Mutations

PSEN1 S290C;T291_S319del (ΔE9)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Spastic Paraparesis, Alzheimer's Disease
Coding/Non-Coding: Both
Mutation Type: Complex
Genomic Region: Intron 8, Exon 9

Findings

This deletion mutation in PSEN1 removes a 5.9 kb sequence involving intron 8, exon 9, and intron 9, resulting in the in-frame skipping of exon 9 and an amino acid substitution at the splice junction of exons 8 and 10. It is one of several known pathogenic mutations that involve exclusion of exon 9, which are variously known as ΔE9, Δ9, delE9, or deltaE9.

This mutation was identified in an Australian pedigree (Aus-1) with 13 affected individuals over three generations (Smith et al., 2001). The clinical and neuropathological phenotypes in this family were variable with instances of overlap of Alzheimer’s disease with spastic paraparesis (SP). The first known affected individual in this family developed cognitive symptoms at age 53. She died at age 58 with advanced dementia, but no motor symptoms. Seven of her 10 children also developed dementia, but none had SP. Spastic paraparesis appeared in the next generation; of four siblings, one had both dementia and SP (onset at 54 years) and three had SP but no dementia (onset at 46, 48, and 50 years). An affected cousin developed dementia at age 36 and died 10 years later without symptoms of SP. The mutation in this family was identified as a 5.9 kb deletion in the PSEN1 gene which juxtaposed intron 8 and 9 sequences and resulted in the in-frame skipping of exon 9. The break points did not match those of the previously reported deletion mutation in a Finnish AD pedigree (ΔE9Finn), which also involves deletion of exon 9 (Prihar et al., 1999).

Neuropathology

Like the clinical presentation in this family, the neuropathology was variable. Data were available for six affected individuals. Notably, some of the plaques observed were described as "variant." These were large, non-cored plaques with a cotton-wool appearance. These plaques were particularly noted in two cases (one with both Alzheimer's disease and spastic paraparesis and one with spastic paraparesis alone). Corticospinal tract degeneration was also present in these two cases (Smith et al., 2001).

Cotton-wool plaques were also noted in two additional cases carrying the exon 9 deletion, who had died at age 52 and 59 years. Overall, 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

The following summary refers to studies of PSEN1 mutants that result in the exclusion of exon 9 (denoted here as PSEN1ΔE9). PSEN1ΔE9 mutants appear to fail to undergo endoproteolytic processing in brains of transgenic mice (Lee et al., 1997), consistent with results in cultured mammalian cells (Thinakaran et al., 1996). Moreover, several cell-based studies indicate processing of APP is impaired. While some have reported decreased Aβ40 levels and increased Aβ42 levels (Dumanchin et al., 2006; Kumar-Singh et al., 2006), others have found no change in Aβ40 levels but increased Aβ42 levels (Steiner et al., 1999), or a decrease in both Aβ species (Bentahir et al., 2006). In an early study, the Aβ42(43):Aβ40 ratio was reported to be elevated in cell media, as well as in the brains of young transgenic animals co-expressing the mutant and APPswe (Borchelt et al., 1996).

Consistent with these findings, neurons derived from human iPSC lines carrying at least one copy of a PSEN1ΔE9 mutation produced less Aβ40 and had a greater Aβ42/Aβ40 ratio than controls expressing only wildtype PSEN1 (Woodruff et al., 2013). Moreover, mutant-carrying cells had significantly increased levels of the γ-secretase substrates APP α- and β-CTFs, suggesting impaired γ-secretase activity.

In vitro studies with isolated proteins also indicate an increase in the Aβ42/Aβ40 ratio, and decreases in Aβ40 and Aβ42 production (Cacquevel et al., 2012; Sun et al., 2017). A study monitoring the production of an array of Aβ peptides in mouse embryonic fibroblasts expressing a PSEN1ΔE9 mutant indicated that total secreted Aβ peptides, including Aβ38, Aβ40, Aβ42, and Aβ43, were substantially reduced compared with those of cells expressing wild-type PSEN1 (Chávez-Gutiérrez et al., 2012). Also, sizeable reductions in the Aβ38/Aβ42 and Aβ40/Aβ43 ratios were observed, both in cells and in vitro. Interestingly, the levels of the shorter peptides, Aβ40 and Aβ38, were particularly decreased, while those of longer peptides, greater than Aβ42, were increased. These data suggest impairment of the fourth γ-secretase cleavage in the two Aβ production lines that sequentially digest Aβ49 and Aβ48 into shorter peptides.

Consistent with these findings, others have reported that, compared with wildtype PSEN1 activity measured in vitro, PSEN1ΔE9 generates elevated Aβ42/Aβ40, with reduced levels of Aβ40 and Aβ38, and increased levels of longer Aβ peptides (Aβ46 and Aβ46+) (Svedružić et al., 2012). Large reductions in Aβ38/Aβ42 and Aβ40/Aβ43 were also reported.

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, astrocytic response to inflammatory stimulation, and APP intracellular localization have been reported (Woodruff et al., 2016; Oct 2016 news; Cho et al., 2019; Oh and Chung, 2017; Oksanen et al., 2019).

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 line to generate APPSwe/PSEN1dE9, which have 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) and astrocytes, which display several features of AD pathology (Oksanen et al., 2017).

Last Updated: 05 Nov 2019

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References

Mutation Position Table Citations

  1. PSEN1 S290 Mutations

Mutations Citations

  1. PSEN1 S290C;T291_S319del (ΔE9Finn)

News Citations

  1. Beyond γ-Secretase: FAD Mutations Affect Calcium Channel via Lipid Messenger
  2. Cholesterol Trafficking Takes a Hit in Alzheimer’s Neurons

Paper Citations

  1. . Hyperaccumulation of FAD-linked presenilin 1 variants in vivo. Nat Med. 1997 Jul;3(7):756-60. PubMed.
  2. . 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. . 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. . Variable phenotype of Alzheimer's disease with spastic paraparesis. Ann Neurol. 2001 Jan;49(1):125-9. PubMed.
  5. . Alzheimer disease PS-1 exon 9 deletion defined. Nat Med. 1999 Oct;5(10):1090. PubMed.
  6. . Pick bodies in a family with presenilin-1 Alzheimer's disease. Ann Neurol. 2005 Jan;57(1):139-43. PubMed.
  7. . Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 1996 Jul;17(1):181-90. PubMed.
  8. . 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.
  9. . 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.
  10. . 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.
  11. . Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. PubMed.
  12. . 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.
  13. . 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.
  14. . 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.
  15. . 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. . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.
  17. . Modulation of γ-secretase activity by multiple enzyme-substrate interactions: implications in pathogenesis of Alzheimer's disease. PLoS One. 2012;7(3):e32293. 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. . 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.
  20. . 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.
  21. . 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.
  22. . NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes. Glia. 2019 Oct 31; PubMed.

Other Citations

  1. APPSwe/PSEN1dE9

External Citations

  1. May 2010 news
  2. Cho et al., 2019

Further Reading

Papers

  1. . 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.
  2. . Convergence of pathology in dementia with Lewy bodies and Alzheimer's disease: a role for the novel interaction of alpha-synuclein and presenilin 1 in disease. Brain. 2014 Jul;137(Pt 7):1958-70. Epub 2014 May 24 PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Variable phenotype of Alzheimer's disease with spastic paraparesis. Ann Neurol. 2001 Jan;49(1):125-9. PubMed.

Other mutations at this position

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