695 and BACE1, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage activity of PSEN1. This resulted in reduced secreted Aβ40, increased Aβ42, and an increased Aβ42/Aβ40 ratio (Li et al., 2016). 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).

Last Updated: 24 Oct 2019


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News Citations

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

Paper Citations

  1. . A novel presenilin mutation (M233V) causing very early onset Alzheimer's disease with Lewy bodies. Neurosci Lett. 2001 Nov 2;313(1-2):93-5. PubMed.
  2. . Pathology of familial Alzheimer's disease with Lewy bodies. J Neural Transm Suppl. 1997;51:121-35. PubMed.
  3. . PSEN1 p.Met233Val in a Complex Neurodegenerative Movement and Neuropsychiatric Disorder. J Mov Disord. 2018 Jan;11(1):45-48. Epub 2018 Jan 11 PubMed.
  4. . Diagnostic Approach of Early-Onset Dementia with Negative Family History: Implications from Two Cases of Early-Onset Alzheimer's Disease with De Novo PSEN1 Mutation. J Alzheimers Dis. 2019;68(2):551-558. PubMed.
  5. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  6. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A novel presenilin mutation (M233V) causing very early onset Alzheimer's disease with Lewy bodies. Neurosci Lett. 2001 Nov 2;313(1-2):93-5. PubMed.

Other mutations at this position


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