Mutations

PSEN1 M146V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Genomic Mutation Name (MET1): g.25639A>G
Genomic Mutation Name (NT1): g.42193A>G
dbSNP ID: rs63750306
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: ATG to GTG
Research Models: 3

Findings

This mutation was first reported in three families known as Fin1, Man92/20 and NY5201(Clark et al., 1995). In Fin1, a Swedish family of Finnish descent, there were three affected individuals reported over three generations. The mean age of onset was 36 years. This family was also described in Haltia et al., 1994 and Schöll et al., 2011.

In Man92/20 there were two affected individuals reported, one with post-mortem confirmation of a diagnosis of Alzheimer's disease. The mean age of onset in this family was 40 years.

The third family, NY5201, had seven reported affected individuals over two generations, two with post-mortem confirmation of the diagnosis. The mean age of onset in this family was 37 years. The mutation segregated with disease in all three families (Clark et al., 1995).

The M146V mutation was found in one individual with AD, but no further details were provided, other than that it was coinherited with a second PSEN1 mutation, S365Y (Rogaeva et al., 2001).

This mutation was also reported in Cervenakova et al., 1996.

More recently the M146V mutation was reported in an Argentine family with familial dementia with 13 affected individuals over four generations (Riudavets et al., 2013).The family was originally from Lisbon, Portugal, then moved to Argentina in the early 20th century  In this family, the proband was a 51 year-old male who at age 39 years sought medical attention due to personality changes including apathy and disinhibition. Neuropsychological assessment revealed executive dysfunction and memory loss. He met diagnostic criteria (Lund and Manchester) for the behavioral variant of frontotemporal dementia. He developed extrapyramidal signs, including rigidity, akinesia and movement disorders, but without tremor. Later he developed myoclonus, seizures and mutism. Little is known about the clinical course of the disease in other affected family members, but according to relatives, the proband’s mother and five other family members died before the age of 50 with a clinical diagnosis of FTD.

Neuropathology

In two of the original families, Man92/20 and NY5201, there was post-mortem confirmation of the diagnosis of AD, indicating neuropathology consistent with AD. In the Argentine family with a clinical presentation of FTD, autopsy of the proband was performed and detailed neuropathological findings reported (Riudavets et al., 2013). In brief, the post-mortem examination revealed mainly frontal and temporal atrophy and the coexistence of both AD and Pick’s disease including frequent β-amyloid deposits (CERAD Score C) occasionally with a cotton-wool appearance. Tangles were also observed (
Braak SCORE VI). Pick bodies were seen throughout the cortex and hippocampus, sufficient for a diagnosis of Pick’s disease. TDP-43-positive inclusions were absent.

Biological Effect

In COS1 cells co-transfected with APP 695, mutant PSEN1 increased the ratio of Aβ42/Aβ40 (Murayama et al., 1999).  The mutation also affects store-operated calcium channel activity in human neuroblastoma SK–N–SH cells, specifically, causing inhibition (Ryazantseva et al., 2013).

Research Models

This mutation was been introduced into several mouse models, including a knock-in animal, PSEN1(M146V) Knock-In, a transgenic, PS1(M146V), and a multi-transgenic, 3xTg.

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References

Research Models Citations

  1. PSEN1(M146V) Knock-In
  2. PS1(M146V)
  3. 3xTg

Mutations Citations

  1. PSEN1 S365Y

Paper Citations

  1. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Alzheimer's Disease Collaborative Group. Nat Genet. 1995 Oct;11(2):207-9. PubMed.
  2. . Chromosome 14-encoded Alzheimer's disease: genetic and clinicopathological description. Ann Neurol. 1994 Sep;36(3):362-7. PubMed.
  3. . Time course of glucose metabolism in relation to cognitive performance and postmortem neuropathology in Met146Val PSEN1 mutation carriers. J Alzheimers Dis. 2011;24(3):495-506. PubMed.
  4. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  5. . Identification of presenilin-1 gene point mutations in early-onset Alzheimer's disease families. American Journal of Human Genetics 59 Supp: A252, 1996.
  6. . Familial Dementia With Frontotemporal Features Associated With M146V Presenilin-1 Mutation. Brain Pathol. 2013 Mar 14; PubMed.
  7. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
  8. . Familial Alzheimer's disease-linked presenilin-1 mutation M146V affects store-operated calcium entry: does gain look like loss?. Biochimie. 2013 Jul;95(7):1506-9. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database