ANALYSIS OF THE INTRON-EXON ORGANIZATION OF THE HUMAN MULTIDRUG-RESISTANCE PROTEIN GENE (MRP) AND ALTERNATIVE SPLICING OF ITS MESSENGER-RNA

Overexpression of multidrug-resistance protein (MRP) and P-glycoprotei n confers similar but not identical multidrug-resistance phenotypes. H owever, unlike P-glycoprotein, which comprises two membrane-spanning d omains (MSDs) and two nucleotide-binding domains, MRP contains a third NH2-proximal MSD, a feature now identified in several other ATP-bindi ng cassette transmembrane transporters. MRP is located on chromosome 1 6 at band 13.1 close to the short-arm breakpoint of the pericentric in version associated with the M4Eo subclass of acute myeloid leukemia. W e have defined the intron-exon structure of MRP and characterized a nu mber of splicing variants of MRP mRNA. The gene spans at least 200 kb, It contains 31 exons and a high proportion of class 0 introns, altern ative splicing of which results in significant levels of variant trans cripts that maintain the original open reading frame of MRP mRNA. Anal yses of the conservation of intron-exon organization and protein prima ry structure suggest that the MRP-related transporters evolved from a common ancestor shared with the cystic fibrosis transmembrane conducta nce regulator, by fusion with one or more genes encoding polytopic mem brane proteins. (C) 1997 Academic Press.