Biological network inferences for a protection mechanism against familial Creutzfeldt-Jakob disease with E200K pathogenic mutationReportar como inadecuado

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BMC Medical Genomics

, 7:52

Functional and structural genomics


BackgroundHuman 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.

MethodsExome 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.

ResultsNineteen 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.

ConclusionThrough 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.

KeywordsPRNP E200K-dependent fCJD 85-year-old non-CJD individual with the E200K Whole exome sequencing Biological network analysis Candidate protective factor against fCJD with E200K AbbreviationsfCJDFamilial Creutzfeldt-Jakob disease

IPDInherited prion diseases

PRNPPrion protein gene

SNVsSingle nucleotide variants

FFIFatal familial insomnia

GSSGertsmann-striussler-scheinker syndrome

FMFamily Member

PRNDPrion protein doublet

PRNTPrion protein testis specific

SPRNShadow of prion protein

PCRPolymerase chain reaction.

Electronic supplementary materialThe online version of this article doi:10.1186-1755-8794-7-52 contains supplementary material, which is available to authorized users.

Sol Moe Lee, Myungguen Chung contributed equally to this work.

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