Mutations

PSEN1 G384A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73217147 G>C
Position: (GRCh37/hg19):Chr14:73683855 G>C
dbSNP ID: rs63750646
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGA to GCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11
Research Models: 1

Findings

This mutation was first identified by linkage analysis in a large Belgian family affected by early onset Alzheimer’s disease (Cruts et al., 1995). The family, known as AD/B, included at least 16 affected individuals over five generations. The mutation was shown to segregate with disease: three affected siblings carried the mutation, while three unaffected siblings did not. The average age of onset was 35 (34.7 ± 3.0 years). The diagnosis of AD was confirmed in several family members at autopsy. Clinical information related to this family was reported in Martin et al., 1991.

A Japanese family with this mutation has also been identified (Tanahashi et al., 1996). This family, known as FAD-Yg, included four family members affected by early onset AD. Symptom onset ranged from 31 to 37 years old. Two family members had postmortem confirmed AD.

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

Neuropathology

Neuropathology consistent with AD was observed in members of the AD/B family. In addition to typical AD pathology of cortical plaques and tangles, amyloid plaques were also noted in the cerebellum. Typical AD pathology was observed in at least two members of the FAD-Yg family from Japan (Tanahashi et al., 1996).

Biological Effect

This mutation impairs APP processing, affecting cleavage by γ-secretase at both ε- and γ-sites. It has been reported to block ε-cleavage by 40 to 75 percent (Chávez-Gutiérrez et al., 2012; Do et al., 2023; Devkota et al., 2023), reducing the generation of Aβ48 and Aβ49 peptides, particularly Aβ48 (Do et al., 2023). Moreover, several cell-based and in vitro experiments have shown it increases the Aβ42/Aβ40 ratio (DeJonghe et al., 1999; Bentahir et al., 2006; Fluhrer et at., 2008; Li et al. 2016; Sun et al., 2017), and reduces the Aβ38/Aβ42 and Aβ40/Aβ43 ratios (Chávez-Gutiérrez et al., 2012; Svedružić et al., 2012; Li et al., 2016; Kakuda et al., 2021; Devkota et al., 2023) suggesting impairment of the fourth γ-site cleavage in the sequential digestion of Aβ49 and Aβ48 into shorter peptides. It has also been suggested that G384A disrupts the Aβ49 and Aβ48 pathways, enabling Aβ43 production via the Aβ48 line instead of the Aβ49 line (Kakuda et al., 2021).

Moreover, G384A was reported to reduce two Aβ ratios reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity: Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 (Apr 2022 news; Petit et al., 2022; Liu et al., 2022). The former ratio also correlated with AD age at onset.

The molecular underpinnings of these alterations are under investigation. In vitro assays revealed that mutant γ-secretase activity is more sensitive to increased temperatures than the wild-type protein, suggesting the mutation destabilizes the enzyme-substrate interaction required for sequential Aβ peptide proteolysis, resulting in the release of longer Aβ peptides (Szaruga et al., 2017; Jul 2017 news). As reported in a preprint, however, data from fluorescence lifetime imaging microscopy (FLIM) experiments suggest the mutation may instead stabilize the enzyme-substrate complex which, based on data from other mutations that also resulted in stalled, membrane-anchored complexes, may itself be toxic to synapses (Devkota et al., 2023; Nov 2023 news).

G384 is located in the GxGD motif, a region considered central to substrate cleavage (Pérez-Revuelta et al., 2010; Steiner et al., 2000). Cryo-electron microscopy studies have implicated it in the interaction of γ-secretase with both APP and Notch, with its amide group possibly donating a conserved H-bond to anchor the transmembrane helix of each substrate (Zhou et al., 2019; Yang et al., 2019; Jan 2019 news; Jun 2024 news). G384A may destabilize this interaction by disrupting the hydrogen bond (Odorčić et al., 2024), and/or the substitution of glycine's small side chain by alanine's bulkier one may lead to a steric clash around the active-site pocket, potentially leading to reduced γ-secretase processivity (Guo et al., 2024).

Additional proposals, not always consistent with each other, have been put forth. For example, an early study using FLIM suggested G384A increases the proximity of residues in the N- and C-termini of PSEN1, affecting how the APP substrate is presented to the active site of γ-secretase (Berezovska et al., 2005). Moreover, a study based on computational simulations suggested that the replacement of a glycine by an alanine reduces the stability of the protein and favors a more open conformation in which the substrate is held more loosely, resulting in imprecise cleavage and earlier release of longer Aβ peptides (Dehury et al., 2020). Another computational study predicted the active subpocket of the mutant protein is smaller than that of the wildtype, with the APP-bound active site being more restricted (Do et al., 2023). 

