PSEN1 c.869-22_869-23ins18


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


This mutation involves the insertion of 18 nucleotides in intron 8 (c.869-22_869-23insTGGAATTTTGTGCTGTTG) and results in the in-frame skipping of exon 9. It is one of several mutations in PSEN1 that are notable for exclusion of exon 9, which are variously referred to as ΔE9, Δ9, delE9, or deltaE9. This particular mutation was identified in a French patient whose family had a history of dementia (three affected family members in two generations). Onset ranged from 42 to 47 years, and two of the affected individuals also developed nearly concurrent symptoms of spasticity (Dumanchin et al., 2006).

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


Neuropathological examination of two brains revealed widespread neurofibrillary tangles and numerous plaques, including both large, non-neuritic cotton-wool plaques and neuritic plaques more typical of AD. Marked cerebral amyloid angiopathy was also observed (Dumanchin et al., 2006).

Biological Effect

Analysis of patient mRNA extracted from peripheral blood cells and analyzed by RT-PCR followed by ethidium bromide gel separation showed transcripts lacking exon 9. Ex vivo splicing assays confirmed these results in HeLa cells and in the neuroblastoma cell line SH-SY5Y (Dumanchin et al., 2006). Several in silico algorithms predicted this variant is damaging (Xiao et al., 2021).

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 their 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 (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).

Research Models

Transgenic mice expressing PSEN1 lacking exon 9 have beeen generated, such as line S-9 (Lee et al., 1997), which was subsequently bred to an APP transgenic mouse to generate APPSwe/PSEN1dE9, which has more extensive pathology than either of the parental lines. Another double transgenic model was made by coinjecting 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), astrocytes (Oksanen et al., 2017), and brain endothelial cells (Oikari et al., 2020) which display several features of AD pathology.

Last Updated: 29 Jul 2021


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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. . 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. . 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.
  6. . 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.
  7. . Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 1996 Jul;17(1):181-90. PubMed.
  8. . 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.
  9. . 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.
  10. . Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. PubMed.
  11. . 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. . 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.
  13. . 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.
  14. . 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.
  15. . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.
  16. . Modulation of γ-secretase activity by multiple enzyme-substrate interactions: implications in pathogenesis of Alzheimer's disease. PLoS One. 2012;7(3):e32293. PubMed.
  17. . 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.
  18. . 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.
  19. . 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.
  20. . 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.
  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.

Other Citations

  1. APPSwe/PSEN1dE9

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . 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.

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