Mutations

PSEN1 A246E

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659540 C>A
dbSNP ID: rs63750526
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCG to GAG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7
Research Models: 4

Findings

This mutation was originally reported in 1995 in conjunction with the cloning of the PSEN1 gene (Sherrington et al., 1995). It was detected in a Canadian family of Anglo Saxon-Celtic origin known as FAD1. This pedigree is remarkable for its size and detail. It describes 531 individuals over eight generations and includes 52 affected family members (see Nee et al., 1983). The pattern of transmission is consistent with autosomal-dominant inheritance, and genetic analysis confirmed that the mutation segregated with disease. 

Thirty-nine members of the family were assessed at the NIH, and pathology was available for a subset of these. Clinical findings and pathology were consistent with AD. Diagnostic criteria for AD included: 1) insidious onset of memory disorder, intellectual dysfunction, and disintegration of social interaction and personal habits; 2) a gradually progressive course of failure in these functions for a minimum of 12 months; 3) exclusion of known reversible causes of dementia; and 4) the absence of stroke-like neurological episodes or deficits. The average age of onset in this family was 53 years, with a mean duration of six years.

The A246E was later found in a Polish patient from a pedigree called W.T. The patient met diagnostic criteria for probable AD according to NINCDS-ADRDA criteria (McKhann et al., 1984), with onset around age 50. He was thought to have autosomal dominant early onset AD; a parent and two siblings were also affected by dementia. Segregation could not be assessed (Kowalska et al., 2003; Kowalska et al., 2004). See Kowalska et al., 2004b for pedigree.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Postmortem data are available for several members of the FAD1 family. Generalized atrophy was present, most prominently in the frontal lobes and hippocampus. Neuronal loss was observed, as well as gliosis, neurofibrillary tangles, and plaques. Pick bodies were not seen. Autopsy of a presymptomatic carrier of the A246E mutation was reported to have accumulation of progranulin in the brain in addition to amyloid plaques (Gliebus et al., 2009).

Biological Effect

PSEN1 A246E affects APP processing in several ways. In cultured cells, it is associated with an increase in the Aβ42/Aβ total ratio (Murayama et al., 1999) and the Aβ42/Aβ40 ratio (Borchelt et al., 1996). In differentiating neural precursor cells and neurons derived from patient induced pluripotent stem cells (iPSCs), elevations in Aβ42 and Aβ43 secretion, Aβ42/Aβ40 ratio, and phospho-tau were reported (Mahairaki et al., 2014; Yang et al., 2017; Armijo et al., 2017; Kwart et al., 2019; Schrank et al., 2020). The Aβ42/Aβ40 ratio was also elevated in the brains of young transgenic mice co-expressing PSEN1 A246E and APP with the Swedish mutation (APPSwe/PSEN1(A246E)) compared with mice either expressing APPSwe alone or co-expressing wild-type PSEN1 with APPSwe (Borchelt et al., 1996). In vitro experiments with isolated proteins recapitulated the elevated Aβ42/Aβ40 ratio observed in cells and animals, but revealed a dramatic decrease in the production of both Aβ peptides (Sun et al., 2017). Moreover, in addition to affecting Aβ peptide production, A246E promotes the accumulation of APP β-C-terminal fragments (β-CTFs) which appears to disrupt endosomes (Kwart et al., 2019, Aug 2019 news). Enlarged endosomes and altered expression of genes involved in endocytic vesicle pathways were observed in iPSC-derived neurons. This phenotype correlated with β-CTF, but not Aβ, levels.

Studies using APP substrates with photosensitive cross-linkable amino acids revealed the mutant likely causes mispositioning of the APP C99 cleavage domain (Fukumori and Steiner, 2016; Trambauer et al., 2020). In particular, altered cross-linking at T48 and L49, the initial substrate cleavage sites of C99, was reported. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). Also, in silico modeling of the structure of the mutant PSEN1 predicted a reduced distance between transmembrane domains 6 and 7 which could impair the interaction between APP and the PSEN1 active site (Soto-Ospina et al., 2021).

Interestingly, this variant may also fuel tau pathology. Injection of exosomes from neurons derived from patient induced pluripotent stem cells (iPSCs) were reported to induce tau deposits in mouse brains (Podvin et al., 2021). Their protein cargo differed from that of non-carrier exosomes, including increased levels of APP, and altered levels of phosphatases and kinases involved in regulating tau phosphorylation.

