Mutations

PSEN1 C410Y

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73683933 G>A
dbSNP ID: rs661
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TGT to TAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This comparatively well-studied mutation has been identified in at least three families affected by early onset Alzheimer’s disease, with symptom onset typically in the mid- to late 40s.

The C410Y mutation was reported by Sherrington et al., 1995, in conjunction with the cloning of the PSEN1 gene, known at the time as S182. The report utilized genetic data from 14 pedigrees, including two carrying the C410Y mutation. Both C410Y families (FAD3 and NIH2) were Ashkenazi Jewish. Five affected carriers and one unaffected non-carrier were identified in the FAD3 family, indicating co-segregation of the variant with disease. Clinical details of the FAD3 family, including pedigree, are reported in Goudsmit et al., 1981. This FAD3 family, also known as the S.W. or SNW family, had at least 20 affected individuals, five with neuropathological confirmation of AD. Age of onset for the confirmed cases ranged from 48 to 56 years (Poorkaj et al., 1998). Alzforum was unable to find published data on the NIH2 family.

A third kindred, known as ROU 011, was identified in France. This kindred includes at least 14 affected family members (see Campion et al., 1995, for pedigree). Symptom onset ranged from 40 to 60 years of age. The mutation was shown to segregate with disease in this family, supported by the identification of two affected carriers and one unaffected non-carrier. See also Campion et al., 1999.

The C410Y mutation was also one of several rare variants detected by exome sequencing in a British cohort composed of 47 unrelated early onset AD cases and 179 elderly controls who were free of AD-associated neuropathology (Sassi et al., 2014). The mutation was detected in one Caucasian individual who developed cognitive decline at age 49. The patient died at age 57 with autopsy-confirmed AD.

Of note, at least one carrier of this mutation presented with seizures. These started at age 48, eight years after disease onset (Zarea et al., 2016).

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

Neuropathology

Neuropathology consistent with AD has been reported in multiple affected members from at least two families.

In addition, amyloid imaging has been performed in several members of a C410Y kindred. Specifically, amyloid levels in five presymptomatic mutation carriers (35 to 45 years of age) and one non-carrier family member (age 35) were measured by PiB-PET. Most notable was high focal PiB retention in the striatum coupled with a relative lack of PiB in cortical areas typically affected by AD. These findings suggest that, at least in this family, amyloid deposition begins in the striatum well before the onset of cognitive symptoms (Klunk et al., 2007). Consistent with an extended prodromal phase, Aβ42 levels in the CSF of presymptomatic C410Y carriers are already very low compared with levels in control subjects, at four to 11 years prior to estimated age of onset (Moonis et al., 2005).

At least one report has indicated plaques of the cotton-wool type, diffuse deposits that lack a dense core (Haleem et al., 2007).

Biological Effect

Many studies have examined the effects of C410Y mutation in isolated proteins, cell cultures, or mouse models. Earlier studies (Xia et al., 1997; Murayama et al., 1999; Heilig et al., 2013; Sun et al., 2017; Xia et al., 2015, Veugelen et al., 2016) showed effects on APP processing but whether the variant resulted in a loss- or gain-of-function was cause for debate (April 2016 news). 

More recent studies, examining a broader range of Aβ peptides, have helped clarify the variant’s effects. One such study, reported in a preprint, found that in HEK293 cells expressing C410Y, the Aβ42/Aβ40 ratio was increased relative to that of cells expressing wildtype PSEN1, and the ratio of short to long Aβ species was decreased (Schultz et al., 2023). In this study, an indicator of γ-secretase function as a percentage of wildtype activity was developed combining the Aβ (37 + 38 + 40) / (42 + 43) ratio—a measure of γ-processivity—with the commonly used Aβ42/Aβ40 ratio—a measure of the relative production of aggregation-prone Aβ. This composite score, 32.79 for C410Y, was strongly associated with AD age at onset, as well as biomarker and cognitive trajectories across multiple PSEN1 variants.

C410Y has also been reported to reduce PSEN1 gene expression (Ahmadi et al., 2014) and impair processing and signaling of Notch-1 (Baumeister et al., 1997; Song et al., 1999; Nakajima et al., 2000) and neurexins, neuronal membrane proteins that regulate synaptic formation (Saura et al., 2011).

