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Infection and Immunity, June 2002, p. 2763-2771, Vol. 70, No. 6
0019-9567/02/$04.00+0 DOI: 10.1128/IAI.70.6.2763-2771.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.
Mapping and Sequencing of the Canine NRAMP1 Gene and Identification of Mutations in Leishmaniasis-Susceptible Dogs
Laura Altet,1* Olga Francino,1 Laia Solano-Gallego,2 Corinne Renier,3 and Armand Sánchez1Departament de Ciència Animal i dels Aliments,1 Departament de Farmacologia, Terapèutica i Toxicologia, Facultat de Veterinària, Universitat Autònoma de Barcelona, Barcelona, Spain,2 UPR 41 CNRS, Recombinaisons Génétiques, Faculté de Médecine, 35043 Rennes Cédex, France3
Received 2 August 2001/ Returned for modification 15 November 2001/ Accepted 28 January 2002
The NRAMP1 gene (Slc11a1) encodes an ion transporter protein involved in the control of intraphagosomal replication of parasites and in macrophage activation. It has been described in mice as the determinant of natural resistance or susceptibility to infection with antigenically unrelated pathogens, including Leishmania. Our aims were to sequence and map the canine Slc11a1 gene and to identify mutations that may be associated with resistance or susceptibility to Leishmania infection. The canine Slc11a1 gene has been mapped to dog chromosome CFA37 and covers 9 kb, including a 700-bp promoter region, 15 exons, and a polymorphic microsatellite in intron 1. It encodes a 547-amino-acid protein that has over 87% identity with the Slc11a1 proteins of different mammalian species. A case-control study with 33 resistant and 84 susceptible dogs showed an association between allele 145 of the microsatellite and susceptible dogs. Sequence variant analysis was performed by direct sequencing of the cDNA and the promoter region of four unrelated beagles experimentally infected with Leishmania infantum to search for possible functional mutations. Two of the dogs were classified as susceptible and the other two were classified as resistant based on their immune responses. Two important mutations were found in susceptible dogs: a G-rich region in the promoter that was common to both animals and a complete deletion of exon 11, which encodes the consensus transport motif of the protein, in the unique susceptible dog that needed an additional and prolonged treatment to avoid continuous relapses. A study with a larger dog population would be required to prove the association of these sequence variants with disease susceptibility.
* Corresponding author. Mailing address: Departament de Ciència Animal i dels Aliments, Facultat de Veterinària, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain. Phone: (34) 93 5812087. Fax: (34) 93 5812106. E-mail: Laura.Altet{at}uab.es.
Infection and Immunity, June 2002, p. 2763-2771, Vol. 70, No. 6
0019-9567/02/$04.00+0 DOI: 10.1128/IAI.70.6.2763-2771.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.
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