Mutations

PSEN1 M146V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Frontotemporal Dementia : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
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 has been found in several families worldwide. It was first reported in three families with early onset AD known as Fin1, Man92/20, and NY5201 (Clark et al., 1995). In Fin1, a Swedish family of Finnish descent, there were three affected individuals, spanning 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 the Man92/20 family, there were two affected individuals, 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 spanning 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). Additional AD families and individuals carrying this mutation were identified by Cervenakova et al., 1996 and Rogaeva et al., 2001, and Pagnon de la Vega et al., 2022. In the Rogaeva study, the M146V mutation was co-inherited with a second PSEN1 mutation, S365Y.

The M146V mutation was also reported in an Argentine family with familial dementia, including 13 affected individuals spanning 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. Of note, movement deficits, including myoclonic epileptic seizures and gait difficulties, were also reported in Swedish/Finnish patients diagnosed with AD (Schöll et al., 2011Pagnon de la Vega et al., 2022).

In addition, this variant has been reported in two kindreds of East Asian ancestry. A family of the Chinese Familial Alzheimer's Disease Network included three affected siblings who carried the mutation, with ages at onset ranging from 36 to 38 years (Jia et al., 2020). Co-segregation with disease was suggested by the absence of the variant in a sibling who did not carry the mutation and remained cognitively healthy at age 48. In addition, the variant was identified in a man diagnosed with AD from a large cohort study in South China in which 14 genes associated with neurodegenerative dementias from 1795 patients were sequenced (Jiao et al., 2021). His age at onset was 42 years. He had a family history of the disease and his symptoms included memory loss, language impairment, as well as mental and behavioral deficits. Of note, in both studies, all affected carriers were APOE4 heterozygotes.

This mutation was absent from two exome variant databases, EVS and ExAC (Hsu et al., 2020).

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. Severe AD pathology was also described in two patients from the Swedish family of Finnish descent (Schöll et al., 2011). 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.

Three Swedish/Finnish individuals diagnosed with AD had widespread cortical hypometabolism as assessed by FDG-PET (Schöll et al., 2011Pagnon de la Vega et al., 2022).

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). An elevated Aβ42/Aβ40 ratio was also reported in mouse neuroblastoma cells which secreted more Aβ42 and less Aβ40 than cells expressing wild-type PSEN1 (Hsu et al., 2020), as well as in neurons derived from induced pluripotent stem cells (iPSCs), which showed decreased total Aβ production and elevated levels of Aβ42 and Aβ43 in culture supernatants (Kwart et al., 2019, Aug 2019 news). These findings were confirmed and extended in a study of human embryonic kidney cells lacking endogenous PSEN1/PSEN2 and expressing M146V showing that the Aβ37/Aβ42 ratio, reported to outperform the Aβ42/Aβ40 ratio as an indicator of AD pathogenicity, was decreased relative to cells expressing wildtype PSEN1 (Liu et al., 2022, Apr 2022 news). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicated that, in wild-type PSEN1, M146 closely contacts the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

M146V was also shown to promote the accumulation of APP β-C-terminal fragments which disrupt endosomes (Kwart et al., 2019, Aug 2019 news). Moreover, in knock-in mice expressing the variant, late endosome acidification and axonal transport declined with age, ultimately resulting in dystrophic neurites (Lie et al., 2022May 2022 news). These disruptions were traced to a harmful cascade triggered by overactivation of calcium channel TRPML1.

Additional effects reported in the literature include lowering wild-type PSEN1 gene expression in neuronal-like cells (Ahmadi and Wade-Martins, 2014) and inhibiting store-operated calcium channel activity in human neuroblastoma SK-N-SH cells (Ryazantseva et al., 2013) and in hippocampal neurons from knock-in mice resulting in loss of dendritic spines (Sun et al., 2014). Moreover, the mutation appears to increase calcineurin activity, impairing synaptic trafficking of glutamate AMPA receptors in mouse primary hippocampal neurons (Kim et al., 2015). It has also been reported to increase the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs), induce oxidative stress, and disurpt mitochondrial function (Han et al., 2021). 

