Mutations Position Table

PSEN1 S290 Mutations

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Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
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.

This is a 5.9 kb deletion including the entire exon 9 and extending into the flanking intronic sequences. It results in the in-frame skipping of exon 9 and an amino acid substitution at the splice junction of exons 8 and 10 (S290C).

[MET1] g.56305_62162del
[NT1] g.72916_78773del

Non-Coding Coding
Intron 8, Exon 9
Complex
0 Smith 2001
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.

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

[MET1] g.56681_61235del
[NT1] g.73292_77846del

Non-Coding Coding
Intron 8, Exon 9
Complex
0 Crook 1998;
Prihar 1999
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 a splice acceptor site in intron 8 resulting in an in-frame skipping of exon 9 and an amino acid change at the splice junction of exons 8 and 10 (S290C).

[MET1] g.58304G>A
[NT1] g.74916G>A
rs63750219
Non-Coding Coding
Intron 8, Exon 9
Complex
0 Sato 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 an amino acid change at the splice junction of exon 8 and 10 (S290C).

[MET1] g.58304G>T
[NT1] g.74916G>T
rs63750219 
Non-Coding Coding
Intron 8, Exon 9
Complex
0 Perez-Tur 1995;
Hutton 1996

Although quite different in nature, the four 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 two 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 have subsequently been observed in the brains of patients with ΔE9 mutations, as well as some missense mutations.

Multiple mouse models which 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.