Mutations

PSEN1 M146V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Reference Assembly: GRCh37 (105)
Position: Chr14:73640371 A>G
dbSNP ID: rs63750306
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to GTG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5
Research Models: 6

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 postmortem 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 postmortem 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 co-inherited 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 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 postmortem 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 postmortem examination revealed mainly frontal and temporal atrophy and the coexistence of both AD and Pick’s disease, including frequent Aβ 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

When expressed in HEK293 or COS-1 cells, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage activity of PSEN1, resulting in higher levels of secreted Aβ42 and an increased Aβ42/Aβ40 ratio (Murayama et al., 1999Li et al., 2016). PSEN1 M146V has also been reported to lower wild-type PSEN1 gene expression in neuronal-like cells (Ahmadi and Wade-Martins, 2014).

Additionally, the mutation inhibits store-operated calcium channel activity in human neuroblastoma SK-N-SH cells (Ryazantseva et al., 2013), and in hippocampal neurons from the PSEN1(M146V) Knock-In mouse model, which results in loss of dendritic spines (Sun et al., 2014). Moreover, the mutation has been found to increase calcineurin activity, impairing synaptic trafficking of glutamate AMPA receptors in mouse primary hippocampal neurons (Kim et al., 2015).

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. It has also been introduced into human induced pluripotent stem cells using CRISPR/Cas9 to generate heterozygous and homozygous cell lines (Paquet et al., 2016).

Last Updated: 15 Mar 2019

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References

Research Models Citations

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

Paper Citations

  1. . Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9. Nature. 2016 May 5;533(7601):125-9. Epub 2016 Apr 27 PubMed.
  2. . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
  3. . Chromosome 14-encoded Alzheimer's disease: genetic and clinicopathological description. Ann Neurol. 1994 Sep;36(3):362-7. PubMed.
  4. . 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.
  5. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  6. . Identification of presenilin-1 gene point mutations in early-onset Alzheimer's disease families. Am J Hum Genet. 1996;59(Suppl):A252
  7. . Familial Dementia With Frontotemporal Features Associated With M146V Presenilin-1 Mutation. Brain Pathol. 2013 Mar 14; PubMed.
  8. . 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.
  9. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  10. . Familial Alzheimer's disease coding mutations reduce Presenilin-1 expression in a novel genomic locus reporter model. Neurobiol Aging. 2014 Feb;35(2):443.e5-443.e16. PubMed.
  11. . 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.
  12. . Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice. Neuron. 2014 Apr 2;82(1):79-93. PubMed.
  13. . Reduction of increased calcineurin activity rescues impaired homeostatic synaptic plasticity in presenilin 1 M146V mutant. Neurobiol Aging. 2015 Dec;36(12):3239-46. Epub 2015 Sep 18 PubMed.

Other Citations

  1. S365Y

Further Reading

Papers

  1. . Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer's Disease. J Int Neuropsychol Soc. 2017 Mar;23(3):195-203. Epub 2017 Jan 12 PubMed.
  2. . Presenilin 1 mutations influence processing and trafficking of the ApoE receptor apoER2. Neurobiol Aging. 2017 Jan;49:145-153. Epub 2016 Oct 11 PubMed.
  3. . miR-342-5p decreases ankyrin G levels in Alzheimer's disease transgenic mouse models. Cell Rep. 2014 Jan 30;6(2):264-70. Epub 2014 Jan 16 PubMed.
  4. . Endogenous expression of FAD-linked PS1 impairs proliferation, neuronal differentiation and survival of adult hippocampal progenitors. Mol Neurodegener. 2013 Oct 20;8(1):41. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.

Other mutations at this position

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