A splice mutation in the human canalicular multispecific organic anion transporter gene causes Dubin-Johnson syndrome

The human Dubin Johnson syndrome (DJS) is a rare autosomal recessive disorder characterized by chronic conjugated hyperbilirubinemia and impaired hepatobiliary transport of non-bile salt organic anions. A highly homologous phenotype exists in the transport deficient (TR-) Wistar rat, which has a defective canalicular multispecific organic anion transporter (cMOAT). This protein mediates adenosine triphosphate-dependent transport of a broad range of endogenous and xenobiotic compounds across the (apical) canalicular membrane of the hepatocyte. The cDNA encoding rat cMOAT has recently been cloned, and this mutation in the TR- rat has been identified. Subsequently the human homologue of rat cMOAT localized in the liver was found to be the cause of DJS. In an individual with DJS, we have identified a single novel nucleotide substitution in the exon-intron junction of the cMOAT gene which generates liver cDNA with a 67bp exon deletion.