Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Ataxia
Genomic Mutation Name (MET1): g.25552C>G
Genomic Mutation Name (NT1): g.42106C>G
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: CCA to GCA
This mutation was first reported in a family with three members affected by early-onset progressive ataxia and dementia (Anheim et al., 2007). The clinical phenotype in this family was fairly homogenous with onset before age 35 and death between 35 and 40 years. The proband developed balance, writing, and memory problems at age 34. Her father developed symptoms at age 29 including tremor and problems with gait. The proband’s paternal grandmother reportedly experienced onset at age 24 including gait ataxia and balance impairment and died at age 35. The mutation was detected in the proband, but not in her unaffected mother. The other two affected individuals could not be genotyped as they were predeceased. The proband also carried a known polymorphism in PSEN1, E318G, which was initially thought to be benign, but has subsequently been associated with increased risk of late-onset AD (Benitez et al., 2013).
Ataxia was not among the symptoms reported in a Colombian pedigree found to carry the P117A mutation. As reported, the pedigree contained eight individuals over four generations who developed dementia during the fourth decade of life. The proband developed progressive memory impairment with gradual onset at 32 years of age and met NINCDS-ADRDA criteria for probable Alzheimer’s disease. Transmission of AD in this family is consistent with autosomal-dominant inheritance (Kauwe et al., 2008).
In vitro, the Aβ42/Aβtotal ratio was higher in HEK cells expressing P117A than in cells expressing wild-type PSEN1. Total Aβ levels were not significantly different (Kauwe et al., 2008).
- Anheim M, Hannequin D, Boulay C, Martin C, Campion D, Tranchant C. Ataxic variant of Alzheimer's disease caused by Pro117Ala PSEN1 mutation. J Neurol Neurosurg Psychiatry. 2007 Dec;78(12):1414-5. PubMed.
- Benitez BA, Karch CM, Cai Y, Jin SC, Cooper B, Carrell D, Bertelsen S, Chibnik L, Schneider JA, Bennett DA, , Fagan AM, Holtzman D, Morris JC, Goate AM, Cruchaga C. The PSEN1, p.E318G Variant Increases the Risk of Alzheimer's Disease in APOE-ε4 Carriers. PLoS Genet. 2013 Aug;9(8):e1003685. PubMed.
- Kauwe JS, Wang J, Chakraverty S, Goate AM, Henao-Martinez AF. Novel presenilin 1 variant (P117A) causing Alzheimer's disease in the fourth decade of life. Neurosci Lett. 2008 Jun 20;438(2):257-9. Epub 2008 Apr 15 PubMed.