ABCG transporters and disease

Abstract

ATP-binding cassette (ABC) transporters form a large family of transmembrane proteins that facilitate the transport of specific substrates across membranes in an ATP-dependent manner. Transported substrates include lipids, lipopolysaccharides, amino acids, peptides, proteins, inorganic ions, sugars and xenobiotics. Despite this broad array of substrates, the physiological substrate of many ABC transporters has remained elusive. ABC transporters are divided into seven subfamilies, A-G, based on sequence similarity and domain organization. Here we review the role of members of the ABCG subfamily in human disease and how the identification of disease genes helped to determine physiological substrates for specific ABC transporters. We focus on the recent discovery of mutations in ABCG2 causing hyperuricemia and gout, which has led to the identification of urate as a physiological substrate for ABCG2.

Fig. 1. Phylogenetic tree of all human ABC genes and specifically the ABCG subgroup of genes

(after [19, 66]). Disease phenotypes reported include only human diseases associated with specific ABCG mutations, not information from model organisms.

Fig. 2. Topographical representation of the ABCG2 monomer in the plasma membrane

Transmembrane domains experimentally determined by Wang and colleagues (2008) [67]; Nucleotide binding domain (NBD) begins at Y44 and ends at residue N288 [68]. The Walker A and B and ABC signature motif of the nucleotide binding domain are indentified, as are the 6 human polymorphisms associated with hyperuricemia and gout (in red) [21, 41]. Amino acid residues: pink = aromatic; green = + charged; light blue = − charged; blue = nonpolar; yellow = polar residues.

Fig. 3. ABCG2 is a urate transporter

(A) C-14 urate accumulation from Xenopus oocytes injected with mRNA coding for either ABCG2 or H₂O controls. (B) Urate efflux in oocytes incubated overnight in 500 μM C-14 urate as relative efflux over time (blue = control; red = ABCG2). (C) Urate accumulation in oocytes expressing either the wild type ABCG2 or the mutant Q141K ABCG2. (**p<0.01, ± S.E.M.)(A–C originally from [29]; © 2009 by the National Academy of Sciences of the USA). (D) Model of urate transport in the proximal tubule of the human kidney overlaying fluorescent micrograph of LLCPK-1 proximal tubule cell with endogenous ABCG2 labeled in green and the nucleus in blue. Proteins influencing urate absorption and secretion and with significance for human diseases are shown with the direction of urate transport indicated [21, 69, 70]. Other transporters expressed in the human kidney and shown to transport urate in model systems: ¹OAT4; ²OAT1, OAT3; ³MRP4; ⁴OAT1, OAT3 [71, 72].

Fig. 4

The cycle of translational research can begin with the description of a disease phenotype like the destruction of joints that occurs in patients with gout from urate crystal deposition. Genome-wide association studies allowed the identification of genes that associate with elevated serum urate levels and gout. Subsequent in-depth physiological characterization of the gene and its protein product lays the foundation for an improved understanding of physiology and pathophysiology and may reveal a therapeutic target. Finally, drug development can be attempted in order to better treat hyperuricemia or gout.