Presenilin 1 Met146Leu variant due to an A --> T transversion in an early-onset familial Alzheimer's disease pedigree from Argentina.
Most of the cases of early-onset familial Alzheimer's disease (FAD) are related to missense mutations in the presenilin 1 (PS-1) gene on chromosome 14. Although PS-1 mutations are distributed throughout the entire open reading frame, most mutations are found in transmembrane region II and hydrophilic loop VI encoded by exons 5 and 8, respectively. These two groups of substitutions are associated with an age of onset of 40-43 years for exon 5 and 45-55 years for exon 8, respectively. We have previously described a South American pedigree from Argentina with early-onset FAD (mean age of onset 38.9 +/- 3.9 years) with no mutations in exons 16 and 17 of the beta-protein precursor gene (betaPP770 transcript). Here we report the identification of an A --> T transversion at the first position of codon 146 of PS-1 in these patients. This missense mutation results in a Met --> Leu substitution, as reported for the Italian pedigrees Tor1.1 and FAD4. The significant differences in ages of onset and death among members of generations II-III and IV suggest that other genetic and/or environmental factors may influence disease phenotype in this pedigree.
IDEHU-CONICET, Department of Microbiology, Immunology and Biotechnology, University of Buenos Aires, Argentina.
L
L
Morelli
M I
MI
Prat
E
E
Levy
C A
CA
Mangone
E M
EM
Castaño
D000225:Adenine; D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics*; D019943:Amino Acid Substitution; D001118:Argentina; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007930:Leucine / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008715:Methionine / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree; D053764:Presenilin-1; D013941:Thymine
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D008715:Methionine; D007930:Leucine; D000225:Adenine; D013941:Thymine