Mutations

PSEN1 Y115H

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.25546T>C
Genomic Mutation Name (NT1): g.42100T>C
dbSNP ID: rs63749962
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: TAT to CAT

Findings

This mutation was first identified in a small French kindred, known as “Family ALZ 025" or "ALZ 25”. This family had two affected individuals over two generations, the proband and the proband’s father, with onset at age 35 and 37. The mutation was absent in the proband’s unaffected mother who was cognitively healthy at age 80 and absent in 50 unrelated control subjects. The proband’s paternal grandparents were unaffected by age 75, so the authors speculated the mutation may have arisen de novo in the proband’s father (Campion et al., 1995; Campion et al., 1999). A second family, also from France, has been identified. The family, known as "ALZ 76" had three affected members over three generations. Age at onset ranged from 36 to 47 years (Campion et al., 1999).

The mutation was also found in a German kindred with at least four affected individuals over two generations. The proband was a 44 year-old patient ("Patient p.39") who died severely demented after three years. The proband’s sister also died around age 40 with symptoms including epileptic seizures and myoclonus. The proband’s brother died at age 43 after a very similar disease course; autopsy confirmed AD. The proband’s mother died severely demented in her early forties (Finckh et al., 2005).

Neuropathology

Postmortem analysis revealed pathology consistent with AD (Finckh et al., 2005).

Biological Effect

In COS-1 cells co-transfected with APP695 and either wild-type or mutant PSEN1, mutant PSEN1 increased the proportion of Aβ42 relative to total Aβ levels (Murayama et al., 1999). Similarly, in HEK-293 cells expression of the mutant PSEN1 significantly increased Aβ42 secretion and the ratio of Aβ42/Aβ40 compared to cells expressing wild-type PSEN1. There was no significant effect on Aβ40 (Shioi et al., 2007).

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References

Paper Citations

  1. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. 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. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
  4. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
  5. . FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem. 2007 May;101(3):674-81. Epub 2007 Jan 24 PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.

Other mutations at this position

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