Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PP1, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73673093 G>T
dbSNP ID: rs63750219 
Coding/Non-Coding: Both
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Deletion-Insertion
Genomic Region: Intron 8, Exon 9

Findings

This point mutation at a splice site in intron 8 was the first mutation in PSEN1 determined to result in the deletion of exon 9 from mRNA transcripts. Now, several unique mutations have been identified that result in the exclusion of exon 9 and are variously known as ΔE9, Δ9, delE9, or deltaE9. This deletion occurs in-frame, so presenilin protein is produced, but it lacks amino acids 290-319.

This mutation was first identified in a British family known as F74 (Perez-Tur et al., 1995). The reported pedigree contains seven affected individuals over three generations with symptoms typical of early onset AD, with onset ranging from 39 to 50 years of age. Disease in this family had previously been shown to be linked to chromosome 14, but the precise genetic lesion had been elusive. The mutation was shown to segregate with disease in this family (it was present in three affected individuals and absent in five unaffected). It was also absent in 100 control individuals. This family was described in Hutton et al., 1996.

This mutation was also identified in a pedigree known as EOFAD-3 whose affected members met NINCDS-ADRDA criteria for probable AD (Kwok et al., 1997). This pedigree was also affected by familial spastic paraparesis, a rare neurodegenerative disorder of the central motor system characterized by progressive spasticity of the lower limbs. Spastic paraparesis and AD co-occurred, but also appeared separately. The mean age of onset was reported as 44.4 years (ranging from 41 to 47 years) and it was noted that the dementia was typically less prominent in individuals with spasticity. Further clinical details and associated pathology are reported in Brooks et al., 2003.

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

Neuropathology

Neuropathological examination of two brains from the EOFAD-3 family revealed numerous cotton-wool plaques throughout the neocortex. Cored plaques were less frequent. Neurofibrillary tangles, neuronal loss, gliosis, and cerebral amyloid angiopathy also were noted. Both cases fulfilled NIA-Reagan criteria for AD (Brooks et al., 2003).

Cotton-wool plaques also were noted in two additional cases with exon 9 deletion who had died at age 52 and 59, respectively. However, it was not clear from the report which exon 9 deletion mutation these individuals carried. Over all, these cases had frequent plaques and neurofibrillary tangles (a Braak score of 5 in both). One of the cases also had Pick bodies in the dentate gyrus; no other brain regions were examined (Halliday et al., 2005).

Biological Effect

This point mutation abrogates the splice acceptor site so that exon 9 (encoding residues 290-319) is spliced out of mature transcripts (Perez-Tur et al., 1995). The skipping of exon 9 occurs in-frame and also results in an amino acid change at the splice junction of exon 8 and 10 (S290C). 

The following summary refers to studies of PSEN1 mutants that result in the exclusion of exon 9 (denoted here as PSEN1ΔE9). Multiple in vitro and in vivo assays have shown that PSEN1ΔE9 impairs endoproteolytic processing of PSEN1 (Thinakaran et al., 1996, Lee et al., 1997) and alters the production of Aβ42 and Aβ40 peptides resulting in an increased Aβ42/Aβ40 ratio (Borchelt et al., 1996, Steiner et al., 1999, Dumanchin et al., 2006; Kumar-Singh et al., 2006, Bentahir et al., 2006, Woodruff et al., 2013, Cacquevel et al., 2012, Sun et al., 2017). Moreover, studies surveying the production of Aβ peptides of different lengths have indicated that these mutations result in increased levels of longer Aβ peptides, and decreased levels of shorter peptides (Chávez-Gutiérrez et al., 2012; Svedružić et al., 2012; Kakuda et al., 2021). Chávez-Gutiérrez and colleagues proposed this is the result of impairment of the fourth γ-secretase cleavage in the two Aβ production lines that sequentially digest Aβ49 and Aβ48 into shorter peptides (Chávez-Gutiérrez et al., 2012).

Consistent with these findings, three more recent studies revealed PSEN1ΔE9 mutants decrease the Aβ (37 + 38 + 40) / (42 + 43) ratio and the Aβ37/Aβ42 ratio, both of which reflect γ-processivity, compared with cells expressing wildtype PSEN1 (Apr 2022 news; Petit et al., 2022; Liu et al., 2022). The two ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset. Moreover, a follow-up study reported in a preprint, combined the Aβ (37 + 38 + 40) / (42 + 43) ratio with the commonly used Aβ42/Aβ40 ratio (a measure of the relative production of aggregation-prone Aβ) to yield a composite measure which reflects γ-secretase function as a percentage of wildtype activity (Schulz et al., 2023). This composite score (36.87 for PSEN1ΔE9) was strongly associated, not only with age at onset, but with biomarker and cognitive trajectories.

Exon 9 deletion mutations may also affect PSEN1 transcription. In a bacterial artificial chromosome (BAC)-based expression model, PSEN1ΔE9-expressing cells exhibited reduced PSEN1 gene expression and partial loss of function relative to cells expressing wild-type PSEN1 (Ahmadi et al., 2014).

