A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease

Am J Hum Genet. 1998 Jan;62(1):70-6. doi: 10.1086/301672.


We have examined genomic DNA from 40 cases of autopsy-confirmed early-onset Alzheimer disease (EOAD) (age at onset <=65 years) that were all unselected for family history. We have sequenced the 10 exons and flanking intronic sequences of the presenilin-1 (PS-1) gene for all 40 individuals. A single mutation, a deletion of a G from the intron 4 splice-donor consensus sequence, was detected in two individuals in this study. The mutation was associated with two shortened transcripts, both with shifted reading frames resulting in premature-termination codons. All the PS-1 mutations described elsewhere have been missense or in-frame splice mutations, and recent data suggest that these result in disease by gain-of-function or dominant-negative mechanisms. The mutation that we have identified is likely to result in haploinsufficiency and would be most consistent with other mutations acting in a dominant-negative manner. However, we cannot exclude the possibility that the small amounts of truncated transcripts exert a gain of function. Since no other mutations or polymorphisms were detected in our patients, mutations in the coding regions and splice consensus sequences of PS-1 are likely to be rare in EOAD cases unselected for family history.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Amino Acid Sequence
  • Autopsy
  • Brain / pathology
  • DNA, Complementary / analysis
  • Female
  • Haplotypes
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation*
  • Pedigree
  • Polymerase Chain Reaction
  • Presenilin-1
  • RNA / analysis
  • Sequence Analysis, RNA


  • DNA, Complementary
  • Membrane Proteins
  • PSEN1 protein, human
  • Presenilin-1
  • RNA