| First Author | Min-Oo G | Year | 2007 |
| Journal | J Exp Med | Volume | 204 |
| Issue | 3 | Pages | 511-24 |
| PubMed ID | 17312006 | Mgi Jnum | J:122131 |
| Mgi Id | MGI:3713261 | Doi | 10.1084/jem.20061252 |
| Citation | Min-Oo G, et al. (2007) Complex genetic control of susceptibility to malaria: positional cloning of the Char9 locus. J Exp Med 204(3):511-24 |
| abstractText | Mouse strains AcB55 and AcB61 are resistant to malaria by virtue of a mutation in erythrocyte pyruvate kinase (Pklr(I90N)). Linkage analysis in [AcB55 x A/J] F2 mice detected a second locus (Char9; logarithm of odds = 4.74) that regulates the blood-stage replication of Plasmodium chabaudi AS independently of Pklr. We characterized the 77 genes of the Char9 locus for tissue-specific expression, strain-specific alterations in gene expression, and polymorphic variants that are possibly associated with differential susceptibility. We identified Vnn1/Vnn3 as the likely candidates responsible for Char9. Vnn3/Vnn1 map within a conserved haplotype block and show expression levels that are strictly cis-regulated by this haplotype. The absence of Vnn messenger RNA expression and lack of pantetheinase protein activity in tissues are associated with susceptibility to malaria and are linked to a complex rearrangement in the Vnn3 promoter region. The A/J strain also carries a unique nonsense mutation that leads to a truncated protein. Vanin genes code for a pantetheinase involved in the production of cysteamine, a key regulator of host responses to inflammatory stimuli. Administration of cystamine in vivo partially corrects susceptibility to malaria in A/J mice, as measured by reduced blood parasitemia and decreased mortality. These studies suggest that pantetheinase is critical for the host response to malaria. |
