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Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity

2009; Springer Nature; Volume: 54; Issue: 1 Linguagem: Inglês

10.1038/jhg.2008.1

1435-232X

Moto Kajiwara, Tomohiro Terada, K. OGASAWARA, Junko Iwano, Toshiya Katsura, Atsushi Fukatsu, Toshio Doi, Ken‐ichi Inui,

Pharmacological Effects and Toxicity Studies

H+/organic cation antiporters (multidrug and toxin extrusion: MATE1 and MATE2-K) play important roles in the renal tubular secretion of cationic drugs. We have recently identified a regulatory single nucleotide polymorphism (SNP) of the MATE1 gene (−32G>A). There is no other information about SNPs of the MATE gene. In this study, we evaluated the functional significance of genetic polymorphisms in MATE1 and MATE2-K. We sequenced all exons of MATE1 and MATE2-K genes in 89 Japanese subjects and identified coding SNPs (cSNPs) encoding MATE1 (V10L, G64D, A310V, D328A and N474S) and MATE2-K (K64N and G211V). All the variants except for MATE1 V10L showed significant decrease in transport activity. In particular, MATE1 G64D and MATE2-K G211V variants completely lost transport activities. When membrane expression level was evaluated by cell surface biotinylation, those of MATE1 (G64D and D328A) and MATE2-K (K64N and G211V) were significantly decreased compared with that of wild type. These findings suggested that the loss of transport activities of the MATE1 G64D and MATE2-K G211V variants were due to the alteration of protein expression in cell surface membranes. This is the first demonstration of functional impairment of the MATE family induced by cSNPs.