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The genetic Creutzfeldt-Jakob disease with E200K mutation: analysis of clinical, genetic and laboratory features of 30 Chinese patients.

ABSTRACT: Genetic Creutzfeldt-Jakob disease (gCJD) with E200K mutation is one of the common subtypes of human genetic prion diseases worldwide. In this study, we systematically analyzed 30 Chinese E200K gCJD cases for their epidemiological, clinical, laboratory and genetic features. The patients came from 12 different provinces, majority in northern part of China. The onset age varied from 42 to 71 year-old (y), with the median of was 57?y. The CYP4X1 gene rs9793471 SNP was tested. Only one patient's rs9793471 genotype was GA and the others' were AA. The gender ratio (M: F) was 1:1.73 (11:19). The foremost symptoms and clinical progression of Chinese E200K gCJD patients were quite similar as sporadic CJD cases. Only a few cases (4/30) recalled clearly disease related family history. 74.1% (20/27), 86.7% (26/30) and 50.0% (13/26) of the cases were CSF 14-3-3 positive, sCJD associated abnormalities on MRI and special PSWC on EEG, respectively. The median clinical duration was 9 months (varying from 2 to 26 months). All 30 Chinese E200K gCJD patients were M129M and E219E homozygous. 21 members from 3 families conducted PRNP sequencing and 16 asymptomatic carriers of E200K mutation with M129M and E219E homozygous were identified. This is the largest study on E200K gCJD patients in China, which would benefit to the knowledge of E200K gCJD.

SUBMITTER: Gao LP

PROVIDER: S-EPMC6372685 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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The genetic Creutzfeldt-Jakob disease with E200K mutation: analysis of clinical, genetic and laboratory features of 30 Chinese patients.

Gao Li-Ping LP Shi Qi Q Xiao Kang K Wang Jing J Zhou Wei W Chen Cao C Dong Xiao-Ping XP

Scientific reports 20190212 1

Genetic Creutzfeldt-Jakob disease (gCJD) with E200K mutation is one of the common subtypes of human genetic prion diseases worldwide. In this study, we systematically analyzed 30 Chinese E200K gCJD cases for their epidemiological, clinical, laboratory and genetic features. The patients came from 12 different provinces, majority in northern part of China. The onset age varied from 42 to 71 year-old (y), with the median of was 57 y. The CYP4X1 gene rs9793471 SNP was tested. Only one patient's rs97 ...[more]

PMID: 30755683

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Project description: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. CONCLUSION: 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.

Project description:The familial or genetic Creutzfeldt-Jakob disease (fCJD or gCJD) is the inherent form of human prion diseases, which accounts for approximately 10-15% of human prion diseases that are caused by mutations of the prion protein gene (PRNP). In this study, the global expression patterns of the parietal cortex from a patient with G114V gCJD were comparatively analyzed with the normal controls by using a commercial human genome expression chip. Totally 8774 genes showed differential expression, among them 2769 genes were upregulated and 6005 ones were downregulated. The reliability of the results was confirmed by the real-time RT-PCR assays for several specific genes. The most differentially expressed genes involved in the functions of regulation of transcription, ion transport, transcription, cell adhesion, signal transduction. The gene associated with gliosis was upregulated and the genes marked for neurons were downregulated, while the transcription of PRNP gene maintained unchanged. 169 different pathways showed significantly changed in the brain of G114V gCJD. The most significantly regulated pathways included that of Alzheimer’s and Parkinson’s disease, oxidative phosphorylation, regulation of actin cytoskeleton, MAPK signaling pathway and proteasome, which were described in prion diseases previously. In addition, some rarely addressed pathways in prion diseases, such as axon guidance, gap junction and purine metabolism, were also significantly changed in G114V gCJD. The transcriptional situations of the most genes in the top ten changed pathways were down-regulated. The extensive reductions of gene expressions in G114V gCJD showed the comparable profiles with sporadic CJD. The data here raised the useful clues for understanding the pathogenesis of the disease and selecting the potential biomarkers for diagnostic and therapeutic tools. Brain tissues of parietal cortex from a definitely diagnosed G114V gCJD were enrolled into this study. The patient was a 47-year-old Han-Chinese woman at the onset. Neuropathological assays of ten different brain regions revealed typical sCJD-like abnormality and PrPSc deposits. Meanwhile, a commercial normal human parietal cortex total RNA (Clontech) pooled from four male/female aged 35-89 was utilized as control.

Dataset Information

The genetic Creutzfeldt-Jakob disease with E200K mutation: analysis of clinical, genetic and laboratory features of 30 Chinese patients.

Publications

The genetic Creutzfeldt-Jakob disease with E200K mutation: analysis of clinical, genetic and laboratory features of 30 Chinese patients.

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