Mutations Position Table

PSEN1 L282 Mutations

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Mutation Pathogenicity DNA Change Expected RNA | Protein Consequence Coding/Non-Coding Genomic Region Neuropathology Biological Effect Primary
Papers
L282R
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Neuropathology consistent with Alzheimer's disease.

Decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios and increased Aβ43. The Aβ42/Aβ40 ratio was increased or unchanged.

Aldudo et al., 1998
L282P
AD : Not Classified Substitution Substitution | Missense Coding Exon 8

Unknown, but in one patient, MRI revealed mild, diffuse cortical atrophy, and FDG-PET showed severe, bilateral hypometabolism in parietal and temporal cortices.

Unknown, but multiple in silico algorithms predicted damaging

Kim et al., 2020
L282F
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Unknown; MRI showed mild medial temporal atrophy. FDG-PET showed glucose hypometabolism in the bilateral parietal cortices and posterior cingulate gyri.

Although Aβ42/Aβ40 was similar to controls, Aβ37/Aβ42 was decreased and Aβ43 levels were increased in a cell-based assay.

Hamaguchi et al., 2009
L282V
AD : Pathogenic Substitution Substitution | Missense Coding Exon 8

Extensive neurofibrillary tangles and amyloid deposits including both dense-cored plaques and diffuse plaques. Severe cerebral amyloid angiopathy (CAA) in the neocortex, hippocampus, and cerebellum. CAA deposits associated with dystrophic neurites and inflammatory gliosis. Severe white-matter loss. Cerebellar amyloid pathology associated with severe CAA and loss of Purkinje cells.

Increased Aβ42/Aβ40 ratio and decreased Aβ37/Aβ42 ratio in cells. In vitro, Aβ42 and Aβ40 production, as well as Aβ42/Aβ40 ratio, similar to wild-type. Impairs trafficking of the APOE receptor apoER2.

Dermaut et al., 2001

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