Instability of the Octarepeat Region of the Human Prion Protein Gene

摘要: Prion diseases are a family of unique fatal transmissible neurodegenerative that affect humans and many animals. Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common prion in humans, accounting for 85-90% all human cases, exhibits high degree diversity phenotypes. The etiology sCJD remains to be elucidated. protein gene has an octapeptide repeat region (octarepeats) normally contains 5 repeats 24-27 bp (1 nonapeptide 4 coding sequences). An increase octarepeat numbers six or more decrease number three linked genetic with heterogeneous phenotypes humans. Here we report prone either contraction expansion when subjected PCR amplification vitro using Taq Pwo polymerase replicated wild type E. coli cells. Octarepeat insertion mutants were even less stable, mutation rate octarepeats was much higher DNA mismatch repair-deficient All observed resulting from replication contained head-to-head plasmid dimers mfold analysis (http://mfold.rna.albany.edu/?q=mfold/DNA-Folding-Form) indicates both strands would likely form multiple stable hairpin structures, suggesting sequence may structures during repair cause instability. These results provide first evidence supporting somatic mutation-based model etiology: 1) instability leads accumulation mutations brain cells development aging, 2) this augmented by compromised aged cells, 3) eventually some mutation-containing start spontaneous de novo formation initiate sCJD.