The absence of exon 9 may impair Notch processing as well. Although one study found no effect of the mutation on this substrate (Chávez-Gutiérrez et al., 2012), others have reported impaired Notch S3 cleavage and corresponding alterations in the differentiation and self-renewal of neural progenitor cells in the adult mouse brain (Bentahir et al., 2006; Veeraraghavalu et al., 2010; May 2010 news).

PSEN1ΔE9 mutations have also been implicated in the disruption of several intracellular functions. For example, by lowering PIP2 levels, PSEN1ΔE9 appears to block a cation channel that mediates capacitive calcium entry (Landman et al., 2006; Dec 2006 news). In addition, impairments in endocytosis, cholesterol homeostasis, autophagy, and APP intracellular localization have been reported (Woodruff et al., 2016; Oct 2016 news; Cho et al., 2019; Oh and Chung, 2017). In addition, alterations in tight and adherens junction protein expression, as well as in efflux properties, were found in iPSC-derived brain endothelial cells, a model of blood-brain barrier function (Oikari et al., 2020).

Interestingly, PSEN1 was reported to play a key role in ApoE secretion and cytoplasmic localization. In experiments with PSEN-deficient fibroblasts, PSEN1ΔE9 transfection was less able to rescue these functions compared with transfection of wildtype PSEN1 (Islam et al., 2022).

PSEN1ΔE9 had little effect on microglia, a cell type that normally expresses very low levels of PSEN1, although it appeared to weaken the cells’ inflammatory response (Konttinen et al., 2019, Sep 2019 news).

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.

Research Models

Multiple mouse models that express PSEN1 lacking exon 9 have been developed. One line, referred to as S-9 (Lee et al., 1997), was subsequently bred to an APP-transgenic mouse to generate a double-transgenic (APPSwe/PSEN1dE9), which has a more severe phenotype than either of the parental lines. Another double-transgenic model was made by co-injecting vectors expressing PSEN1ΔE9 and APP with the Swedish mutation (APPswe/PSEN1dE9 (Borchelt mice)). Although cotton-wool plaques are sometimes prominent in the brains of AD patients with ΔE9 mutations, this pathology has not been observed in ΔE9 mouse models.

In addition, induced pluripotent stem cell lines derived from patients have been used to generate neurons (Woodruff et al., 2013), astroctyes (Oksanen et al., 2017), and brain endothelial cells (Oikari et al., 2020) which display several features of AD pathology.

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References

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022
2. Notch Your Average Joe—Grounds for PS1 Neurogenesis Inhibition? 21 May 2010
3. Beyond γ-Secretase: FAD Mutations Affect Calcium Channel via Lipid Messenger 8 Dec 2006
4. Cholesterol Trafficking Takes a Hit in Alzheimer’s Neurons 28 Oct 2016
5. Among AD Mutations, Only ApoE4 Seems to Hobble Microglia 14 Sep 2019

