Mutations

PSEN1 M233V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.44716A>G
Genomic Mutation Name (NT1): g.61322A>G
dbSNP ID: rs63751287
Coding/Non-Coding: Coding
Genomic Region: Exon 7
Mutation Type: Point, Missense
Codon Change: ATG to GTG

Findings

This mutation was detected in woman with very early-onset Alzheimer’s disease (onset 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 years. 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.

Neuropathology

Neuropathological examination of the proband 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).

Biological Effect

Unknown. This is the third mutation identified which alters the M233 residue in PSEN1, the earlier ones being M233L (A>C) and M233T. The homologous codon in PSEN2 has known pathogenic mutations as well, see M239V which notably has the same nucleotide change (ATG to GTG) and amino acid change (M>V), and M239I.

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References

Mutations Citations

  1. PSEN1 M233L (A>C)
  2. PSEN1 M233T
  3. PSEN2 M239V
  4. PSEN2 M239I

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.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

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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