title: Biological network inferences for a protection mechanism against familial Creutzfeldt-Jakob disease with E200K pathogenic mutation.
abstract: BACKGROUND
  Human prion diseases are caused by abnormal accumulation of misfolded prion protein in the brain tissue. Inherited prion diseases, including familial Creutzfeldt-Jakob disease (fCJD), are associated with mutations of the prion protein gene (PRNP). The glutamate (E)-to-lysine (K) substitution at codon 200 (E200K) in PRNP is the most common pathogenic mutation causing fCJD, but the E200K pathogenic mutation alone is regarded insufficient to cause prion diseases; thus, additional unidentified factors are proposed to explain the penetrance of E200K-dependent fCJD. Here, exome differences and biological network analysis between fCJD patients with E200K and healthy individuals, including a non-CJD individual with E200K, were analysed to gain new insights into possible mechanisms for CJD in individuals carrying E200K.
  
  
  METHODS
  Exome sequencing of the three CJD patients with E200K and 11 of the family of one patient (case1) were performed using the Illumina HiSeq 2000. The exome sequences of 24 Healthy Koreans were used as control. The bioinformatic analysis of the exome sequences was performed using the CLC Genomics Workbench v5.5. Sanger sequencing for variants validation was processed using a BigDye Terminator Cycle Sequencing Kit and an ABI 3730xl automated sequencer. Biological networks were created using Cytoscape (v2.8.3 and v3.0.2) and Pathway Studio 9.0 software.
  
  
  RESULTS
  Nineteen sites were only observed in healthy individuals. Four proteins (NRXN2, KLKB1, KARS, and LAMA3) that harbour rarely observed single-nucleotide variants showed biological interactions that are associated with prion diseases and/or prion protein in our biological network analysis.
  
  
  CONCLUSIONS
  Through this study, we confirmed that individuals can have a CJD-free life, even if they carry a pathogenic E200K mutation. Our research provides a possible mechanism that involves a candidate protective factor; this could be exploited to prevent fCJD onset in individuals carrying E200K.
authors.forename: Sol Moe
authors.initials: SM
authors.lastname: Lee
authors.forename: Myungguen
authors.initials: M
authors.lastname: Chung
authors.forename: Kyu Jam
authors.initials: KJ
authors.lastname: Hwang
authors.forename: Young Ran
authors.initials: YR
authors.lastname: Ju
authors.forename: Jae Wook
authors.initials: JW
authors.lastname: Hyeon
authors.forename: Jun-Sun
authors.initials: JS
authors.lastname: Park
authors.forename: Chi-Kyeong
authors.initials: CK
authors.lastname: Kim
authors.forename: Sangho
authors.initials: S
authors.lastname: Choi
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Zoonoses, Center for Immunology and Pathology, National Institute of Health, Korea Center for Disease Control and Prevention, Cheongju-si 363-700, Korea. tenksy@korea.kr.
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D003062:Codon / Q000235:genetics*; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D023281:Genomics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree
chemical_list: D003062:Codon