Mutations Position Table
PSEN1 M146 Mutations
| Mutation | Pathogenicity | DNA Change | Expected RNA | Protein Consequence | Coding/Non-Coding | Genomic Region | Neuropathology | Biological Effect | Primary Papers |
|---|---|---|---|---|---|---|---|---|
| M146I (G>A) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 5 | Neuropathology consistent with AD. |
Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons. Altered protein stability. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments. (M146I, nt change unspecified). |
Jørgensen et al., 1996 |
| M146I (G>C) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 5 | 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. Altered protein stability. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments. (M146I, nt change unspecified). |
Gustafson et al., 1998 |
| M146I (G>T) |
AD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 5 | Unknown, but carriers of a different nucleotide change 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. Altered protein stability. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments. (M146I, nt change unspecified). |
Rogaeva et al., 2001 |
| M146L (A>C) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 5 | 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, Aβ42/Aβ total, Aβ42/Aβ40 in cells and in vitro assays and decreased Aβ37/Aβ42. Impaired calcium dynamics, mitochondrial permeability, expression of synaptic and neuronal differentiation genes. |
Sherrington et al., 1995; Sorbi et al., 1995; Alzheimer's Disease Collaborative Group, 1995 |
| M146L (A>T) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 5 | 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 and decreased Aβ37/Aβ42. Impaired calcium dynamics, mitochondrial permeability, expression of synaptic and neuronal differentiation genes. |
Mangone et al., 1995; Morelli et al., 1998 |
| M146V |
AD : Pathogenic, FTD : Not Classified | Substitution | Substitution | Missense | Coding | Exon 5 | 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. |
Alzheimer's Disease Collaborative Group, 1995 |
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