G384A may also affect APP processing by altering the subcellular localization of PSEN1. One study reported this variant redirected PSEN1 to endolysosomal compartments which resulted in altered substrate specificity and an increased Aβ42/Aβ40 ratio in the Aβ intracellular pool (Sannerud et al., 2016; see May 2016 news).

A tool that may provide additional functional clues and alternatives for targeting some of these alterations is a yeast reporter system expressing membrane-bound APP fused to the Gal4 transcriptional activator. Two suppressor mutations identified in this system activated Aβ trimming and reduced Aβ42 production in mouse fibroblasts expressing PSEN1 G384A (Futai et al., 2016).

G384A may also disrupt other cellular functions relevant to AD. For example, PSEN1 was reported to play a key role in ApoE secretion and cytoplasmic localization. In experiments with PSEN-deficient fibroblasts, G384A transfection was less able to rescue these functions compared with transfection of wildtype PSEN1 (Islam et al., 2022). The G384A mutation may also affect PSEN1's putative activity as a passive calcium leak channel in the endoplasmic reticulum. This activity was reported as abolished in mouse embryonic fibroblasts expressing the mutant protein (Nelson et al., 2007). In addition, G384A reduced the interaction of PSEN1 with the glutamate transporter GLT-1, an alteration that may impair GLT-1 homo-oligomerization and its transport to the cell surface (Perrin et al., 2024).

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. G384A: 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. G384A: 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)

Last Updated: 13 Jun 2024

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  2. sAPP Binds GABA Receptor, and More News on APP
  3. Patricidal Protein? Aβ42 said to Inhibit Its Parent, γ-Secretase
  4. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  5. Caught in the Act: Cryo-EM Exposes γ-Secretase Catalytic Pose
  6. Lodged in Late Endosomes, Presenilin 2 Churns Out Intraneuronal Aβ