A dominant-negative effect on wild-type PSEN1 may also contribute to C410Y pathogenicity. Experiments using cultured cells and isolated proteins revealed the mutant alters production of Aβ peptides by wild-type presenilin, an effect that was differentially sensitive to detergents suggesting inhibition through hetero-oligomerization (Heilig et al., 2013; Zhou et al., 2017).

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, Sassi et al., 2014).

 

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. C410Y: Functional observations are mixed, but all suggest a damaging effect.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. C410Y: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

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. C410Y: 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

A non-human primate model of AD carrying this variant has been created using CRISPR/Cas9 technology in marmosets (Sukoff Rizzo et al., 2023).

Last Updated: 25 Aug 2023

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References

News Citations

  1. Pathogenic Presenilin Mutations Generate Aβ43

Paper Citations

  1. Sukoff Rizzo SJ, Homanics G, Schaeffer DJ, Schaeffer L, Park JE, Oluoch J, Zhang T, Haber A, Seyfried NT, Paten B, Greenwood A, Murai T, Choi SH, Huhe H, Kofler J, Strick PL, Carter GW, Silva AC. Bridging the rodent to human translational gap: Marmosets as model systems for the study of Alzheimer's disease. Alzheimers Dement (N Y). 2023;9(3):e12417. Epub 2023 Aug 21 PubMed.
  2. 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.
  3. Goudsmit J, White BJ, Weitkamp LR, Keats BJ, Morrow CH, Gajdusek DC. Familial Alzheimer's disease in two kindreds of the same geographic and ethnic origin. A clinical and genetic study. J Neurol Sci. 1981 Jan;49(1):79-89. PubMed.
  4. Poorkaj P, Sharma V, Anderson L, Nemens E, Alonso ME, Orr H, White J, Heston L, Bird TD, Schellenberg GD. Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PubMed.
  5. Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S. Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
  6. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  7. Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, Mann D, Snowden J, Neary D, Harris J, Bras J, ARUK Consortium, Morgan K, Powell JF, Singleton A, Hardy J. Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. Epub 2014 May 2 PubMed.
  8. Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
  9. Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Hoge JA, Cohen AD, Ikonomovic MD, Saxton JA, Snitz BE, Pollen DA, Moonis M, Lippa CF, Swearer JM, Johnson KA, Rentz DM, Fischman AJ, Aizenstein HJ, Dekosky ST. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. PubMed.
  10. Moonis M, Swearer JM, Dayaw MP, St George-Hyslop P, Rogaeva E, Kawarai T, Pollen DA. Familial Alzheimer disease: decreases in CSF Abeta42 levels precede cognitive decline. Neurology. 2005 Jul 26;65(2):323-5. PubMed.
  11. Haleem K, Lippa CF, Smith TW, Kowa H, Wu J, Iwatsubo T. Presenilin-1 C410Y Alzheimer disease plaques contain synaptic proteins. Am J Alzheimers Dis Other Demen. 2007 Apr-May;22(2):137-44. PubMed.
  12. Xia W, Zhang J, Kholodenko D, Citron M, Podlisny MB, Teplow DB, Haass C, Seubert P, Koo EH, Selkoe DJ. Enhanced production and oligomerization of the 42-residue amyloid beta-protein by Chinese hamster ovary cells stably expressing mutant presenilins. J Biol Chem. 1997 Mar 21;272(12):7977-82. PubMed.
  13. 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.
  14. Heilig EA, Gutti U, Tai T, Shen J, Kelleher RJ. Trans-dominant negative effects of pathogenic PSEN1 mutations on γ-secretase activity and Aβ production. J Neurosci. 2013 Jul 10;33(28):11606-17. PubMed.
  15. 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.
  16. Xia D, Watanabe H, Wu B, Lee SH, Li Y, Tsvetkov E, Bolshakov VY, Shen J, Kelleher RJ 3rd. Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. Neuron. 2015 Mar 4;85(5):967-81. PubMed.
