|Pathogenicity||Neuropathology||Biological Effect||Genomic Position||Genomic Region||Mutation Type
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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