ABSTRACT
Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18-50% of autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Also, PSEN1 has been suggested as a potential risk gene in late-onset AD cases. We recently showed genetic association in a population-based study of EOAD, pointing to the 5' regulatory region of PSEN1. In this study we systematically screened 3.5 kb of the PSEN1 upstream region and found four novel polymorphisms. Genetic analysis confirmed association of two polymorphisms with increased risk for EOAD. In addition, we detected two different mutations in EOAD cases at-280 and-2818 relative to the transcription initiation site in exon 1A of PSEN1. Analysis of the mutant and wild-type-280 variants using luciferase reporter gene expression in transiently transfected neuroblastoma cells showed a 30% decrease in transcriptional activity for the mutant-280G PSEN1 promoter variant compared with the wild-type variant-280C. Our data suggest that the increased risk for EOAD associated with PSEN1 may result from genetic variations in the regulatory region leading to altered expression levels of the PSEN1 protein.
Subject(s)
Alzheimer Disease/genetics , Membrane Proteins/genetics , Regulatory Sequences, Nucleic Acid , Aged , Animals , Cell Line , DNA/blood , DNA Mutational Analysis , Female , Genes, Reporter , Genetic Variation , Humans , In Situ Hybridization, Fluorescence , Male , Membrane Proteins/metabolism , Mice , Middle Aged , Molecular Sequence Data , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Polymorphism, Single-Stranded Conformational , Presenilin-1 , Restriction Mapping , Risk Factors , TransfectionABSTRACT
HNA is an autosomal dominant recurrent focal neuropathy involving the brachial plexus. The etiology of HNA is unknown but the genetic defect most likely affects a non-neuronal tissue. We previously described linkage to chromosome 17q24-q25 in two HNA-families. Here we report the mutation analysis of two candidate genes: a cDNA encoding a putative sialyltransferase and the SFRS2 splicing factor including the c-myb ET-locus which is encoded on the opposite strand of the SFRS2 gene. The complete protein coding regions of both genes were studied by direct DNA sequencing. We did not find a disease associated mutation indicating that these genes are most likely not involved in the pathogenesis of HNA. However, we identified and characterized a rare AvaII polymorphism in the SFRS2 gene and detected a sequencing error, leading to an amino acid change (Val11Leu) in the published sequence of the putative sialyltransferase.
Subject(s)
Brachial Plexus Neuritis/genetics , Nuclear Proteins/genetics , Proto-Oncogene Proteins/genetics , Ribonucleoproteins , Sialyltransferases/genetics , Trans-Activators/genetics , DNA Mutational Analysis , Female , Humans , Male , Models, Genetic , Pedigree , Polymorphism, Genetic , Polymorphism, Restriction Fragment Length , Proto-Oncogene Proteins c-myb , Serine-Arginine Splicing FactorsABSTRACT
One of the major pathological hallmarks of Alzheimer's disease is the deposition in the brain parenchyma and cerebral blood vessel walls of amyloid beta-protein, a 4kDa proteolytic product of the longer beta-amyloid precursor protein (APP). Six different single base mutations in the APP gene have been reported causing early-onset Alzheimer's disease (age at onset < or = 65 years) or related amyloidosis in a small number of families. Cell transfection experiments using wild-type and mutant APP cDNA indicated that APP mutations result in the production of more or longer, aggregation prone, A beta peptides.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Mutation , Alzheimer Disease/genetics , Alzheimer Disease/physiopathology , Amino Acid Sequence , Amyloidosis/genetics , Amyloidosis/metabolism , Amyloidosis/physiopathology , Brain/blood supply , Brain/metabolism , Cerebrovascular Circulation , Down Syndrome/metabolism , Humans , Molecular Sequence DataABSTRACT
Screening for the APP717 mutation in 5 further families with early onset Alzheimer's disease failed to reveal further cases with this variant. Screening a further 100 normal individuals for this mutation also failed to reveal further occurrences of this variant in the general population. Sequencing of exons 16 and 17 of the beta-amyloid precursor protein gene (the exons which encode the beta-amyloid fragment) in pedigree FAD4 revealed them to be of normal sequence. The significance of these observations to the genetics of Alzheimer's disease is discussed.
