Mutations

PSEN1 P117R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.25553C>G
Genomic Mutation Name (NT1): g.42107C>G
dbSNP ID: rs63749805
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: CCA to CGA

Findings

This mutation was first reported in a Polish woman who developed memory complaints at age 36 (Zekanowski et al., 2003). Other symptoms included apathy, stereotyped behavior, and seizures. She met NINCDS-ADRDA criteria for Alzheimer’s disease. Family history was unavailable, therefore pathogenicity could not be assessed, but the authors noted that other pathogenic mutations have been detected at the this codon in other Polish families (see P117S and P117L; Dowjat et al., 2002; Wisniewski et al., 1998).

This mutation was also identified in a 35 year-old woman originally from Colombia who experienced memory problems beginning at age 33 (Gómez-Tortosa et al. , 2010). Although motor disturbances were not part of her initial presentation, she developed myoclonus, seizures, and gait impairment within two years of onset. She died at age 37. She had a family history of dementia including an affected father and three older siblings. Her father experienced onset at age 37 and died at age 42. Her brother had onset at 38 and died at 41. Two older sisters had onset at ages 36 and 37 years, and at the time of the report, were living with severe dementia at ages 39 and 40 years.

Neuropathology

Unknown.

Biological Effect

HEK cells co-expressing P117R PSEN1 and APP with the Swedish mutation released more Aβ40 and Aβ42 than cells transfected with wild-type PSEN1. Although both peptides were elevated, the increase in Aβ42 was greater (Bialopiotrowicz et al., 2012).

This mutation was found to affect cell cycle progression in immortalized B-lymphocytes from mutation carriers. Specifically, G1 phase was prolonged and S phase shortened in conjunction with increased levels of p53 and p21 (Bialopiotrowicz et al., 2012).

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References

Mutations Citations

  1. PSEN1 P117S
  2. PSEN1 P117L

Paper Citations

  1. . Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol. 2003 Dec;184(2):991-6. PubMed.
  2. . 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.
  3. . A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years. Neuroreport. 1998 Jan 26;9(2):217-21. PubMed.
  4. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
  5. . Highly Pathogenic Alzheimer's Disease Presenilin 1 P117R Mutation Causes a specific Increase in p53 and p21 Protein Levels and Cell Cycle Dysregulation in Human Lymphocytes. J Alzheimers Dis. 2012 Jan 1;32(2):397-415. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol. 2003 Dec;184(2):991-6. PubMed.

Other mutations at this position

View Table