Alternative splicing of the RAGE gene: analysis and characterization in humans and mice

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The alternative splicing of pre-mRNAs is a critical mechanism in genomic complexity, disease, and development. Studies on the Receptor for Advanced Glycation End-products (RAGE) indicate this gene undergoes a variety of splice events; however, no studies have analyzed the tissue distribution or compared evolutionary differences between species of RAGE isoforms. We recently reported on the analysis of RAGE splicing in lung by a novel method we termed the Rapid Identification, Characterization and Expression of Splice forms (RICE-SPLICE). We applied this method to cDNA from multiple human and mouse tissue extracts for RAGE including lung, heart, brain, kidney, pancreas and placenta and compared the splice forms found between these two species. In humans, numerous splice variants were identified ranging from deletion of multiple exons (entire or in part) and intronic inclusions. These variants were predicted to change the structure and function of RAGE since they resulted in alterations in the ligand-binding domain, extensive removal of the extracellular region, production of novel proteins, and the production of soluble forms lacking the transmembrane region. In contrast, in mice, fewer splice variants were identified, mainly resulting in forms lacking the transmembrane region. Comparison of splice variants between humans and mice revealed homologous regions in the RAGE gene which undergo splicing and similar splice forms. Further analysis of these forms revealed the biological significance of the conserved splice variants. In conclusion, we have identified differences in the tissue and cross-species distribution of RAGE splice forms which further expands the biological repertoire of this receptor in health and disease.