Also of note, this mutation appears to impair cellular health in multiple ways. For example, the viability of iPSC-derived neurons dropped more dramatically than that of controls after exposure to increasing concentrations of Aβ42 oligomers (Armijo et al., 2017). In addition, premature neuronal differentiation with decreased proliferation and increased apoptosis was observed in neural precursor cells derived from patient iPSCs (Yang et al., 2017). The authors note that the differentiation alteration may be mediated, at least in part, by disruption of the Wnt-Notch pathway. Impairments in autophagy, mitophagy, and lysosomal functions were also reported in patient cells (Coffey et al., 2014; Martin-Maestro et al., 2017). Moreover, the mutant appears to disrupt intracellular calcium dynamics. PSEN1 has been reported to act as a passive calcium leak channel in the endoplasmic reticulum, and the A246E mutant was reported to abolish this activity in mouse embryonic fibroblasts and primary fibroblasts from a patient (Nelson et al., 2007). Additionally, iPSC-derived neurons were found to release elevated levels of calcium from the endoplasmic reticulum in response to ryanodine receptor stimulation, a response that was normalized by incubation with dantrolene, a negative allosteric modulator (Schrank et al., 2020). 

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

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.

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. A246E: 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.

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. A246E: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.

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

Several research models expressing this mutation have been generated. Mouse models of disease include the double mutant mice APP(V717I) x PS1(A246E) and APPSwe/PSEN1(A246E). In addition, induced pluripotent stem cell (iPSC) lines have been generated from mutation carrier cells (Mahairaki et al., 2014; Yang et al., 2017; Armijo et al., 2017; Muñoz et al., 2018; Podvin et al., 2021; Raska et al., 2021; Caldwell et al., 2022), and CRISPR technology has been used to generate a collection of isogenic iPSCs with familial AD mutations, including A246E (Kwart et al., 2019). Of note, Caldwell and colleagues identified four AD-associated endotypes in iPSC-derived neurons which they used for evaluating candidate therapy effects: activation of cell cycle re-entry and de-differentiation combined with repression of neuronal lineage definition and neuronal function (Caldwell et al., 2022). Also, a three-dimensional cell culture model that recapitulates Aβ aggregation has been created using iPSC-derived neurons (Hernández-Sapiéns et al., 2020).

