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. 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 |
Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.