Mutations

PSEN1 S290C;T291_S319del (ΔE9Finn)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Coding/Non-Coding: Both
Mutation Type: Complex
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Intron 8, Exon 9

Findings

This mutation involves the deletion of 4,555 nucleotides spanning exons 8, 9, and 10 of PSEN1 and results in the skipping of the entire exon 9. With the exception of the amino acids encoded by exon 9, an otherwise full-length protein is expressed. This was the first deletion mutation in PSEN1 reported to be pathogenic for AD (Crook et al., 1998; Prihar et al., 1999). There are now several known mutations that result in the exclusion of exon 9 due to deletion events as well as splice-site mutations. These mutations are variously referred to as ΔE9, Δ9, delE9, or deltaE9.

This mutation has been observed in two Finnish families. It was first described in a pedigree known as Finn2, which previously had been shown to be affected by early onset Alzheimer's disease due to an unidentified genomic change that resulted in the exclusion of exon 9 from PSEN1 transcripts (Crook et al., 1998). The reported pedigree contains 17 affected individuals over three generations. Disease in this family was characterized by progressive dementia frequently preceded by spastic paraparesis (SP). In this family, onset of SP ranged from 45 to 55 years old and cognitive decline at 45 to 57 years. Death typically occurred five to 12 years after onset. Additional clinical and neuroimaging data for this family, as well as an extended pedigree, are reported in Verkkoniemi et al., 2000.

In the second Finnish family, the same 4.6 kb deletion was found to be associated with disease over two generations (Hiltunen et al., 2000). In contrast to the Finn2 family, the clinical presentation of the four affected patients was typical for AD without indications of spastic paraparesis or any other major motor disturbance. The mean age at onset was 43.5 years. The E318G polymorphism in exon 9 of PSEN1 was also detected in two affected and eight healthy family members. The deletion mutation segregated with disease in this family and was absent in 102 unrelated AD patients and 51 control subjects from Finland.

Neuropathology

Neuropathological examination of two patients from the Finn2 pedigree revealed unusual plaques in addition to the typical amyloid plaques and neurofibrillary tangles of AD. The plaques were described as “reminiscent of loosely packed cotton-wool balls” that were large (100-150 μM in diameter) and not congophilic, suggesting a lack of amyloid at the core (Crook et al., 1998). Cotton-wool plaques have since been associated with multiple other PSEN1 mutations, such as I83_M84del, G217D, G217R, V261F, P264L, E280G, P284L, A431E, and DelT440.

Neuropathological findings were reported in one individual from the other Finnish family. In accordance with the clinical features, the pathology was typical of AD with numerous congophilic amyloid plaques, neurofibrillary tangles, neuritic plaques, and reactive astrocytes and microglia near plaques. Cerebral amyloid angiopathy was observed both in the parenchyma and in the leptomeninges. Cotton-wool plaques were not observed. Overall, the neuropathology supported the diagnosis of definite AD according to CERAD criteria (Hiltunen et al., 2000).

Biological Effect

This is a deletion of 4.6 kb including the entire exon 9 and extending into the flanking intronic sequences. It results in an in-frame skipping of exon 9 and an amino acid change (S290C) at the splice junction of exons 8 and 10.

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, and APP intracellular localization have been reported i(Woodruff et al., 2016; Oct 2016 news; Cho et al., 2019; Oh and Chung, 2017).

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). 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: 17 May 2019

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References

Research Models Citations

  1. APPSwe/PSEN1dE9 (C3-3 x S-9)

Mutation Position Table Citations

  1. PSEN1 S290 Mutations

News Citations

  1. Notch Your Average Joe—Grounds for PS1 Neurogenesis Inhibition?
  2. Beyond γ-Secretase: FAD Mutations Affect Calcium Channel via Lipid Messenger
  3. 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. . A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med. 1998 Apr;4(4):452-5. PubMed.
  5. . Alzheimer disease PS-1 exon 9 deletion defined. Nat Med. 1999 Oct;5(10):1090. PubMed.
  6. . Variant Alzheimer's disease with spastic paraparesis: clinical characterization. Neurology. 2000 Mar 14;54(5):1103-9. PubMed.
  7. . Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer's disease family: an Alu core sequence-stimulated recombination?. Eur J Hum Genet. 2000 Apr;8(4):259-66. PubMed.
  8. . Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 1996 Jul;17(1):181-90. PubMed.
  9. . 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.
  10. . 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.
  11. . 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.
  12. . Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. PubMed.
  13. . 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.
  14. . 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.
  15. . 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.
  16. . 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.
  17. . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.
  18. . Modulation of γ-secretase activity by multiple enzyme-substrate interactions: implications in pathogenesis of Alzheimer's disease. PLoS One. 2012;7(3):e32293. PubMed.
  19. . 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. . 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.
  21. . 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.
  22. . 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.
  23. . 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.

Other Citations

  1. APPswe/PSEN1dE9

Further Reading

Papers

  1. . Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol. 2000 Nov;48(5):806-8. 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. . A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med. 1998 Apr;4(4):452-5. PubMed.
  2. . Alzheimer disease PS-1 exon 9 deletion defined. Nat Med. 1999 Oct;5(10):1090. PubMed.

Other mutations at this position

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