Complex genetic control of susceptibility to malaria: positional cloning of the Char9 locus.
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.
Min-Oo
Gundula
G
Department of Biochemistry, The Research Institute of McGill University Health Centre, McGill University, Montreal H3G-1Y6, Quebec, Canada.
Fortin
Anny
A
Pitari
Giuseppina
G
Tam
Mifong
M
Stevenson
Mary M
MM
Gros
Philippe
P
D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D058851:GPI-Linked Proteins; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006867:Hydrolases / Q000235:genetics*; D008288:Malaria / Q000201:enzymology* / Q000235:genetics*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D016788:Plasmodium chabaudi / Q000276:immunology; D040641:Quantitative Trait Loci
D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D005819:Genetic Markers; D006867:Hydrolases; D000581:Amidohydrolases; C022314:pantetheinase; C511525:Vnn3 protein, mouse