Single Nucleotide Polymorphisms in Genes for 2′-5′-Oligoadenylate Synthetase and RNase L in Patients Hospitalized with West Nile Virus Infection

• Published in: The Journal of infectious diseases Vol. 192; no. 10; pp. 1741 - 1748
• Main Authors: Yakub, Imtiaz, Lillibridge, Kristy M., Moran, Ana, Gonzalez, Omar Y., Belmont, John, Gibbs, Richard A., Tweardy, David J.
• Format: Journal Article
• Language: English
• Published: Chicago, IL The University of Chicago Press 15.11.2005; University of Chicago Press; Oxford University Press
• Subjects: Biological and medical sciences; Disease susceptibility; Epidemiology; Exons; Flavivirus; Fundamental and applied biological sciences. Psychology; Genes; Genetic mutation; Haplotypes; Infections; Infectious diseases; Medical sciences; Mice; Microbiology; Miscellaneous; Nonsense mutation; Virology; Viruses; West Nile virus; Human; Microbiology; Enzyme; Esterases; Flavivirus; Virus; Infection; Gene; Ligases; West Nile virus; Hydrolases; Japanese encephalitis group virus; Single nucleotide polymorphism; Flaviviridae; Pancreatic ribonuclease
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/497340

BackgroundInfection with the flavivirus West Nile virus (WNV) is a growing problem across the United States, where there is a case-fatality rate of 15%–29% in individuals >70 years old and no consistently effective treatment. Susceptibility to WNV disease in inbred strains of mice was mapped to a nonsense mutation in the gene encoding the 1b isoform of 2′-5′-oligoadenylate synthetase (OAS), a member of the OAS/RNase L system of innate viral resistance. Genetic susceptibility to severe WNV disease in humans has not been determined MethodsWe sequenced each exon within all OAS and RNASEL genes in 33 individuals hospitalized with WNV infection in Houston to assess if there is a defect in this system in patients with severe WNV disease ResultsSequencing did not reveal any insertions, deletions, or nonsense mutations in any OAS or RNASEL gene. However, comparison of the exonic sequences between case patients and control subjects identified 23 single nucleotide polymorphisms (SNPs), including a synonymous SNP in OASL exon 2 (rs3213545), in which the reference allele occurred at a higher frequency in case patients (P<.004) ConclusionBecause the reference allele contains a splice enhancer site, our finding suggests that the RNA transcripts generated from this allele may undergo increased splicing, which results in a dominant-negative OASL isozyme similar to the nonsense/truncation mutant form of Oas1b in mice