Heterozygosity and functional allelic variation in the Candida albicans efflux pump genes CDR1 and CDR2.

Abstract:

:Elevated expression of the plasma membrane drug efflux pump proteins Cdr1p and Cdr2p was shown to accompany decreased azole susceptibility in Candida albicans clinical isolates. DNA sequence analysis revealed extensive allelic heterozygosity, particularly of CDR2. Cdr2p alleles showed different abilities to transport azoles when individually expressed in Saccharomyces cerevisiae. Loss of heterozygosity, however, did not accompany decreased azole sensitivity in isogenic clinical isolates. Two adjacent non-synonymous single nucleotide polymorphisms (NS-SNPs), G1473A and I1474V in the putative transmembrane (TM) helix 12 of CDR2, were found to be present in six strains including two isogenic pairs. Site-directed mutagenesis showed that the TM-12 NS-SNPs, and principally the G1473A NS-SNP, contributed to functional differences between the proteins encoded by the two Cdr2p alleles in a single strain. Allele-specific PCR revealed that both alleles were equally frequent among 69 clinical isolates and that the majority of isolates (81%) were heterozygous at the G1473A/I1474V locus, a significant (P < 0.001) deviation from the Hardy-Weinberg equilibrium. Phylogenetic analysis by maximum likelihood (Paml) identified 33 codons in CDR2 in which amino acid allelic changes showed a high probability of being selectively advantageous. In contrast, all codons in CDR1 were under purifying selection. Collectively, these results indicate that possession of two functionally different CDR2 alleles in individual strains may confer a selective advantage, but that this is not necessarily due to azole resistance.

journal_name

Mol Microbiol

journal_title

Molecular microbiology

authors

Holmes AR,Tsao S,Ong SW,Lamping E,Niimi K,Monk BC,Niimi M,Kaneko A,Holland BR,Schmid J,Cannon RD

doi

10.1111/j.1365-2958.2006.05357.x

subject

Has Abstract

pub_date

2006-10-01 00:00:00

pages

170-86

issue

1

eissn

0950-382X

issn

1365-2958

pii

MMI5357

journal_volume

62

pub_type

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