Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genome Build: 105
Position: Chr14:73664768 C>T
dbSNP ID: rs63751229
Genomic Region: Exon 8
Mutation Type: Point, Missense
Codon Change: CCA to TCA
When expressed in mouse embryonic fibroblasts lacking endogenous presenilin-1 and presenilin-2, expression of the P267S mutant protein produces much lower levels of Aβ42 and Aβ40 compared to Aβ levels produced by wild-type protein. The relative ratio of Aβ42/Aβ40 is unchanged.
This mutation abolishes a recognition site for cyclophilin B, a chaperone protein in the endoplasmic reticulum that assists in presenilin-1 folding and maturation. In vitro, presenilin-1 protein carrying this mutation undergoes enhanced proteolytic degredation. When expressed in presenilin–deficient cells, γ-secretase activity is virtually abolished (Ben-Gedalya et al., 2015).
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