Paper Citations

  1. Cruts M, Backhovens H, Wang SY, Van Gassen G, Theuns J, De Jonghe CD, Wehnert A, De Voecht J, De Winter G, Cras P. Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
  2. Martin JJ, Gheuens J, Bruyland M, Cras P, Vandenberghe A, Masters CL, Beyreuther K, Dom R, Ceuterick C, Lübke U. Early-onset Alzheimer's disease in 2 large Belgian families. Neurology. 1991 Jan;41(1):62-8. PubMed.
  3. Tanahashi H, Kawakatsu S, Kaneko M, Yamanaka H, Takahashi K, Tabira T. Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.
  4. Chávez-Gutiérrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, Lismont S, Zhou L, Van Cleynenbreugel S, Esselmann H, Wiltfang J, Serneels L, Karran E, Gijsen H, Schymkowitz J, Rousseau F, Broersen K, De Strooper B. The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.
  5. Do HN, Devkota S, Bhattarai A, Wolfe MS, Miao Y. Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein. Commun Biol. 2023 Feb 14;6(1):174. PubMed.
  6. Devkota S, Williams TD, Wolfe MS. Familial Alzheimer's disease mutations in amyloid protein precursor alter proteolysis by γ-secretase to increase amyloid β-peptides of ≥45 residues. J Biol Chem. 2021;296:100281. Epub 2021 Jan 12 PubMed.
  7. De Jonghe C, Cras P, Vanderstichele H, Cruts M, Vanderhoeven I, Smouts I, Vanmechelen E, Martin JJ, Hendriks L, Van Broeckhoven C. Evidence that Abeta42 plasma levels in presenilin-1 mutation carriers do not allow for prediction of their clinical phenotype. Neurobiol Dis. 1999 Aug;6(4):280-7. PubMed.
  8. Bentahir M, Nyabi O, Verhamme J, Tolia A, Horré K, Wiltfang J, Esselmann H, De Strooper B. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. PubMed.
  9. Fluhrer R, Fukumori A, Martin L, Grammer G, Haug-Kröper M, Klier B, Winkler E, Kremmer E, Condron MM, Teplow DB, Steiner H, Haass C. Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation. J Biol Chem. 2008 Oct 31;283(44):30121-8. PubMed.
  10. Li N, Liu K, Qiu Y, Ren Z, Dai R, Deng Y, Qing H. Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  11. 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.
  12. Svedružić ZM, Popović K, Smoljan I, Sendula-Jengić V. Modulation of γ-secretase activity by multiple enzyme-substrate interactions: implications in pathogenesis of Alzheimer's disease. PLoS One. 2012;7(3):e32293. PubMed.
  13. Kakuda N, Takami M, Okochi M, Kasuga K, Ihara Y, Ikeuchi T. Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
  14. Petit D, Fernández SG, Zoltowska KM, Enzlein T, Ryan NS, O'Connor A, Szaruga M, Hill E, Vandenberghe R, Fox NC, Chávez-Gutiérrez L. Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
  15. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. 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. Szaruga M, Munteanu B, Lismont S, Veugelen S, Horré K, Mercken M, Saido TC, Ryan NS, De Vos T, Savvides SN, Gallardo R, Schymkowitz J, Rousseau F, Fox NC, Hopf C, De Strooper B, Chávez-Gutiérrez L. Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed. Correction.
  17. Pérez-Revuelta BI, Fukumori A, Lammich S, Yamasaki A, Haass C, Steiner H. Requirement for small side chain residues within the GxGD-motif of presenilin for gamma-secretase substrate cleavage. J Neurochem. 2010 Feb;112(4):940-50. Epub 2009 Dec 15 PubMed.
  18. Steiner H, Kostka M, Romig H, Basset G, Pesold B, Hardy J, Capell A, Meyn L, Grim ML, Baumeister R, Fechteler K, Haass C. Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nat Cell Biol. 2000 Nov;2(11):848-51. PubMed.
  19. 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.
  20. Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, Lei J, Shi Y. Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.
  21. Odorčić I, Hamed MB, Lismont S, Chávez-Gutiérrez L, Efremov RG. Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform. Nat Commun. 2024 May 27;15(1):4479. PubMed.
  22. Guo X, Li H, Yan C, Lei J, Zhou R, Shi Y. Molecular mechanism of substrate recognition and cleavage by human γ-secretase. Science. 2024 Jun 7;384(6700):1091-1095. Epub 2024 Jun 6 PubMed.
  23. 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.
  24. Dehury B, Somavarapu AK, Kepp KP. A computer-simulated mechanism of familial Alzheimer's disease: Mutations enhance thermal dynamics and favor looser substrate-binding to γ-secretase. J Struct Biol. 2020 Dec 1;212(3):107648. Epub 2020 Oct 21 PubMed.
  25. Sannerud R, Esselens C, Ejsmont P, Mattera R, Rochin L, Tharkeshwar AK, De Baets G, De Wever V, Habets R, Baert V, Vermeire W, Michiels C, Groot AJ, Wouters R, Dillen K, Vints K, Baatsen P, Munck S, Derua R, Waelkens E, Basi GS, Mercken M, Vooijs M, Bollen M, Schymkowitz J, Rousseau F, Bonifacino JS, Van Niel G, De Strooper B, Annaert W. Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool. Cell. 2016 Jun 30;166(1):193-208. Epub 2016 Jun 9 PubMed.
