Single nucleotide polymorphisms in genes for 2'-5'-oligoadenylate synthetase and RNase L inpatients hospitalized with West Nile virus infection.
BACKGROUND
Infection 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.


METHODS
We 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.


RESULTS
Sequencing 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).


CONCLUSIONS
Because 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.
Yakub
Imtiaz
I
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Lillibridge
Kristy M
KM
Moran
Ana
A
Gonzalez
Omar Y
OY
Belmont
John
J
Gibbs
Richard A
RA
Tweardy
David J
DJ
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics*; D000328:Adult; D000368:Aged; D004722:Endoribonucleases / Q000235:genetics*; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014901:West Nile Fever / Q000235:genetics* / Q000821:virology; D014902:West Nile virus / Q000472:pathogenicity
D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease