International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


A TRUNCATED FORM OF L1 2'-5'-OLIGO- ADENYLATE SYNTHETASE IS ASSOCIATED WITH GENETIC SUSCEPTIBILITY TO FLAVIVIRUS INFECTIONS

Tomoji Mashimo
Unité de Génétique des Mammifères
Département d'Immunologie
Institut Pasteur
25, rue du Docteur Roux
75724 Paris, France

Co-Author: 1)Simon-Chazottes D, 2)Lucas M, 2)Frenkiel MP, 1)Montagutelli X, 3)Deubel V, 2)Desprès P, 1)Guénet JL Institution: 1)Unité de Génétique des Mammifères, Institut Pasteur, Paris, 2)Unité des Arbovirus et Virus des Fièvres Hémorragiques, Institut Pasteur, 3)Unité de Biologie des Infections Virales Emergentes, Centre de Recherche Mérieux-Pasteur

The susceptibility of mice to the encephalitogenic effects of flaviviruses is controlled by a major locus (Flv - Chr 5) with at least two alleles. Most inbred strains are homozygous for the recessive allele Flvs and develop fatal encephalitis 7 to 11 days after infection. Most strains derived from recently trapped wild mice are resistant (Flvr). With the aim of identifying the responsible gene by positional cloning, we refined the mapping of the Flv locus within 0.46-cM interval on Chr 5. Combining the data from mouse T31 Radiation Hybrid map within the same interval and merging information from the homologous region of human chromosome 12q, we established a high resolution composite/consensus map of the region. Among several candidate genes in this region, the Oas cluster, encoding the multimember family of a/b interferon induced 2'-5' oligoadenylate synthetase enzymes, appeared the most likely. Comparing the cDNA sequences of the 3 isoforms (L1, L2 and L3) of the 2'-5'OAS genes, we identified a STOP codon in exon 4 of Oas1 gene in all susceptible strains (8 strains), which is not present in resistant strains (6 strains derived from unrelated wild specimens of the genus Mus). The perfect concordance between the occurrence of a STOP codon with the Flv phenotype of resistance/susceptibility suggests that the truncated form of Oas1 is the cause of the innate susceptibility to flavivirus infection.


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