  26. Futai E, Osawa S, Cai T, Fujisawa T, Ishiura S, Tomita T. Suppressor Mutations for Presenilin 1 Familial Alzheimer Disease Mutants Modulate γ-Secretase Activities. J Biol Chem. 2016 Jan 1;291(1):435-46. Epub 2015 Nov 11 PubMed.
  27. Islam S, Sun Y, Gao Y, Nakamura T, Noorani AA, Li T, Wong PC, Kimura N, Matsubara E, Kasuga K, Ikeuchi T, Tomita T, Zou K, Michikawa M. Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis. J Neurosci. 2022 Feb 23;42(8):1574-1586. Epub 2022 Jan 5 PubMed.
  28. 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.
  29. Perrin F, Anderson LC, Mitchell SP, Sinha P, Turchyna Y, Maesako M, Houser MC, Zhang C, Wagner SL, Tanzi RE, Berezovska O. PS1/gamma-secretase acts as rogue chaperone of glutamate transporter EAAT2/GLT-1 in Alzheimer's disease. Acta Neuropathol Commun. 2024 Oct 21;12(1):166. PubMed.
  30. 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. Kamimura K, Tanahashi H, Yamanaka H, Takahashi K, Asada T, Tabira T. Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.
  2. Svedružić ŽM, Popović K, Šendula-Jengić V. Decrease in catalytic capacity of γ-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer's disease. Mol Cell Neurosci. 2015 Jul;67:55-65. Epub 2015 Jun 4 PubMed.
  3. Soejima N, Ohyagi Y, Nakamura N, Himeno E, Iinuma KM, Sakae N, Yamasaki R, Tabira T, Murakami K, Irie K, Kinoshita N, Laferla FM, Kiyohara Y, Toru I, Kira JI. Intracellular Accumulation of Toxic Turn Amyloid-β is Associated with Endoplasmic Reticulum Stress in Alzheimer's disease. Curr Alzheimer Res. 2012 Aug 30; PubMed.
  4. Mutoh T, Kawamura N, Hirabayashi Y, Shima S, Miyashita T, Ito S, Asakura K, Araki W, Cazzaniga E, Muto E, Masserini M. Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis. FASEB J. 2012 Jul;26(7):3065-74. PubMed.
  5. Hahn S, Brüning T, Ness J, Czirr E, Baches S, Gijsen H, Korth C, Pietrzik CU, Bulic B, Weggen S. Presenilin-1 but not amyloid precursor protein mutations present in mouse models of Alzheimer's disease attenuate the response of cultured cells to γ-secretase modulators regardless of their potency and structure. J Neurochem. 2011 Feb;116(3):385-95. PubMed.
  6. Ma L, Ohyagi Y, Miyoshi K, Sakae N, Motomura K, Taniwaki T, Furuya H, Takeda K, Tabira T, Kira J. Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors. J Alzheimers Dis. 2009;16(3):565-75. PubMed.
  7. Miyoshi K, Ohyagi Y, Sakae N, Motomura K, Ma L, Taniwaki T, Furuya H, Tabira T, Kira J. Enhancement of activation of caspases by presenilin 1 gene mutations and its inhibition by secretase inhibitors. J Alzheimers Dis. 2009;16(3):551-64. PubMed.
  8. Yagishita S, Morishima-Kawashima M, Tanimura Y, Ishiura S, Ihara Y. DAPT-induced intracellular accumulations of longer amyloid beta-proteins: further implications for the mechanism of intramembrane cleavage by gamma-secretase. Biochemistry. 2006 Mar 28;45(12):3952-60. PubMed.
  9. Herzig MC, Paganetti P, Staufenbiel M, Jucker M. BACE1 and mutated presenilin-1 differently modulate Abeta40 and Abeta42 levels and cerebral amyloidosis in APPDutch transgenic mice. Neurodegener Dis. 2007;4(2-3):127-35. PubMed.
  10. Qi Y, Morishima-Kawashima M, Sato T, Mitsumori R, Ihara Y. Distinct mechanisms by mutant presenilin 1 and 2 leading to increased intracellular levels of amyloid beta-protein 42 in Chinese hamster ovary cells. Biochemistry. 2003 Feb 4;42(4):1042-52. PubMed.
  11. Hendriks L, De Jonghe C, Lübke U, Woodrow S, Vanderhoeven I, Boons J, Cras P, Martin JJ, Van Broeckhoven C. Immunoreactivity of presenilin-1 and tau in Alzheimer's disease brain. Exp Neurol. 1998 Feb;149(2):341-8. PubMed.
  12. Vanderhoeven I, Cras P, Martin JJ, Van Broeckhoven C, De Jonghe C. Proteolytic processing of presenilin-1 in human lymphoblasts is not affected by the presence of the I143T and G384A mutations. Neurosci Lett. 1999 Oct 29;274(3):183-6. PubMed.
  13. Koch M, Enzlein T, Chen SY, Petit D, Lismont S, Zacharias M, Hopf C, Chávez-Gutiérrez L. APP substrate ectodomain defines amyloid-β peptide length by restraining γ-secretase processivity and facilitating product release. EMBO J. 2023 Dec 1;42(23):e114372. Epub 2023 Oct 18 PubMed.

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. Cruts M, Backhovens H, Wang SY, Van Gassen G, Theuns J, De Jonghe CD, Wehnert A, De Voecht J, De Winter G, Cras P. Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
  2. Tanahashi H, Kawakatsu S, Kaneko M, Yamanaka H, Takahashi K, Tabira T. Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.

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