Mutations Position Table

PSEN1 S290 Mutations

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Mutation Pathogenicity DNA Change Expected RNA | Protein Consequence Coding/Non-Coding Genomic Region Neuropathology Biological Effect Primary
Papers
S290_S319delinsC G>A
(ΔE9, Δ9, c.869-1G>A)
AD : Pathogenic Substitution Splicing Alteration | Deletion-Insertion Both Intron 8, Exon 9

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. Δ9 mutations generally result in increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. They also disrupt multiple cellular functions.

Sato et al., 1998
S290_S319delinsC G>T
(ΔE9, Δ9)
AD : Pathogenic Substitution Splicing Alteration | Deletion-Insertion Both Intron 8, Exon 9

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. Δ9 mutations generally result in increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. They also disrupt multiple cellular functions.

Perez-Tur et al., 1995;
Hutton et al., 1996
S290_S319delinsC A>G
(ΔE9, Δ9, c.869-2A>G)
AD : Pathogenic Substitution Splicing Alteration | Deletion-Insertion Both Intron 8, Exon 9

Unknown; in one patient, MRI showed supratentorial atrophy, particularly of parietal and occipital cortex. Also, reduced Aβ42 in CSF.

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. Δ9 mutations generally result in increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. They also disrupt multiple cellular functions.

Rovelet-Lecrux et al., 2015
S290_R377delinsW (Δ9-10)
(Δ9-10, Delta9-10, p.Ser290_Arg377delinsTrp, g.73671948_73682054del)
AD : Not Classified Deletion Deletion | Deletion-Insertion Both Introns 8-10, Exons 9-10

No data.

This mutation involves the deletion of 10.1 kilobases including exons 9 and 10. Severe deficits in endopeptidase and carboxypeptidase activity; decreased production of Aβ42, Aβ40, and Aβ38, with increased Aβ43.

Le Guennec et al., 2017;
Lanoiselée et al., 2017
S290_S319delinsC
(ΔE9Finn, Δ9Finn, Δ9)
AD : Pathogenic Deletion Deletion | Deletion-Insertion Both Intron 8, Exon 9, Intron 9

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. Δ9 mutations generally result in increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. They also disrupt multiple cellular functions.

Crook et al., 1998;
Prihar et al., 1999
S290_S319delinsC
(ΔE9, Δ9)
AD : Pathogenic Deletion Deletion | Deletion-Insertion Both Intron 8, Exon 9, Intron 9

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. Δ9 mutations generally result in increased Aβ42/Aβ40 ratio and decreased Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios. They also disrupt multiple cellular functions.

Smith et al., 2001

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 and c.856+3089_943+467del, are referred to as ΔE9, Δ9, delE9, or deltaE9 mutations. Of the ΔE9 mutations, three 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 S290_R377delinsW (Δ9-10) 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.

The biological effects of these mutations include decreased production of short Aβ peptides (Aβ38, Aβ40) and increased production of long Aβ peptides (Aβ42+) in cellular and in vitro assays, as well as in mouse brain. The Aβ ratios generated by ΔE9 mutants—Aβ42/Aβ40, Aβ (37 + 38 + 40) / (42 + 43), and Aβ37/Aβ42—are consistent with AD pathogenicity and early age at onset. In addition, ΔE9 mutants have been reported to disrupt several other cellular functions, including endocytosis, calcium dynamics, and protein localization.

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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