Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype

John B.J. Kwok, Kevin Taddei, Marianne Hallupp, Christopher Fisher, William S. Brooks, Gerald A. Broe, John Hardy, Michael J. Fulham, Garth A. Nicholson, Rick Stell, Peter H. St. George Hyslop, Paul E. Fraser, Byron Kakulas, Roger Clarnette, Norman Relkin, Samuel E. Gandy, Peter R. Schofield, Ralph N. Martins*

*Corresponding author for this work

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

Eleven early-onset dementia families, all with affected individuals who have either presented clinical symptoms of early onset familial Alzheimer's disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and - 2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products amplified from genomic DNA templates of affected individuals. Three pedigrees were attributable to known mutations in the PS- 1 gene: P264L, E280A and the splice acceptor site (G to T) mutation, which results in the deletion of residues 290-319 of PS-1 (PS-1 Δ290-319). In a fourth pedigree, a novel PS-1 mutation was identified in exon 7 (M233T), which is homologous to a pathogenic PS-2 mutation (M239V), and is characterized by a very early average age of onset (before the age of 35). In one early onset case, another novel PS-1 mutation was identified in exon 8 (R278T). Of the five remaining families and the other early onset case, none have missense mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the APP gene. Moreover, two of the PS-1 mutations, PS-1 Δ290-319 and R278T, are associated with the co-presentation of familial spastic paraparesis (FSP) in some of the affected family members. Our data raise the possibility that the phenotypic spectrum associated with PS-1 mutations may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data suggest that other novel EOFAD loci, in addition to APP and the presenilin genes, are involved in the aetiology of up to 50% of EOFAD cases.

Original languageEnglish
Pages (from-to)1537-1542
Number of pages6
JournalNeuroReport
Volume8
Issue number6
Publication statusPublished - 1997
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Missense mutation
  • Presenilin genes
  • Sequence analysis

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