Mutations Position Table

PSEN1 M146 Mutations

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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
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 : Not Classified

Unknown, but carriers of a different nucleotide mutation resulting in the same amino acid substitution had neuropathology consistent with AD.

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)
Alzheimer's Disease, Pick's disease Alzheimer's Disease : Pathogenic

Neuropathology consistent with AD in multiple affected mutation carriers. Pick bodies and Lewy body pathology, as assessed by α-synuclein staining, have been noted in some cases.

Increased Aβ42/Aβ total ratio, Aβ42/Aβ40 ratio, and Aβ42. Disrupted 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. In one case, Lewy body pathology in the amygdala, cingulate gyrus, and substantia nigra. 

Increased Aβ42, Aβ42/Aβ total, Aβ42/Aβ40 in cells and in vitro assays. 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 : Not Classified

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; lowered wild-type PSEN1 gene expression. Disrupted endosomes via accumulation of APP β-CTF. Disrupted calcium channels, triggered cascade resulting in altered axonal transport, damage/loss of neurites. Increased calcineurin activity, impaired trafficking of glutamate AMPA receptors. Disrupted mitochondrial function, altered trophic factor function, and cerebral blood flow.

rs63750306
Coding
Exon 5
Point, Missense
ATG to GTG
6 , 1995

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