  17. Veugelen S, Saito T, Saido TC, Chávez-Gutiérrez L, De Strooper B. Familial Alzheimer's Disease Mutations in Presenilin Generate Amyloidogenic Aβ Peptide Seeds. Neuron. 2016 Apr 20;90(2):410-6. PubMed.
  18. Schultz S, Liu L, Schultz A, Fitzpatrick C, Levin R, Bellier J-P, Shirzadi Z, Mathurin N, Chen C, Benzinger T, Day G, Farlow M, Gordon B, Hassenstab J, Jack C, Jucker M, Karch C, Lee J, Levin J, Perrin R, Schofield P, Xiong C, Johnson K, McDade E, Bateman R, Sperling R, Selkoe D, Chhatwal J, theDominantlyInheritedAlzheimer'sNetworkInvestigators. Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer's disease. 2023 Jul 25 10.1101/2023.07.04.547688 (version 2) bioRxiv.
  19. Ahmadi S, Wade-Martins R. 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.
  20. Baumeister R, Leimer U, Zweckbronner I, Jakubek C, Grünberg J, Haass C. Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct. 1997 Apr;1(2):149-59. PubMed.
  21. Song W, Nadeau P, Yuan M, Yang X, Shen J, Yankner BA. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6959-63. PubMed.
  22. Nakajima M, Shimizu T, Shirasawa T. Notch-1 activation by familial Alzheimer's disease (FAD)-linked mutant forms of presenilin-1. J Neurosci Res. 2000 Oct 15;62(2):311-7. PubMed.
  23. Saura CA, Servián-Morilla E, Scholl FG. Presenilin/γ-secretase regulates neurexin processing at synapses. PLoS One. 2011;6(4):e19430. PubMed.
  24. Zhou R, Yang G, Shi Y. Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through heterooligomerization. Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):12731-12736. Epub 2017 Oct 9 PubMed.
  25. 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. Mann DM, Pickering-Brown SM, Takeuchi A, Iwatsubo T, . Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease. Am J Pathol. 2001 Jun;158(6):2165-75. PubMed.
  2. Mondadori CR, Buchmann A, Mustovic H, Schmidt CF, Boesiger P, Nitsch RM, Hock C, Streffer J, Henke K. Enhanced brain activity may precede the diagnosis of Alzheimer's disease by 30 years. Brain. 2006 Nov;129(Pt 11):2908-22. PubMed.
  3. Kim H, Ki H, Park HS, Kim K. Presenilin-1 D257A and D385A mutants fail to cleave Notch in their endoproteolyzed forms, but only presenilin-1 D385A mutant can restore its gamma-secretase activity with the compensatory overexpression of normal C-terminal fragment. J Biol Chem. 2005 Jun 10;280(23):22462-72. PubMed.
  4. Bobrysheva IV, Grigorenko AP, Novosadova EV, Kal'ina NR, Arsenyeva EL, Grivennikov IA, Tarantul VZ, Rogaev EI. Effects of human presenilin 1 isoforms on proliferation and survival of rat pheochromocytoma cell line PC12. Biochemistry (Mosc). 2003 Jun;68(6):611-7. PubMed.
  5. Hashimoto Y, Niikura T, Ito Y, Sudo H, Hata M, Arakawa E, Abe Y, Kita Y, Nishimoto I. Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults. J Neurosci. 2001 Dec 1;21(23):9235-45. PubMed.
  6. Cervenakova L, Brown P, Sandoval F, Foncin JF, Garruto R, Polinsky RJ, Nee L, Goldfarb L. Identification of presenilin-1 gene point mutations in early-onset Alzheimer's disease families. Am J Hum Genet. 1996;59(Suppl):A252
  7. Poorkaj P, Sharma V, Anderson L, Nemens E, Alonso ME, Orr H, White J, Heston L, Bird TD, Schellenberg GD. Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PubMed.
  8. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  9. Heilig EA, Gutti U, Tai T, Shen J, Kelleher RJ. Trans-dominant negative effects of pathogenic PSEN1 mutations on γ-secretase activity and Aβ production. J Neurosci. 2013 Jul 10;33(28):11606-17. PubMed.
  10. Berezovska O, Lleo A, Herl LD, Frosch MP, Stern EA, Bacskai BJ, Hyman BT. Familial Alzheimer's disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein. J Neurosci. 2005 Mar 16;25(11):3009-17. 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.
  2. Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S. Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.

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