Mutations Position Table
PSEN1 M146 Mutations
| Mutation | Clinical Phenotype |
Pathogenicity | Neuropathology | Biological Effect | Genomic Position | Genomic Region | Mutation Type Codon Change |
Research Models |
Primary Papers |
|---|---|---|---|---|---|---|---|---|---|
| M146I (G>A) |
Alzheimer's Disease | Alzheimer's Disease : Pathogenic | Neuropathology consistent with AD. |
Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons, suggesting inefficient carboxypeptidase activity.Variable protein levels, consistent with altered protein stability. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments. |
rs63750391 |
Coding Exon 5 |
Point, Missense ATG to ATA |
0 | Jørgensen et al., 1996; Janssen et al., 2003 |
| M146I (G>C) |
Alzheimer's Disease | Alzheimer's Disease : Pathogenic | Neuropathology consistent with AD in 3 cases, but more involvement of central grey areas, no vascular lesions, and very mild amyloid angiopathy. |
Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons, suggesting inefficient carboxypeptidase activity. Variability in mutant protein levels, consistent with altered protein stability. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments. |
rs63750391 |
Coding Exon 5 |
Point, Missense ATG to ATC |
0 | Gustafson et al., 1998 |
| M146I (G>T) |
Alzheimer's Disease | Alzheimer's Disease : Pathogenic | Unknown |
Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons, suggesting inefficient carboxypeptidase activity. High degree of variablilty in mutant protein levels, consistent with altered protein stability. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments. |
rs63750391 |
Coding Exon 5 |
Point, Missense ATG to ATT |
0 | Rogaeva et al., 2001 |
| M146L (A>C) |
Pick's disease, Alzheimer's Disease | Alzheimer's Disease : Pathogenic | Neuropathology consistent with AD in multiple affected mutation carriers. Pick bodies also have been noted in some cases. |
Increased Aβ42/Aβ total ratio; increased Aβ42/Aβ40 ratio; increased Aβ42. No change in Aβ38 or Aβ40 levels. Increased tau hyperphosphorylation. Disrupts calcium dynamics and mitochondrial permeability. |
rs63750306 |
Coding Exon 5 |
Point, Missense ATG to CTG |
14 | Sherrington et al., 1995; Sorbi et al., 1995; , 1995 |
| M146L (A>T) |
Alzheimer's Disease | Alzheimer's Disease : Pathogenic | Neuropathology consistent with AD. |
Increased Aβ42, Aβ42/Aβ total, Aβ42:Aβ40 in cells and in vitro assays. No significant change in Aβ38 or Aβ40. Impaired calcium dynamics and mitochondrial permeability. |
rs63750306 |
Coding Exon 5 |
Point, Missense ATG to TTG |
0 | Mangone et al., 1995; Morelli et al., 1998 |
| M146V |
Alzheimer's Disease, Frontotemporal Dementia | Alzheimer's Disease : Pathogenic, Frontotemporal Dementia : Unclear Pathogenicity | Variable: Neuropathology consistent with AD in some cases, but also, in at least one case, mixed pathology including frequent Aβ deposits, tangles, and Pick bodies. |
Increased Aβ42/Aβ40 ratio; increased Aβ42 and Aβ43; lowers wild-type PSEN1 gene expression. Inhibits store-operated calcium channel activity, associated with loss of dendritic spines. Increases calcineurin activity, impairs trafficking of glutamate AMPA receptors. Disrupts endosomes via accumulation of APP β-CTF. |
rs63750306 |
Coding Exon 5 |
Point, Missense ATG to GTG |
6 | , 1995 |
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