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Mapping of Char10, a novel malaria susceptibility locus on mouse chromosome 9

Genes & Immunity volume 11, pages 113–123 (2010)Cite this article

Abstract

Resistance to blood-stage malaria in AcB55 and AcB61 is caused by a loss of function mutation in pyruvate kinase (PklrI90N). Likewise, pyruvate kinase (PK) deficiency in humans is protective against Plasmodium replication in vitro. We identified a third AcB strain, AcB62 that also carries the PklrI90N mutation. However, AcB62 mice were susceptible to P.chabaudi infection and showed high levels of parasite replication (54–62% peak parasitemia). AcB62 mice showed the hallmarks of PK deficiency-associated anemia similar to AcB55/61 with reticulocytosis, splenic red pulp expansion, tissue iron overload, and increased expression of iron metabolism proteins. This suggests that malaria susceptibility in AcB62 is not because of absence of PK deficiency-associated pathophysiology. To map novel genetic factors affecting malaria susceptibility in AcB62, we generated an informative F2 population using AcB62 (PklrI90N) and CBA-Pkslc (PklrG338D) as progenitors and identified a novel locus on chromosome 9 (Char10; LOD=7.24) that controls peak parasitemia. A weaker linkage to the Pklr region of chromosome 3 (LOD=3.7) was also detected, a finding that may reflect the segregation of the two defective Pklr alleles. AcB62 alleles at both loci are associated with higher peak parasitemia. These results identify Char10 as a novel locus modulating severity of malaria in the context of PK deficiency.

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Acknowledgements

We acknowledge Patrick Fortin, Silayuv Bongfen, and Erin Lafferty for technical help with genotyping, Susan Gauthier for breeding and maintaining the mice, Joanne Berghout for assistance with phenotyping and Irena Radovanovic for help with histology. This work was supported by a CIHR Team Grant in Malaria (CTP 79842) and operating Grant FRN-79343 (PG, MMS).

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Authors and Affiliations

  1. Department of Biochemistry, McGill University, Montreal, Quebec, Canada

    G Min-Oo & P Gros

  2. Centre de Recherche de Gif-sur-Yvette, UPR2301, CNRS, Institut de Chimie des Substances Naturelles, Gif-Sur-Yvette, France

    A Willemetz & F Canonne-Hergaux

  3. Research Institute of the MGH, McGill University Health Centre, Montreal, Quebec, Canada

    M Tam & M M Stevenson

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  1. G Min-Oo
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  2. A Willemetz
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  3. M Tam
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  4. F Canonne-Hergaux
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Correspondence to P Gros.

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Min-Oo, G., Willemetz, A., Tam, M. et al. Mapping of Char10, a novel malaria susceptibility locus on mouse chromosome 9. Genes Immun 11, 113–123 (2010). https://doi.org/10.1038/gene.2009.78

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