Mutations Position Table

PSEN1 S290 Mutations

Mutation Clinical
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change

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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