Mutations Position Table
PSEN2 M239 Mutations
| Mutation | Pathogenicity | DNA Change | Expected RNA | Protein Consequence | Coding/Non-Coding | Genomic Region | Neuropathology | Biological Effect | Primary Papers |
|---|---|---|---|---|---|---|---|---|
| M239I |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 8 | Moderate cortical atrophy; Numerous neurofibrillary tangles; Numerous senile plaques, especially in the amygdala. |
Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF; Reduced calcium release. |
Finckh et al., 2000 |
| M239T |
AD : Uncertain Significance | Substitution | Substitution | Missense | Coding | Exon 8 | Unknown, but florbetapir-PET indicated amyloid accumulation in one carrier and CSF biomarkers were consistent with AD in another. Atrophy of the parietal lobe was observed in both patients, with one of them also having occipital cortex atrophy. In the latter patient, FDG-PET suggested hypometabolism in parietal, temporal, and occipital cortices. |
Unknown, but in silico algorithms predicted deleterious (PHRED-scaled CADD score > 20). |
Li et al., 2021; Jiao et al., 2021; Mao et al., 2021 |
| M239V |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 8 | Diffuse cerebral atrophy; Senile plaques; Neurofibrillary tangles (stage VI of Braak and Braak); Ectopic neurons in the subcortical white matter; Extracellular "ghost" neurofibrillary tangles. |
Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF. |
Rogaev et al., 1995 |
There are three reported variants at codon 239 in the fifth transmembrane domain of PSEN2. M239I and M239V were two of the earliest mutations in PSEN2 to be reported, and both have been shown to segregate with AD in their respective kindreds. In addition, both have been shown to produce elevated levels of Aβ42 in vitro and increase the Aβ42/Aβ40 ratio compared to wild-type PSEN2 (Walker et al., 2005).
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