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. 2009 Jul 9;38(2):116-24.
doi: 10.1152/physiolgenomics.90309.2008. Epub 2009 May 5.

Analysis of a large cluster of SLC22 transporter genes, including novel USTs, reveals species-specific amplification of subsets of family members

Wei Wu  1 , Michael E Baker, Satish A Eraly, Kevin T Bush, Sanjay K Nigam
Affiliations

Analysis of a large cluster of SLC22 transporter genes, including novel USTs, reveals species-specific amplification of subsets of family members

Wei Wu et al. Physiol Genomics. .

Abstract

When the organic anion transporter Oat1 was first identified as NKT (Lopez-Nieto CE, You G, Bush KT, Barros EJ, Beier DR, Nigam SK. J Biol Chem 272: 6471-6478, 1997), it was argued that it, together with Oct1, may be part of a larger subfamily (now known as SLC22) involved in organic ion and xenobiotic transport. The least studied among SLC22 transporters are the so-called unknown substrate transporters (USTs). Here, five novel genes located in a cluster on mouse chromosome 19, immediately between Slc22a8 (Oat3)/Slc22a6 (Oat1) and Slc22a19 (Oat5), were identified as homologs of human USTs. These genes display preferential expression in liver and kidney, and one gene, AB056422, has several splicing variants with differential tissue expression and embryonic expression. Along with Slc22a6, Slc22a8, and Slc22a19, these Usts define the largest known cluster of mammalian Slc22 genes. Given the established functions of Oats, these genes may also be involved in organic anion transport. Usts have characteristic motifs and share a signature residue in the possible active site of transmembrane domain 7, a conserved, positively charged, amino acid, Arg356, possibly a site for interaction with organic anions. In certain species, Oat1 and Oat3 appeared to be highly conserved, whereas the Ust part of this cluster appeared to undergo repeated species-specific amplification, suggesting strong environmental selection pressure, and perhaps providing an explanation for copy number variation in the human locus. One Ust amplification in mouse appears to be recent. This cluster may be coordinately regulated and under selective pressure in a species-specific manner.

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Figures

Fig. 1.
Fig. 1.
Identification of a cluster of novel mouse genes of the Slc22 family related to human UST genes. Diagrams depicting the organization of the UST cluster on human chromosome 11 (top) and the corresponding region on mouse chromosome 19 (bottom). MGC34821 belongs to the UST subfamily of the SLC22 family based on sequence similarity analysis and encodes a gene product of 322 amino acids (a.a.) that is missing a significant portion of the COOH terminus of a full-length transporter.
Fig. 2.
Fig. 2.
Phylogram derived from sequence alignment of human and mouse Slc22 family genes, including the novel Ust genes. Upper case, human genes; lower case, mouse genes.
Fig. 3.
Fig. 3.
Expression profiling of a cluster of 5 novel mouse Slc22 family genes. The relative expression of 5 mouse Slc22 family genes was determined in 8 adult tissues and at multiple stages of embryonic development (E, embryonic day). The expression pattern of the well-characterized mouse gene Slc22a8 was determined as a control.
Fig. 4.
Fig. 4.
A: diagram depicting the genomic organization of four splice variants of the novel Slc22 family member, AB056442. The 4 splice variants were cloned and sequenced, and the genomic structure of each variant was determined. B: expression analysis of AB056442 by RT-PCR. PCR primers designed encompassing the spliced sites revealed multiple bands corresponding to the splice variants of the gene. The 1 kb band represents the full-length transcript (see A), while the 0.8 kb band represents the 1.8 kb transcript and the 0.4 kb band represents the 1.3 kb transcript. The 1.8 kb fragment is the most abundantly expressed transcript variant. e7–e17, Age in embryonic days.
Fig. 5.
Fig. 5.
Alignment of a.a. sequences of human and mouse Ust family genes. Residues conserved in all 9 human and mouse Usts are marked with an asterisk underneath the sequence alignment. Arg356 (AB056422) is Ust specific and is not found in any of the other Slc22 family genes in mouse or human.
Fig. 6.
Fig. 6.
Predicted transmembrane topology of AB056422. The charged a.a. residues and glycoslylation sites that are conserved in all 9 human and mouse Ust genes are highlighted.
Fig. 7.
Fig. 7.
Diagram depicting the hypothetical phylogeny of human and mouse Usts. Tandem duplication of an Oat ancestral gene resulted in Slc22a6 and Slc22a8, and these Oats survived both in mouse and in human. The Ust ancestral gene experienced multiple rounds of duplication and generated several Ust-like genes by the time of divergence of the human and mouse lineages. Some of these Usts survived in human and others survived in mouse, but no orthologous Usts survived in both human and mouse. After the divergence of the human and mouse lineages, some of the Usts in the mouse lineage underwent further duplication to generate additional mouse-specific Ust genes.
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