Mutations

PSEN1 I238M

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.44733C>G
Genomic Mutation Name (NT1): g.61339C>G
dbSNP ID:
Coding/Non-Coding: Coding
Genomic Region: Exon 7
Mutation Type: Point, Missense
Codon Change: ATC to ATG

Findings

This mutation was identified in an African American woman diagnosed with probable Alzheimer’s disease who had a family history of AD/dementia. Her presentation was fairly typical of AD starting with short-term memory loss, poor concentration, an inability to multi-task, and increased anxiety. These symptoms began at age 50 and gradually progressed to multiple cognitive domains and impairment of activities of daily living. This patient was enrolled in the ongoing longitudinal study, the Dominantly Inherited Alzheimer Network (DIAN).

The patient's father was diagnosed with AD in his late fifties and died at the age of 65. Her paternal aunt and grandmother also died with dementia but age of onset and age at death were not known.

It was not possible to confirm disease segregation in this family as DNA was not available from other affected members (all deceased) or unaffected members of the family. Probable pathogenicity was suspected based on the early onset of symptoms, the family history of dementia, the absence of the mutation in over 2000 African Americans screened in the NHLBI GO sequencing project, and the demonstrated in vitro effects on Aβ levels (Ting et al., 2014).

Neuropathology

Unknown; MRI showed progressive cerebral atrophy. PET showed hypometabolism in the frontal and temporal lobes.

Biological Effect

When expressed in HEK293 cells expressing APP with the Swedish mutation, the mutant PSEN1 increased Aβ40, Aβ42, and the Aβ42/Aβ40 ratio compared to cells expressing wild-type PSEN1 (Ting et al., 2014; see also Ringman et al., 2011).

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References

Paper Citations

  1. . A Novel PSEN1 Mutation (I238M) associated with Early-Onset Alzheimer's Disease in an African-American Woman. J Alzheimers Dis. 2014 Jan 7; PubMed.
  2. . Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer's disease due to a novel PSEN1 mutation. Neurosci Lett. 2011 Jan 10;487(3):287-92. PubMed.

External Citations

  1. the Dominantly Inherited Alzheimer Network (DIAN)
  2. NHLBI GO sequencing project

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . A Novel PSEN1 Mutation (I238M) associated with Early-Onset Alzheimer's Disease in an African-American Woman. J Alzheimers Dis. 2014 Jan 7; PubMed.