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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

Results of RT-QuIC analysis.ThT fluorescence was measured by relative fluorescence units (rfu) with saturation occurring at 65,000 for every 42 min. The RT-QuIC responses were performed using 10−3 dilution of sCJD patient with 129MM type brain homogenate (NHBX0/0001), 10−5 CJD negative control brain homogenate (NHBZ0/0005), 15ul of 10−1 dilution of CSF from 4 gCJD cases with V180I (the Patients nos. 1, 2, 3 and 5) and 1 sCJD case with 129MM. Each point represents the mean of 4 replicate rfu readings.
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pone.0157540.g001: Results of RT-QuIC analysis.ThT fluorescence was measured by relative fluorescence units (rfu) with saturation occurring at 65,000 for every 42 min. The RT-QuIC responses were performed using 10−3 dilution of sCJD patient with 129MM type brain homogenate (NHBX0/0001), 10−5 CJD negative control brain homogenate (NHBZ0/0005), 15ul of 10−1 dilution of CSF from 4 gCJD cases with V180I (the Patients nos. 1, 2, 3 and 5) and 1 sCJD case with 129MM. Each point represents the mean of 4 replicate rfu readings.

Mentions: Because the CSF of patient no. 4 was not stored, the RT-QuIC assay with substrate replacement was performed using CSF samples from only four patients, and the sensitivities were 75% (Fig 1).


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)

Results of RT-QuIC analysis.ThT fluorescence was measured by relative fluorescence units (rfu) with saturation occurring at 65,000 for every 42 min. The RT-QuIC responses were performed using 10−3 dilution of sCJD patient with 129MM type brain homogenate (NHBX0/0001), 10−5 CJD negative control brain homogenate (NHBZ0/0005), 15ul of 10−1 dilution of CSF from 4 gCJD cases with V180I (the Patients nos. 1, 2, 3 and 5) and 1 sCJD case with 129MM. Each point represents the mean of 4 replicate rfu readings.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0157540.g001: Results of RT-QuIC analysis.ThT fluorescence was measured by relative fluorescence units (rfu) with saturation occurring at 65,000 for every 42 min. The RT-QuIC responses were performed using 10−3 dilution of sCJD patient with 129MM type brain homogenate (NHBX0/0001), 10−5 CJD negative control brain homogenate (NHBZ0/0005), 15ul of 10−1 dilution of CSF from 4 gCJD cases with V180I (the Patients nos. 1, 2, 3 and 5) and 1 sCJD case with 129MM. Each point represents the mean of 4 replicate rfu readings.
Mentions: Because the CSF of patient no. 4 was not stored, the RT-QuIC assay with substrate replacement was performed using CSF samples from only four patients, and the sensitivities were 75% (Fig 1).

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