| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p15.5 | {Influenza, severe, susceptibility to} | 614680 | 3 | IFITM3 | 605579 |
A number sign (#) is used with this entry because variation in the IFITM3 gene (605579) confers susceptibility to severe influenza virus infection.
Everitt et al. (2012) found enrichment of a SNP in the IFITM3 gene, the C allele of SNP rs12252 (605579.0001), in 53 individuals who required hospitalization as a result of pandemic H1N1/09 or seasonal influenza virus infection in 2009-2010. Presence of the C allele results in a synonymous change but alters the first splice acceptor site and may be associated with an IFITM3 splice variant that encodes an IFITM3 protein lacking the first 21 amino acids due to the use of an alternative start codon. The genotypes associated with rs12252 in Caucasians hospitalized following influenza infection differed significantly from ethnically matched Europeans in 1000 Genomes sequence data and from genotypes imputed against the June 2011 release of the 1000 Genomes phased haplotypes from the U.K., Netherlands, and Germany. Patients' genotypes also departed from Hardy-Weinberg equilibrium (P = 0.003), showing an excess of C alleles in this population. When lymphoblastoid cell lines from CC homozygotes were challenged with influenza A virus, they were far more susceptible to infection than those of TT homozygotes, and this vulnerability correlated with lower levels of IFITM3 protein expression compared to the majority of TT variant cells. Everitt et al. (2012) also found that cells expressing the 21-amino acid deletion protein failed to restrict viral replication when compared to wildtype IFITM3, consistent with data showing that the amino-terminal 21 amino acids of IFITM3 are required for attenuation of vesicular stomatitis virus replication in vitro (Weidner et al., 2010).
Everitt et al. (2012) found that the allele frequencies for rs12252 vary in different human populations. The ancestral C allele, reported in chimpanzees, is rare in sub-Saharan African and European populations, but is more frequent in other populations.
Everitt, A. R., Clare, S., Pertel, T., John, S. P., Wash, R. S., Smith, S. E., Chin, C. R., Feeley, E. M., Sims, J. S., Adams, D. J., Wise, H. M., Kane, L., and 19 others. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484: 519-523, 2012. [PubMed: 22446628] [Full Text: https://doi.org/10.1038/nature10921]
Weidner, J. M., Jiang, D., Pan, X.-B., Chang, J., Block, T. M., Guo, J.-T. Interferon-induced cell membrane proteins, IFITM3 and tetherin, inhibit vesicular stomatitis virus infection via distinct mechanisms. J. Virol. 84: 12646-12657, 2010. [PubMed: 20943977] [Full Text: https://doi.org/10.1128/JVI.01328-10]