The mutation has also been reported to alter trophic factor function and cerebral blood flow. In cortical neuronal cultures from knock-in mice, the mutant protein appeared to inhibit the neuroprotective functions of trophic factors eB1 and BDNF following glutamate excitotoxicity (Al Rahim et al., 2020). The effect was reported as dominant-negative, with mutant PSEN1 altering the stability of complexes formed between PSEN1, the glutamate NMDA receptor, and trophic factor receptors. Moreover, in brains from knock-in mice, the ability of cortical endothelial cells to sprout and form new blood vessels after ischemia was decreased, apparently due to reduced γ-secretase cleavage of the angiogenic peptide ephrinB2 (Yoon et al., 2020). Compromised cerebrovascular function in response to the potassium channel opener diazoxide was also reported in these mice (Liu et al., 2020).

A transcriptomic analysis of SH-SY5Y neuroblastoma cells expressing this variant revealed multiple alterations compared with cells expressing wildtype PSEN1 (Petralia et al., 2022). 

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging (Xiao et al., 2021Hsu et al., 2020). Based on their bioinformatic data, together with the genetic data and the authors' in vitro data on Aβ42 and Aβ40 production, Hsu and colleagues classified the mutation as probably pathogenic.

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. M146V: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. M146V: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. M146V: Cosegregation demonstrated in >1 family.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

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: 11 Aug 2022

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References

Research Models Citations

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

News Citations

  1. Familial AD Mutations, β-CTF, Spell Trouble for Endosomes
  2. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  3. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  4. Presenilin Mutations Stall Endosomal Transport, Swell Axons

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. . Identification of presenilin-1 gene point mutations in early-onset Alzheimer's disease families. Am J Hum Genet. 1996;59(Suppl):A252
  6. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  7. . Mutation analysis of disease causing genes in patients with early onset or familial forms of Alzheimer's disease and frontotemporal dementia. BMC Genomics. 2022 Feb 4;23(1):99. PubMed.
  8. . Familial Dementia With Frontotemporal Features Associated With M146V Presenilin-1 Mutation. Brain Pathol. 2013 Mar 14; PubMed.
  9. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  10. . The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
  11. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  12. . 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.
  13. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  14. . A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ. Neuron. 2019 Oct 23;104(2):256-270.e5. Epub 2019 Aug 12 PubMed.
  15. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  16. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  17. . Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function. Sci Adv. 2022 Apr 29;8(17):eabj5716. PubMed.
  18. . 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.
  19. . 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.
  20. . 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.
  21. . 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.
  22. . Alzheimer's disease-causing presenilin-1 mutations have deleterious effects on mitochondrial function. Theranostics. 2021;11(18):8855-8873. Epub 2021 Aug 17 PubMed.
  23. . Presenilin1 familial Alzheimer disease mutants inactivate EFNB1- and BDNF-dependent neuroprotection against excitotoxicity by affecting neuroprotective complexes of N-methyl-d-aspartate receptor. Brain Commun. 2020;2(2):fcaa100. Epub 2020 Jul 20 PubMed.
  24. . PS1 FAD mutants decrease ephrinB2-regulated angiogenic functions, ischemia-induced brain neovascularization and neuronal survival. Mol Psychiatry. 2020 Jun 15; PubMed.
  25. . Age-related impairment of cerebral blood flow response to KATP channel opener in Alzheimer's disease mice with presenilin-1 mutation. J Cereb Blood Flow Metab. 2020 Nov 17;:271678X20964233. PubMed.
  26. . Computational Analysis of Pathogenetic Pathways in Alzheimer's Disease and Prediction of Potential Therapeutic Drugs. Brain Sci. 2022 Jun 24;12(7) PubMed.
  27. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 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.
  5. . Longitudinal cognitive decline in autosomal-dominant Alzheimer's disease varies with mutations in APP and PSEN1 genes. Neurobiol Aging. 2019 Oct;82:40-47. Epub 2019 Jul 4 PubMed.

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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