ClinVar

In 2 autopsy-confirmed cases with early-onset Alzheimer disease (AD3; 607822), Tysoe et al. (1998) identified a single-base deletion of a G at the splice donor site of intron 4 of the PSEN1 gene. De Jonghe et al. (1999) identified the same mutation in 4 additional, unrelated early-onset AD cases and demonstrated that the mutation segregates in an autosomal dominant manner and that all cases have 1 common ancestor. De Jonghe et al. (1999) showed that the intron 4 mutation produces 3 different transcripts, 2 deletion transcripts (1 involving a deletion of all of exon 4 and the other involving a deletion of part of exon 4), and a transcript that results in insertion of a threonine between codons 113 and 114. The truncated proteins were not detectable in vivo in brain homogenates or in lymphoblast lysates of mutation carriers. In vitro, HEK293 cells overexpressing the insertion cDNA construct or either of the deletion constructs showed amyloid beta-42 secretion approximately 3 to 4 times greater than normal only for the insertion cDNA construct. Increased amyloid beta-42 production was also observed in brain homogenates. De Jonghe et al. (1999) concluded that in the case of the intron 4 mutation, the Alzheimer disease pathophysiology results from increased amyloid beta-42 secretion by the insertion transcript, comparable with cases carrying a dominant PSEN1 missense mutation.