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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

Direct interaction network of genes harboring validated variants with NDs.The red diamonds or circles indicate seed nodes (genes harboring validated variants). Each edge (biological interaction between seeds) status is explained in the legend located in the upper right panel. Terms related to AD and PD are described in purple squares. Because direct interactions of genes harboring validated variants with PrDs were not observed, the term PrDs was excluded.
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pone.0157540.g003: Direct interaction network of genes harboring validated variants with NDs.The red diamonds or circles indicate seed nodes (genes harboring validated variants). Each edge (biological interaction between seeds) status is explained in the legend located in the upper right panel. Terms related to AD and PD are described in purple squares. Because direct interactions of genes harboring validated variants with PrDs were not observed, the term PrDs was excluded.

Mentions: Interestingly, LPA, LRRK2, TET1, and FGF20 were linked directly to AD and/or PD but not to PrDs. However, genes such as ACO1, POSTN, LRRK2, FGF20, and LPA had indirect associations with PrDs (Figs 3 and 4, S1A–S1E Fig).


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)

Direct interaction network of genes harboring validated variants with NDs.The red diamonds or circles indicate seed nodes (genes harboring validated variants). Each edge (biological interaction between seeds) status is explained in the legend located in the upper right panel. Terms related to AD and PD are described in purple squares. Because direct interactions of genes harboring validated variants with PrDs were not observed, the term PrDs was excluded.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0157540.g003: Direct interaction network of genes harboring validated variants with NDs.The red diamonds or circles indicate seed nodes (genes harboring validated variants). Each edge (biological interaction between seeds) status is explained in the legend located in the upper right panel. Terms related to AD and PD are described in purple squares. Because direct interactions of genes harboring validated variants with PrDs were not observed, the term PrDs was excluded.
Mentions: Interestingly, LPA, LRRK2, TET1, and FGF20 were linked directly to AD and/or PD but not to PrDs. However, genes such as ACO1, POSTN, LRRK2, FGF20, and LPA had indirect associations with PrDs (Figs 3 and 4, S1A–S1E Fig).

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