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

• Published in: PloS one Vol. 11; no. 6; p. e0157540
• Main Authors: Lee, Sol Moe, Chung, Myungguen, Hyeon, Jae Wook, Jeong, Seok Won, Ju, Young Ran, Kim, Heebal, Lee, Jeongmin, Kim, SangYun, An, Seong Soo A, Cho, Sung Beom, Lee, Yeong Seon, Kim, Su Yeon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.06.2016; Public Library of Science (PLoS)
• Subjects: Aged; Agricultural biotechnology; Alzheimer's disease; Alzheimers disease; Amino Acid Substitution; Analysis; Biology and Life Sciences; Catalysis; Catalytic activity; Codon; Complications and side effects; Computational Biology; Creutzfeldt-Jakob disease; Creutzfeldt-Jakob Syndrome - diagnosis; Creutzfeldt-Jakob Syndrome - genetics; Creutzfeldt-Jakob Syndrome - metabolism; Development and progression; Disease control; Disease prevention; Disease Progression; Disorders; Epistasis, Genetic; Female; Fibroblast growth factor 20; Gene mutation; Gene Ontology; Gene Regulatory Networks; Gene sequencing; Genes; Genetic aspects; Genomes; Genomics - methods; Health informatics; High-Throughput Nucleotide Sequencing; Humans; Immunology; Isoleucine; LRRK2 protein; Male; Medicine and Health Sciences; Middle Aged; Mutation; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Parkinson's disease; Parkinsons disease; Pathogenesis; Pathology; Patients; Phenotype; Physiological aspects; Prion protein; Prion Proteins - genetics; Proteins; Research and Analysis Methods; Risk factors; tau Proteins - metabolism; Valine; Zoonoses; South Korea
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0157540

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.