Paper Citations

1. Lee MK, Borchelt DR, Kim G, Thinakaran G, Slunt HH, Ratovitski T, Martin LJ, Kittur A, Gandy S, Levey AI, Jenkins N, Copeland N, Price DL, Sisodia SS. Hyperaccumulation of FAD-linked presenilin 1 variants in vivo. Nat Med. 1997 Jul;3(7):756-60. PubMed.
2. Woodruff G, Reyna SM, Dunlap M, Van Der Kant R, Callender JA, Young JE, Roberts EA, Goldstein LS. Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations. Cell Rep. 2016 Oct 11;17(3):759-773. PubMed.
3. Oksanen M, Petersen AJ, Naumenko N, Puttonen K, Lehtonen Š, Gubert Olivé M, Shakirzyanova A, Leskelä S, Sarajärvi T, Viitanen M, Rinne JO, Hiltunen M, Haapasalo A, Giniatullin R, Tavi P, Zhang SC, Kanninen KM, Hämäläinen RH, Koistinaho J. PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease. Stem Cell Reports. 2017 Dec 12;9(6):1885-1897. Epub 2017 Nov 16 PubMed.
4. Oikari LE, Pandit R, Stewart R, Cuní-López C, Quek H, Sutharsan R, Rantanen LM, Oksanen M, Lehtonen S, de Boer CM, Polo JM, Götz J, Koistinaho J, White AR. Altered Brain Endothelial Cell Phenotype from a Familial Alzheimer Mutation and Its Potential Implications for Amyloid Clearance and Drug Delivery. Stem Cell Reports. 2020 May 12;14(5):924-939. Epub 2020 Apr 9 PubMed.
5. Perez-Tur J, Froelich S, Prihar G, Crook R, Baker M, Duff K, Wragg M, Busfield F, Lendon C, Clark RF. A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport. 1995 Dec 29;7(1):297-301. PubMed.
6. Hutton M, Busfield F, Wragg M, Crook R, Perez-Tur J, Clark RF, Prihar G, Talbot C, Phillips H, Wright K, Baker M, Lendon C, Duff K, Martinez A, Houlden H, Nichols A, Karran E, Roberts G, Roques P, Rossor M, Venter JC, Adams MD, Cline RT, Phillips CA, Goate A. Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.
7. Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, Hardy J, Fulham MJ, Nicholson GA, Stell R, St George Hyslop PH, Fraser PE, Kakulas B, Clarnette R, Relkin N, Gandy SE, Schofield PR, Martins RN. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PubMed.
8. Brooks WS, Kwok JB, Kril JJ, Broe GA, Blumbergs PC, Tannenberg AE, Lamont PJ, Hedges P, Schofield PR. Alzheimer's disease with spastic paraparesis and 'cotton wool' plaques: two pedigrees with PS-1 exon 9 deletions. Brain. 2003 Apr;126(Pt 4):783-91. PubMed.
9. Halliday GM, Song YJ, Lepar G, Brooks WS, Kwok JB, Kersaitis C, Gregory G, Shepherd CE, Rahimi F, Schofield PR, Kril JJ. Pick bodies in a family with presenilin-1 Alzheimer's disease. Ann Neurol. 2005 Jan;57(1):139-43. PubMed.
10. Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG, Price DL, Sisodia SS. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 1996 Jul;17(1):181-90. PubMed.
11. 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.
12. Steiner H, Romig H, Grim MG, Philipp U, Pesold B, Citron M, Baumeister R, Haass C. The biological and pathological function of the presenilin-1 Deltaexon 9 mutation is independent of its defect to undergo proteolytic processing. J Biol Chem. 1999 Mar 19;274(12):7615-8. PubMed.
13. Dumanchin C, Tournier I, Martin C, Didic M, Belliard S, Carlander B, Rouhart F, Duyckaerts C, Pellissier JF, Latouche JB, Hannequin D, Frebourg T, Tosi M, Campion D. Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat. 2006 Oct;27(10):1063. PubMed.
14. Kumar-Singh S, Theuns J, Van Broeck B, Pirici D, Vennekens K, Corsmit E, Cruts M, Dermaut B, Wang R, Van Broeckhoven C. Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat. 2006 Jul;27(7):686-95. PubMed.
15. 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.
16. Woodruff G, Young JE, Martinez FJ, Buen F, Gore A, Kinaga J, Li Z, Yuan SH, Zhang K, Goldstein LS. The presenilin-1 ΔE9 mutation results in reduced γ-secretase activity, but not total loss of PS1 function, in isogenic human stem cells. Cell Rep. 2013 Nov 27;5(4):974-85. Epub 2013 Nov 14 PubMed.
17. Cacquevel M, Aeschbach L, Houacine J, Fraering PC. Alzheimer's disease-linked mutations in presenilin-1 result in a drastic loss of activity in purified γ-secretase complexes. PLoS One. 2012;7(4):e35133. PubMed.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. Veeraraghavalu K, Choi SH, Zhang X, Sisodia SS. Presenilin 1 mutants impair the self-renewal and differentiation of adult murine subventricular zone-neuronal progenitors via cell-autonomous mechanisms involving notch signaling. J Neurosci. 2010 May 19;30(20):6903-15. PubMed.
27. Landman N, Jeong SY, Shin SY, Voronov SV, Serban G, Kang MS, Park MK, Di Paolo G, Chung S, Kim TW. Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism. Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19524-9. PubMed.
28. Cho YY, Kwon OH, Park MK, Kim TW, Chung S. Elevated cellular cholesterol in Familial Alzheimer's presenilin 1 mutation is associated with lipid raft localization of β-amyloid precursor protein. PLoS One. 2019;14(1):e0210535. Epub 2019 Jan 25 PubMed.
29. Oh HG, Chung S. Activation of transient receptor potential melastatin 7 (TRPM7) channel increases basal autophagy and reduces amyloid β-peptide. Biochem Biophys Res Commun. 2017 Nov 4;493(1):494-499. Epub 2017 Sep 1 PubMed.
30. 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.
31. Konttinen H, Cabral-da-Silva ME, Ohtonen S, Wojciechowski S, Shakirzyanova A, Caligola S, Giugno R, Ishchenko Y, Hernández D, Fazaludeen MF, Eamen S, Budia MG, Fagerlund I, Scoyni F, Korhonen P, Huber N, Haapasalo A, Hewitt AW, Vickers J, Smith GC, Oksanen M, Graff C, Kanninen KM, Lehtonen S, Propson N, Schwartz MP, Pébay A, Koistinaho J, Ooi L, Malm T. PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia. Stem Cell Reports. 2019 Oct 8;13(4):669-683. Epub 2019 Sep 12 PubMed.

Other Citations

1. APPSwe/PSEN1dE9

External Citations

1. gnomAD v2.1.1

Further Reading