title: Evidence for synergistic effects of PRNP and ATP7B mutations in severe neuropsychiatric deterioration.
abstract: BACKGROUND
  Wilson's disease (WD), a rare cause of neuropsychiatric deterioration, is associated with mutations in the ATP7B gene. Prion diseases are also rare causes of neuropsychiatric deterioration that can occur sporadically without an identifiable cause, or can be attributed to mutations in the PRNP gene.
  
  
  METHODS
  Here we describe a biological "experiment of nature" in which a patient presented with severe neuropsychiatric decline and strong biochemical evidence of WD. Genetic analysis revealed that he was a compound heterozygote for two ATP7B sequence variants (c.2165dupT, p.Arg723Glufs*32; and c.4039G > A, p.Gly1347Ser), the first having been reported once previously, and the second being novel. In addition, the patient was heterozygous for a PRNP variant, c.160G > A, p.Gly54Ser, that has been reported in a neuropsychiatric patient only once previously in association with a similarly severe clinical course of neuropsychiatric disease and early age of onset, but no accompanying information on ATP7B genotype. Of particular interest was the observation that the patient's older sister, who carried the same ATP7B genotype and laboratory evidence for biochemical WD but was clinically asymptomatic, lacked the PRNP variant allele.
  
  
  CONCLUSIONS
  We propose that synergism may occur between at least some allelic variants of ATP7B and PRNP, possibly exerted through effects on cellular copper metabolism.
authors.forename: Nauzer
authors.initials: N
authors.lastname: Forbes
authors.forename: Susan
authors.initials: S
authors.lastname: Goodwin
authors.forename: Kevin
authors.initials: K
authors.lastname: Woodward
authors.forename: David G
authors.initials: DG
authors.lastname: Morgan
authors.forename: Lauren
authors.initials: L
authors.lastname: Brady
authors.forename: Michael B
authors.initials: MB
authors.lastname: Coulthart
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Canada. tarnopol@mcmaster.ca.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics*; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D060045:Genes, Modifier; D006527:Hepatolenticular Degeneration / Q000175:diagnosis* / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques; D010375:Pedigree; D017096:Prion Diseases / Q000175:diagnosis* / Q000235:genetics; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics*
chemical_list: D027682:Cation Transport Proteins; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases