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
13 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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