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Complex genetic control of susceptibility to malaria: positional cloning of the Char9 locus.

Abstract
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.
AuthorsGundula Min-Oo, Anny Fortin, Giuseppina Pitari, Mifong Tam, Mary M Stevenson, Philippe Gros
JournalThe Journal of experimental medicine (J Exp Med) Vol. 204 Issue 3 Pg. 511-24 (Mar 19 2007) ISSN: 0022-1007 [Print] United States
PMID17312006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cell Adhesion Molecules
  • GPI-Linked Proteins
  • Genetic Markers
  • Hydrolases
  • Amidohydrolases
  • pantetheinase
  • Vnn3 protein, mouse
Topics
  • Amidohydrolases (deficiency, genetics, physiology)
  • Animals
  • Cell Adhesion Molecules (genetics)
  • Chromosome Mapping
  • Cloning, Molecular
  • GPI-Linked Proteins
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Hydrolases (genetics)
  • Malaria (enzymology, genetics)
  • Mice
  • Mice, Inbred A
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Plasmodium chabaudi (immunology)
  • Quantitative Trait Loci

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