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Genomic Characteristics of Genetic Creutzfeldt-Jakob Disease Patients with V180I Mutation and Associations with Other Neurodegenerative Disorders.

Lee SM, Chung M, Hyeon JW, Jeong SW, Ju YR, Kim H, Lee J, Kim S, An SS, Cho SB, Lee YS, Kim SY - PLoS ONE (2016)

Bottom Line: More than half of validated variants were categorized in Gene Ontology (GO) terms of binding and/or catalytic activity.Moreover, we found differential genome variants in gCJD patients with V180I mutation, including one uniquely surviving 10 years after diagnosis of the disease.Elucidation of the relationships between gCJD and Alzheimer's disease or Parkinson's disease at the genomic level will facilitate further advances in our understanding of the specific mechanisms mediating the pathogenesis of NDs and gold standard therapies for NDs.

View Article: PubMed Central - PubMed

Affiliation: Division of Zoonoses, Center for Immunology & Pathology, National Institute of Health, Korea Centers for Disease Control & Prevention, Cheongju-si, Chungcheongbuk-do, South Korea.

ABSTRACT
Inherited prion diseases (IPDs), including genetic Creutzfeldt-Jakob disease (gCJD), account for 10-15% of cases of prion diseases and are associated with several pathogenic mutations, including P102L, V180I, and E200K, in the prion protein gene (PRNP). The valine to isoleucine substitution at codon 180 (V180I) of PRNP is the most common pathogenic mutation causing gCJD in East Asian patients. In this study, we conducted follow-up analyses to identify candidate factors and their associations with disease onset. Whole-genome sequencing (WGS) data of five gCJD patients with V180I mutation and 145 healthy individuals were used to identify genomic differences. A total of 18,648,850 candidate variants were observed in only the patient group, 29 of them were validated as variants. Four of these validated variants were nonsense mutations, six were observed in genes directly or indirectly related to neurodegenerative disorders (NDs), such as LPA, LRRK2, and FGF20. More than half of validated variants were categorized in Gene Ontology (GO) terms of binding and/or catalytic activity. Moreover, we found differential genome variants in gCJD patients with V180I mutation, including one uniquely surviving 10 years after diagnosis of the disease. Elucidation of the relationships between gCJD and Alzheimer's disease or Parkinson's disease at the genomic level will facilitate further advances in our understanding of the specific mechanisms mediating the pathogenesis of NDs and gold standard therapies for NDs.

No MeSH data available.


Related in: MedlinePlus

Variant filtering strategy of whole genome sequencing data.Overview of variant filtering to identify gCJD-related genes and gene variants. Each stage was processed followed by stage I–V.
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pone.0157540.g002: Variant filtering strategy of whole genome sequencing data.Overview of variant filtering to identify gCJD-related genes and gene variants. Each stage was processed followed by stage I–V.

Mentions: The genomic variants in the five gCJD patients with V180I mutation were compared with 134 of 135 healthy individuals (see materials and methods, S3 Table and S1 File), and 125 of 18,648,850 variants were selected for validation (Fig 2). Of these 125 candidates, 76 were observed in all five patients, one was observed in four patients, two were observed in two patients, and 46 were observed in only one patient (S4 Table). From these candidates, to eliminate false positives, we performed validation of the 125 candidate variants using Fluidigm SNPtype Assays and Sanger sequencing


Genomic Characteristics of Genetic Creutzfeldt-Jakob Disease Patients with V180I Mutation and Associations with Other Neurodegenerative Disorders.

Lee SM, Chung M, Hyeon JW, Jeong SW, Ju YR, Kim H, Lee J, Kim S, An SS, Cho SB, Lee YS, Kim SY - PLoS ONE (2016)

Variant filtering strategy of whole genome sequencing data.Overview of variant filtering to identify gCJD-related genes and gene variants. Each stage was processed followed by stage I–V.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920420&req=5

pone.0157540.g002: Variant filtering strategy of whole genome sequencing data.Overview of variant filtering to identify gCJD-related genes and gene variants. Each stage was processed followed by stage I–V.
Mentions: The genomic variants in the five gCJD patients with V180I mutation were compared with 134 of 135 healthy individuals (see materials and methods, S3 Table and S1 File), and 125 of 18,648,850 variants were selected for validation (Fig 2). Of these 125 candidates, 76 were observed in all five patients, one was observed in four patients, two were observed in two patients, and 46 were observed in only one patient (S4 Table). From these candidates, to eliminate false positives, we performed validation of the 125 candidate variants using Fluidigm SNPtype Assays and Sanger sequencing

Bottom Line: More than half of validated variants were categorized in Gene Ontology (GO) terms of binding and/or catalytic activity.Moreover, we found differential genome variants in gCJD patients with V180I mutation, including one uniquely surviving 10 years after diagnosis of the disease.Elucidation of the relationships between gCJD and Alzheimer's disease or Parkinson's disease at the genomic level will facilitate further advances in our understanding of the specific mechanisms mediating the pathogenesis of NDs and gold standard therapies for NDs.

View Article: PubMed Central - PubMed

Affiliation: Division of Zoonoses, Center for Immunology & Pathology, National Institute of Health, Korea Centers for Disease Control & Prevention, Cheongju-si, Chungcheongbuk-do, South Korea.

ABSTRACT
Inherited prion diseases (IPDs), including genetic Creutzfeldt-Jakob disease (gCJD), account for 10-15% of cases of prion diseases and are associated with several pathogenic mutations, including P102L, V180I, and E200K, in the prion protein gene (PRNP). The valine to isoleucine substitution at codon 180 (V180I) of PRNP is the most common pathogenic mutation causing gCJD in East Asian patients. In this study, we conducted follow-up analyses to identify candidate factors and their associations with disease onset. Whole-genome sequencing (WGS) data of five gCJD patients with V180I mutation and 145 healthy individuals were used to identify genomic differences. A total of 18,648,850 candidate variants were observed in only the patient group, 29 of them were validated as variants. Four of these validated variants were nonsense mutations, six were observed in genes directly or indirectly related to neurodegenerative disorders (NDs), such as LPA, LRRK2, and FGF20. More than half of validated variants were categorized in Gene Ontology (GO) terms of binding and/or catalytic activity. Moreover, we found differential genome variants in gCJD patients with V180I mutation, including one uniquely surviving 10 years after diagnosis of the disease. Elucidation of the relationships between gCJD and Alzheimer's disease or Parkinson's disease at the genomic level will facilitate further advances in our understanding of the specific mechanisms mediating the pathogenesis of NDs and gold standard therapies for NDs.

No MeSH data available.


Related in: MedlinePlus