title: A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease.
abstract: 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.
authors.affiliation: Department of Medical Genetics, Addenbrooke's NHS Trust, Cambridge, CB2 2QQ, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Tysoe
authors.forename: J
authors.initials: J
authors.lastname: Whittaker
authors.forename: J
authors.initials: J
authors.lastname: Xuereb
authors.forename: N J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: M
authors.initials: M
authors.lastname: Cruts
authors.forename: C
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: G
authors.initials: G
authors.lastname: Wilcock
authors.forename: D C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D001344:Autopsy; D001921:Brain / Q000473:pathology; D018076:DNA, Complementary / Q000032:analysis; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D053764:Presenilin-1; D012313:RNA / Q000032:analysis; D017423:Sequence Analysis, RNA
chemical_list: D018076:DNA, Complementary; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012313:RNA