title: Novel prion protein insert mutation associated with prolonged neurodegenerative illness.
abstract: BACKGROUND
  Mutations in the prion protein gene (PRNP) are found in approximately 13 to 15% of persons classified as dying from a transmissible spongiform encephalopathy. Point and octapeptide repeat insert and deletion mutations are described in the open reading frame (ORF) of PRNP. The authors present a clinicopathologic study of a patient with a family history of a lengthy and progressive neurodegenerative disorder associated with a novel large octapeptide repeat insert mutation.
  
  
  METHODS
  Neuropathologic examination, including immunohistochemistry for the prion protein, was undertaken. The ORF of PRNP was amplified by PCR, cloned, and sequenced. Homogenate of cerebral tissue underwent Western blot analysis for the prion protein before and after proteinase K treatment.
  
  
  RESULTS
  The proband died after a 16-year illness commencing at age 29 years. Confident premortem clinical diagnosis was not achieved despite a brain biopsy. Autopsy examination of the brain confirmed a spongiform encephalopathy. Prion protein immunohistochemistry revealed occasional granular deposits in the cerebellar granular layer. The proband was found to harbor a novel PRNP 168 base pair (bp) insert mutation.
  
  
  CONCLUSIONS
  The authors have identified a novel 168 bp octapeptide repeat insert mutation. Prion protein immunohistochemistry differs from previous cases harboring seven octapeptide repeat and other long insert mutations. Optimization of PRNP analysis, especially PCR conditions, is essential to avoid overlooking this type of mutation and delay the correct molecular genetic diagnosis.
authors.affiliation: Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Lewis
authors.forename: S
authors.initials: S
authors.lastname: Collins
authors.forename: A F
authors.initials: AF
authors.lastname: Hill
authors.forename: A
authors.initials: A
authors.lastname: Boyd
authors.forename: C A
authors.initials: CA
authors.lastname: McLean
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: C L
authors.initials: CL
authors.lastname: Masters
mesh_terms: D000328:Adult; D017668:Age of Onset; D000682:Amyloid / Q000235:genetics*; D015153:Blotting, Western; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D016254:Mutagenesis, Insertional; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017096:Prion Diseases / Q000175:diagnosis / Q000235:genetics*; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors / Q000235:genetics*
chemical_list: D000682:Amyloid; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors