The Journal of Experimental Medicine
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Published online February 20, 2007
doi:10.1084/jem.20061252
The Journal of Experimental Medicine, Vol. 204, No. 3, 511-524
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Min-Oo et al.
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ARTICLE

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

Gundula Min-Oo1, Anny Fortin3, Giuseppina Pitari4, Mifong Tam2, Mary M. Stevenson2, and Philippe Gros1,2

1 Department of Biochemistry and 2 Centre for the Study of Host Resistance, The Research Institute of McGill University Health Centre, McGill University, Montreal H3G-1Y6, Quebec, Canada
3 Emerillon Therapeutics, Inc., Montreal H3A-1L2, Quebec, Canada
4 Dipartimento di Biologia di Base e Applicata, Universita L'Aquila, Coppito 67010, Italy

CORRESPONDENCE Philippe Gros: philippe.gros{at}mcgill.ca

Mouse strains AcB55 and AcB61 are resistant to malaria by virtue of a mutation in erythrocyte pyruvate kinase (PklrI90N). 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.

Abbreviations used: B6, C57BL/6; dNTP, dinucleotide triphosphate; GSH, glutathione; LOD, logarithm of odds; mRNA, messenger RNA; PK, pyruvate kinase; pRBC, parasitized RBC; QTL, quantitative trait locus; RCS, recombinant congenic strain; SNP, single-nucleotide polymorphic.


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