Mutations

PSEN1 P117S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.25552C>T
Genomic Mutation Name (NT1): g.42106C>T
dbSNP ID: rs63750550
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: CCA to TCA

Findings

This mutation has been reported in an American family with early-onset Alzheimer’s disease (Dowjat et al., 2004). The family had three affected individuals over the three generations described in the pedigree. The first symptom in the proband was personality changes at age 33. By age 35 he had severe dementia and was unable to state the date, month, year, place, or name of the president. Myoclonus was also noted, He died at age 54. The proband’s younger sibling had onset of cognitive decline at age 31, which also started with personality problems. At age 36 years, she suffered a grand mal seizure and was subsequently noted to have myoclonus. Two years later, she was immobile, mute, and survived more than 13 years in a persistent vegetative state. The father of these two siblings experienced cognitive decline beginning at age 29 years, leading to his death four years later. Two years prior to his death he had “extreme forgetfulness”, anxiety, depression, unsteady gait, stooped posture, and hand tremor. The P117S mutation was detected in the two affected siblings, but was absent in their unaffected mother, presumably having been transmitted through their affected, predeceased father. No mutations were found in PSEN2 or APP.

Neuropathology

Neuropathological data are available for one patient, the proband from the family described above, and a diagnosis of AD was confirmed by CERAD criteria. In brief, severe brain atrophy was noted with neuronal loss estimated to be greater than 70 percent. There was also extensive loss of white matter and active gliosis throughout the brain. Lewy bodies were also noted (Dowjat et al., 2004).

Biological Effect

In vitro this mutation increased the relative amount of Aβ42 secreted by N2a cells by approximately 2-fold compared to cells stably overexpressing wild-type PSEN1. A similar relative increase in Aβ42 was observed in conditioned media from skin fibroblasts cultured from a P117S patient compared to cells from an age-matched donor. In both skin fibroblasts and PSEN1-transfected N2a cells, the overall amount of secreted Aβ remained the same.

This mutation was also shown to affect neurite outgrowth in N2a cells. Compared to cells expressing wild-type PSEN1, cells expressing either the P117R or P117S mutation had reduced outgrowth (Dowjat et al., 2004).

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References

Paper Citations

  1. . A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 (Pro117Ser): Comparison of clinical, neuropathological and cell culture phenotypes of Pro117Leu and Pro117Ser mutations. J Alzheimers Dis. 2004 Feb;6(1):31-43. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database