Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PS4, PM1, PM2, PP1, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73673093 G>A
dbSNP ID: rs63750219
Mutation Type: Complex
Genomic Region: Intron 8, Exon 9
This point mutation at a splice site in intron 8 results in the exclusion of exon 9 from mRNA transcripts. It is one of several known mutations that result in exon 9 exclusion, which are known as ΔE9, delE9, E9, or deltaE9. This specific mutation (G>A) has been detected in four families with very different ancestries. A similar point mutation (G>T) at the same position has also been reported in two families and appears to have a similar effect on splicing.
The G>A mutation was first reported in a large Japanese pedigree known as TK-1 (Sato et al., 1998). The reported pedigree shows 11 affected family members over five generations. The mean age of onset in this family was reported as 47.50 ± 3.29 and the mean age at death was 54.62 ± 4.37. Symptoms included classic features of AD (e.g., memory impairment, lack of spontaneity, disorientation), but also some extrapyramidal signs and a progressive form of spastic paralysis with rigidity which started in the lower limbs.
The mutation appeared to segregate with disease in TK-1. Of the 11 family members examined, the mutation was present in the proband and in four asymptomatic individuals under the mean age of onset for the family. The mutation was absent in six unaffected family members and in 98 healthy Japanese controls.
The second pedigree, an Australian family known as EOFAD-2, were of Anglo-Celtic origin (Brooks et al., 2003). The reported pedigree shows 14 affected individuals over four generations. The clinical phenotype consisted of progressive cognitive decline with some individuals displaying symptoms of spastic paraparesis (spasticity of the lower limbs, gait disturbance, etc.). The mean onset age was 44.9 years (range: 36 to 52 years) with a trend toward those individuals with spasticity displaying a slightly later onset. A diagnosis of AD was confirmed by autopsy in four individuals. The G>A splice acceptor mutation was found in the proband and test results from 11 other members of the EOFAD-2 family were consistent with segregation of the mutation with the disease phenotype (dementia, spastic paraparesis, or both) in an autosomal-dominant manner.
The mutation was also found in a U.K. genetic screen of patients with dementia (Koriath et al., 2018). The family of the mutation carrier had at least three members, including a first-degree relative, diagnosed with AD across two generations. The carrier’s AD symptoms emerged at age 57.
In addition, the mutation was identified in two male siblings of a Turkish family including 39 members spanning four generations with nine affected individuals (Doğan et al., 2022). The carriers' first clinical symptom was memory impairment, surfacing at ages 40 and 38 years. Both men also suffered from behavioral symptoms, delusions/hallucinations, spastic paraparesis, and myoclonus.
This mutation was absent from genetic variant databases, including ExAC and gnomAD.
Two cases from the TK-1 family were examined neuropathologically (Tabira et al., 2002). The subjects were identical twin brothers with clinical histories typical of their family, including onset at age 45 and 46. One brother developed memory disturbances at age 45, followed by spastic paraparesis with muscular rigidity. He deteriorated gradually, becoming severely demented, with myoclonus and epilepsy, and died at age 64. The other brother first reported trembling and lower leg pain at age 46. His memory impairment became apparent later, developing over time into severe dementia. He also developed progressive spastic paraplegia with myoclonus and seizures. He died at age 61.
In both cases senile plaques were numerous in the hippocampus, frontal, temporal, and parietal cortices, moderate in the occipital cortex, and mild in the cerebellar cortex and the inferior olive. Some plaques had an amyloid core, and mild neuritic changes were observed. Neurofibrillary tangles were likewise abundant and amyloid angiopathy was scattered. Cotton-wool plaques could be seen by hematoxylin and eosin staining. The neuropathology of one of these cases was further investigated in the context of comparison to other mutations that involve exon 9 exclusion (Mann et al., 2001).
Neuropathological findings are also available from four cases within the EOFAD-2 kindred (Brooks et al., 2003). All four cases were affected by early onset dementia, but none had reported symptoms of spasticity. The neuropathology in all four was sufficient to meet NIA-Reagan criteria for Alzheimer's disease, with numerous neurofibrillary tangles and plaques in the hippocampus and cerebral cortex, and neuronal loss throughout the cortex. The plaques were both of the large, cotton-wool type and the neuritic type. Congophilic angiopathy was also noted as being present in all four brains.
Magnetic resonance imaging of the brains of the two Turkish carriers revealed atrophy in the parahippocampal gyrus (Doğan et al., 2022).
This point mutation occurs at a splice acceptor site in intron 8 and causes aberrant splicing leading to the generation of PSEN1 mRNA lacking exon 9 and proteins that lack 28 amino acid residues (291-319). The mutation also causes an amino acid change (S290C) at the splice junction of exons 8 and 10. Koriath and colleagues reported a CADD score of 26.7, predicted to be amongst the top one percent of deleterious variants in the human genome (Koriath et al., 2018), and Xiao and colleagues reported multiple in silico algorithms predicted the mutation was 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 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.Other studies examining the levels of multiple Aβ peptides have reported similar findings (Svedružić et al., 2012; Kakuda et al., 2021). Chávez-Gutiérrez and colleagues proposed the mutant impairs 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).
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, mitochondrial function, calcium homeostasis, 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, Rojas-Charry et al., 2020). Also, 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).
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.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. S290C;T291_S319del G>A : Functional data derive from assays involving exon 9 deletion mutants, not necessarily this specific variant.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. S290C;T291_S319del G>A : The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
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.
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. S290C;T291_S319del G>A : Cosegregation demonstrated in >1 family.
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)|
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) astrocytes (Oksanen et al., 2017), and brain endothelial cells (Oikari et al., 2020) which display several features of AD pathology.
Last Updated: 15 Aug 2022
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Other mutations at this position
- PSEN1 S290_R377delinsW (Δ9-10) (Δ9-10)
- PSEN1 S290C;T291_S319del G>T (ΔE9)
- PSEN1 S290C;T291_S319del A>G (ΔE9)
- PSEN1 S290C;T291_S319del (ΔE9Finn)
- PSEN1 S290C;T291_S319del (ΔE9)
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