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PLoS Negl Trop Dis. 2015 Feb 13;9(2):e0003476. doi: 10.1371/journal.pntd.0003476. eCollection 2015 Feb.

Intrachromosomal amplification, locus deletion and point mutation in the aquaglyceroporin AQP1 gene in antimony resistant Leishmania (Viannia) guyanensis.

Author information

1
Centre de Recherche en Infectiologie du Centre de Recherche du CHU Québec and Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, Québec, Canada.
2
Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brasil.

Abstract

BACKGROUND:

Antimony resistance complicates the treatment of infections caused by the parasite Leishmania.

METHODOLOGY/PRINCIPAL FINDINGS:

Using next generation sequencing, we sequenced the genome of four independent Leishmania guyanensis antimony-resistant (SbR) mutants and found different chromosomal alterations including aneuploidy, intrachromosomal gene amplification and gene deletion. A segment covering 30 genes on chromosome 19 was amplified intrachromosomally in three of the four mutants. The gene coding for the multidrug resistance associated protein A involved in antimony resistance was also amplified in the four mutants, most likely through chromosomal translocation. All mutants also displayed a reduced accumulation of antimony mainly due to genomic alterations at the level of the subtelomeric region of chromosome 31 harboring the gene coding for the aquaglyceroporin 1 (LgAQP1). Resistance involved the loss of LgAQP1 through subtelomeric deletions in three mutants. Interestingly, the fourth mutant harbored a single G133D point mutation in LgAQP1 whose role in resistance was functionality confirmed through drug sensitivity and antimony accumulation assays. In contrast to the Leishmania subspecies that resort to extrachromosomal amplification, the Viannia strains studied here used intrachromosomal amplification and locus deletion.

CONCLUSIONS/SIGNIFICANCE:

This is the first report of a naturally occurred point mutation in AQP1 in antimony resistant parasites.

PMID:
25679388
PMCID:
PMC4332685
DOI:
10.1371/journal.pntd.0003476
[Indexed for MEDLINE]
Free PMC Article

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