Mutations Position Table
PSEN1 H163 Mutations
| Mutation | Pathogenicity | DNA Change | Expected RNA | Protein Consequence | Coding/Non-Coding | Genomic Region | Neuropathology | Biological Effect | Primary Papers |
|---|---|---|---|---|---|---|---|---|
| H163P |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 5 | Brain biopsy of the frontal cortex showed numerous senile plaques and neurofibrillary tangles compatible with a diagnosis of AD. No spongiform changes or abnormal prion proteins were detected. |
Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40. |
Kim et al., 2012 |
| H163R |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 5 | Data are limited, but neuropathology consistent with AD has been observed in at least one case. |
Increased total Aβ, Aβ42, and Aβ43, while reducing Aβ40 and Aβ38 production in cells; drastic reduction of Aβ42 and Aβ40 production in vitro. Affects γ-secretase-dependent neurexin processing. |
Campion et al., 1995; Sherrington et al., 1995; Tanahashi et al., 1995 |
| H163Y |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 5 | Typical AD neuropathology (one case); decreased glucose metabolism in presymptomatic mutation carriers, especially in the thalamus. Widespread brain amyloid (PiB-PET) and shrunken hippocampi. |
Decreased CSF Aβ42 and Aβ38 levels. Increased Aβ42/Aβ total ratio when expressed in COS-1 cells co-transfected with APP695, and increased Aβ42 production in an in vitro assay using purified proteins. |
Alzheimer's Disease Collaborative Group, 1995 |
Three different missense mutations have been described which are predicted to cause amino acid substitutions at position 163. H163R and H163Y were discovered early (1995), whereas H163P was not reported until nearly 20 years later. In addition, whereas H163R is among the most frequently observed AD mutations in diverse populations, H163P has been reported in a single individual, with an intermediate reported frequency for H163Y. Age of onset varies as well, ranging from 37–52 years for H163R, 44-65 years for H163Y, and 33 years for the single H163 patient.
Although individuals with mutations at this position meet clinical criteria for AD, atypical AD symptoms were frequently reported, including early- or late-stage myoclonus and seizures, as well as aphasia, spasticity, and pyramidal signs.
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