Mutations Position Table

PSEN1 S290 Mutations

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
S290C;T291_S319del
(ΔE9Finn, Δ9Finn, Δ9)
Alzheimer's Disease, Spastic Paraparesis Alzheimer's Disease : Pathogenic

Variable across two families: One family had unusual plaques described as “reminiscent of loosely packed cotton-wool balls” which were large (100-150 μM in diameter) and not congophilic, suggesting a lack of amyloid at the core, in addition to more typical AD plaques and tangles. The other family had more typical AD pathology.

4.6 kb deletion including entire exon 9 and extending into flanking intronic sequences; results in skipping of exon 9 and S290C substitution at the splice junction of exons 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.


Non-Coding Coding
Intron 8, Exon 9
Complex
0 Crook et al., 1998;
Prihar et al., 1999
S290C;T291_S319del
(ΔE9, Δ9)
Alzheimer's Disease, Spastic Paraparesis Alzheimer's Disease : Pathogenic

Variable: lesions observed include cotton-wool plaques, cored plaques, and tangles. Corticospinal tract degeneration, cortical atrophy, and congophilic amyloid angiopathy also variably observed.

5.9 kb deletion including entire exon 9 and extending into flanking intronic sequences; results in skipping of exon 9 and S290C substitution at the splice junction of exons 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.


Non-Coding Coding
Intron 8, Exon 9
Complex
0 Smith et al., 2001
S290C;T291_S319del A>G
(ΔE9, Δ9)
Alzheimer's Disease Alzheimer's Disease : Pathogenic

Unknown; MRI showed supratentorial atrophy, particularly of parietal and occipital cortex.

Point mutation in splice acceptor site in intron 8 resulting in skipping of exon 9 and S290C change at the splice junction of exons 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.


Non-Coding Coding
Intron 8, Exon 9
Complex
0 Rovelet-Lecrux et al., 2015
S290C;T291_S319del G>A
(ΔE9, Δ9)
Alzheimer's Disease, Spastic Paraparesis Alzheimer's Disease : Pathogenic

Cotton-wool plaques are common, in addition to classic neuritic, amyloid plaques. Tangles, neuronal loss, atrophy typical of AD.

Point mutation in splice acceptor site in intron 8 resulting in skipping of exon 9 and S290C change at the splice junction of exons 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.

rs63750219
Non-Coding Coding
Intron 8, Exon 9
Complex
0 Sato et al., 1998
S290C;T291_S319del G>T
(ΔE9, Δ9)
Alzheimer's Disease, Spastic Paraparesis Alzheimer's Disease : Pathogenic

Cotton-wool plaques throughout the neocortex. Less frequent cored plaques. Neurofibrillary tangles, some neuronal loss, gliosis, and cerebral amyloid angiopathy.

Point mutation in a splice acceptor site in intron 8 resulting in in-frame skipping of exon 9 and S290C change at the splice junction of exon 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.

rs63750219 
Non-Coding Coding
Intron 8, Exon 9
Complex
0 Perez-Tur et al., 1995;
Hutton et al., 1996
S290W;S291_R377del
(Δ9-10 , Delta9-10, p.Ser290_Arg377delinsTrp, g.73671948_73682054del)
Alzheimer's Disease, Spastic Paraparesis Early-onset : Pathogenic

No data.

This mutation involves the deletion of 10.1 kilobases including exons 9 and 10. A S290W missense mutation is predicted at the junction between exons 8 and 11.


Non-Coding Coding
Introns 8-10, Exons 9-10
Deletion
0 Le Guennec et al., 2017;
Lanoiselée et al., 2017

Although different in nature, five of the mutations listed above result in an amino acid substitution (cysteine in place of serine) at the splice junction of exons 8 and 10. They also result in the exclusion of exon 9 from mRNA transcripts, and therefore, along with 869-22_869-23ins18, are referred to as ΔE9, Δ9, delE9, or deltaE9 mutations. Of the ΔE9 mutations, two are deletion mutations, one is an insertion mutation, and three are splice-site mutations within intron 8. Despite their heterogeneity, they all result in the absence of exon 9 from transcripts and the production of presenilin protein lacking a region of about 30 amino acids. Many, but not all, of the ΔE9 kindreds have a clinical phenotype that involves spastic paraparesis, although heterogeneity exists even within a family. The ΔE9 mutations are also frequently associated with neuropathological features atypical for AD, notably large deposits of Aβ known as "cotton-wool plaques," which lack an amyloid core. These plaques were first described in the Finnish pedigree with exon 9 deletion and subsequently have been observed in the brains of patients with ΔE9 mutations, as well as some missense mutations.

The sixth mutation is a deletion of 10.1 kilobases between introns 8 and 10 and results in the in-frame removal of exons 9 and 10; it is referred to as Δ9-10. Similar to the ΔE9 kindreds, the one individual found with the Δ9-10 mutation also shares the spastic paraparesis phenotype.

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 coinjecting vectors expressing PSEN1ΔE9 and APP with the Swedish mutation (APPswe/PSEN1dE9 (Borchelt mice)). Cotton-wool plaques have not been observed in these mouse models.

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