Last Updated: 15 Aug 2022

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References

Research Models Citations

  1. APP(V717I) x PS1(A246E)
  2. APPSwe/PSEN1(A246E)

News Citations

  1. Familial AD Mutations, β-CTF, Spell Trouble for Endosomes
  2. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. Mahairaki V, Ryu J, Peters A, Chang Q, Li T, Park TS, Burridge PW, Talbot CC Jr, Asnaghi L, Martin LJ, Zambidis ET, Koliatsos VE. Induced pluripotent stem cells from familial Alzheimer's disease patients differentiate into mature neurons with amyloidogenic properties. Stem Cells Dev. 2014 Dec 15;23(24):2996-3010. PubMed.
  2. Yang J, Zhao H, Ma Y, Shi G, Song J, Tang Y, Li S, Li T, Liu N, Tang F, Gu J, Zhang L, Zhang Z, Zhang X, Jin Y, Le W. Early pathogenic event of Alzheimer's disease documented in iPSCs from patients with PSEN1 mutations. Oncotarget. 2017 Jan 31;8(5):7900-7913. PubMed.
  3. Armijo E, Gonzalez C, Shahnawaz M, Flores A, Davis B, Soto C. Increased susceptibility to Aβ toxicity in neuronal cultures derived from familial Alzheimer's disease (PSEN1-A246E) induced pluripotent stem cells. Neurosci Lett. 2017 Feb 3;639:74-81. Epub 2016 Dec 26 PubMed.
  4. Muñoz SS, Balez R, Castro Cabral-da-Silva ME, Berg T, Engel M, Bax M, Do-Ha D, Stevens CH, Greenough M, Bush A, Ooi L. Generation and characterization of human induced pluripotent stem cell lines from a familial Alzheimer's disease PSEN1 A246E patient and a non-demented family member bearing wild-type PSEN1. Stem Cell Res. 2018 Aug;31:227-230. Epub 2018 Aug 13 PubMed.
  5. Podvin S, Jones A, Liu Q, Aulston B, Mosier C, Ames J, Winston C, Lietz CB, Jiang Z, O'Donoghue AJ, Ikezu T, Rissman RA, Yuan SH, Hook V. Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons. ACS Omega. 2021 May 25;6(20):13033-13056. Epub 2021 May 13 PubMed.
  6. Raska J, Hribkova H, Klimova H, Fedorova V, Barak M, Barta T, Pospisilova V, Vochyanova S, Vanova T, Bohaciakova D. Generation of six human iPSC lines from patients with a familial Alzheimer's disease (n = 3) and sex- and age-matched healthy controls (n = 3). Stem Cell Res. 2021 May;53:102379. Epub 2021 Apr 30 PubMed.
  7. Caldwell AB, Liu Q, Zhang C, Schroth GP, Galasko DR, Rynearson KD, Tanzi RE, Yuan SH, Wagner SL, Subramaniam S. Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer's disease. Alzheimers Dement. 2022 Jan 27; PubMed.
  8. Kwart D, Gregg A, Scheckel C, Murphy EA, Paquet D, Duffield M, Fak J, Olsen O, Darnell RB, Tessier-Lavigne M. 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.
  9. Hernández-Sapiéns MA, Reza-Zaldívar EE, Cevallos RR, Márquez-Aguirre AL, Gazarian K, Canales-Aguirre AA. A Three-Dimensional Alzheimer's Disease Cell Culture Model Using iPSC-Derived Neurons Carrying A246E Mutation in PSEN1. Front Cell Neurosci. 2020;14:151. Epub 2020 Jun 12 PubMed.
  10. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
  11. Nee LE, Polinsky RJ, Eldridge R, Weingartner H, Smallberg S, Ebert M. A family with histologically confirmed Alzheimer's disease. Arch Neurol. 1983 Apr;40(4):203-8. PubMed.
  12. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. PubMed.
  13. Kowalska A, Wender M, Florczak J, Pruchnik-Wolinska D, Modestowicz R, Szczech J, Rossa G, Kozubski W. Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznań region. J Appl Genet. 2003;44(2):231-4. PubMed.
  14. Kowalska A, Pruchnik-Wolińska D, Florczak J, Szczech J, Kozubski W, Rossa G, Wender M. Presenilin 1 mutations in Polish families with early-onset Alzheimer's disease. Folia Neuropathol. 2004;42(1):9-14. PubMed.
  15. Kowalska A, Pruchnik-Wolińska D, Florczak J, Modestowicz R, Szczech J, Kozubski W, Rossa G, Wender M. Genetic study of familial cases of Alzheimer's disease. Acta Biochim Pol. 2004;51(1):245-52. PubMed.
  16. Gliebus G, Rosso A, Lippa CF. Progranulin and beta-amyloid distribution: a case report of the brain from preclinical PS-1 mutation carrier. Am J Alzheimers Dis Other Demen. 2009 Dec-2010 Jan;24(6):456-60. PubMed.
  17. Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A. 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.
  18. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996 Nov;17(5):1005-13. PubMed.
  19. Schrank S, McDaid J, Briggs CA, Mustaly-Kalimi S, Brinks D, Houcek A, Singer O, Bottero V, Marr RA, Stutzmann GE. Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer's Disease Pathology. Int J Mol Sci. 2020 Feb 4;21(3) PubMed.
  20. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  21. Fukumori A, Steiner H. Substrate recruitment of γ-secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping. EMBO J. 2016 Aug 1;35(15):1628-43. Epub 2016 May 23 PubMed.
  22. Trambauer J, Rodríguez Sarmiento RM, Fukumori A, Feederle R, Baumann K, Steiner H. Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation. EMBO Rep. 2020 Jan 7;21(1):e47996. Epub 2019 Nov 25 PubMed.
  23. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  24. Soto-Ospina A, Araque Marín P, Bedoya G, Sepulveda-Falla D, Villegas Lanau A. Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer's Disease on the Orthosteric Site. Front Mol Biosci. 2021;8:649990. Epub 2021 Jun 2 PubMed.
  25. Coffey EE, Beckel JM, Laties AM, Mitchell CH. Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer's disease-linked presenilin 1 A246E mutation can be reversed with cAMP. Neuroscience. 2014 Mar 28;263:111-24. Epub 2014 Jan 10 PubMed.
  26. Martín-Maestro P, Gargini R, A Sproul A, García E, Antón LC, Noggle S, Arancio O, Avila J, García-Escudero V. Mitophagy Failure in Fibroblasts and iPSC-Derived Neurons of Alzheimer's Disease-Associated Presenilin 1 Mutation. Front Mol Neurosci. 2017;10:291. Epub 2017 Sep 14 PubMed.
  27. Nelson O, Tu H, Lei T, Bentahir M, de Strooper B, Bezprozvanny I. Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest. 2007 May;117(5):1230-9. Epub 2007 Apr 12 PubMed.
  28. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

Papers

  1. Raja WK, Mungenast AE, Lin YT, Ko T, Abdurrob F, Seo J, Tsai LH. Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer's Disease Phenotypes. PLoS One. 2016;11(9):e0161969. Epub 2016 Sep 13 PubMed.
  2. Liu Q, Waltz S, Woodruff G, Ouyang J, Israel MA, Herrera C, Sarsoza F, Tanzi RE, Koo EH, Ringman JM, Goldstein LS, Wagner SL, Yuan SH. Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol. 2014 Dec;71(12):1481-9. PubMed.
  3. Elsworthy RJ, Crowe JA, King MC, Dunleavy C, Fisher E, Ludlam A, Parri HR, Hill EJ, Aldred S. The effect of citalopram treatment on amyloid-β precursor protein processing and oxidative stress in human hNSC-derived neurons. Transl Psychiatry. 2022 Jul 18;12(1):285. PubMed.

Protein Diagram

Primary Papers

  1. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.

Other mutations at this position

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Alzpedia

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