The hyperbilirubinemia of four Japanese patients with DJS, one of whom had a novel mutation, 1177C>T, of the MRP2 gene, had not worsened with aging.

Dubin-Johnson syndrome is a recessive inherited disorder with conjugated hyperbilirubinemia caused by a dysfunction of multidrug resistance protein 2 (MRP2) on the canalicular membrane of hepatocytes. A mutational analysis of the MRP2 gene was carried out in three Japanese patients and their family members. In two patients, the homozygous mutations c.1901del67 and c,2272del168 were found. In the third patient, a )24C fi T polymorphism and the two mutations c.1901del67 and 2026G fi C were detected. The 2026G fi C mutation was a novel mutation in exon 16 affecting the conversion of Gly 676 to Arg 676 (G676R) in the MRP2 protein, and was not detected in fifty healthy volunteers. The G676R mutation was located in the Walker A motif of the first nucleotide binding domain in the MRP2 protein, and it was suggested that the mutation induced the dysfunction of the MRP2 protein. It was concluded that the compound heterozygosity of the two mutations of the MRP2 gene in the third patient contributed to the induction of hyperbilirubinemia in this case.Keywords Dubin-Johnson syndrome AE Multidrug resistance 2 (MRP2) AE ATP-binding cassette AE Walker A motif AE Mutation Introduction Dubin-Johnson syndrome (DJS) is an inherited metabolic disorder characterized by conjugated hyperbilirubinemia and a re-increase of serum bromosulfophtalein (BSP) in the BSP tolerance test, characteristics that are caused by a dysfunction of the canalicular multispecific anion transporter (cMOAT, multidrug resistance protein 2; MRP2).The human MRP2 gene was identified in cisplatinresistant tumor cells by Taniguchi et al. (1996) following the identification of the rat cmoat (mrp2) gene in hyperbilirubinemia rats (TR ) rats) by Paulusma et al. (1996). The human MRP2 gene was mapped to chromosome 10 at q24 (Taniguchi et al. 1996) and was found to consist of 32 exons (Toh et al. 1999).MRP2 protein is a membrane protein with 1545 amino acids; it contains two ATP-binding cassettes (ABCs) and 17 transmembrane sequences (Taniguchi et al. 1996). It is expressed at the canalicular membrane of hepatocytes and apical membrane of the renal uriniferous tuble (Paulusma et al.1996) and is involved in the excretion of glucronide-conjugated bilirubin and glutathione-conjugates from the liver (Taniguchi et al. 1996;Wada et al. 1998).The first mutation of the MRP2 gene causing hyperbilirubinemia was found by Paulusma et al. (1997) in DJS, and a total of 10 mutations have been found as listed in Table 1.In the present study, we conducted a mutational analysis in three Japanese DJS patients and found two known deletion mutations (c.1901del67, c.2272del168) and a novel missense mutation of G676R in the first nucleotide-binding domain (NBD1) in the MRP2 protein. Subjects and methods Study participantsThree DJS patients and their family members were included in the present study.

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Direct-type hyperbilirubinemia in Dubin-Johnson syndrome is due to the genetic dysfunction of multidrug resistance protein 2. However, serum bilirubin levels may fluctuate as a result of acquired conditions. Iron-reduction therapy by venesection, an alternative to interferon, was performed in a 55-year-old male patient with Dubin-Johnson syndrome complicated by hepatitis C virus-positive chronic liver disease and hepatic iron overload. His pretreatment serum total bilirubin was 10.2 mg/dl, with a dominant direct fraction. The treatment induced a significant reduction in serum total bilirubin, although it remained as high as 7.9 mg/dl. A negative correlation between serum total bilirubin and cumulative bled volume suggested that venesection could suppress bilirubin production from aged erythrocytes. The hepatic iron overload was distributed in hepatocyte lysosomes with Dubin-Johnson granules; thus, it seems that iron removal from the lysosomal granules may also help to reduce serum bilirubin. In conclusion, deep jaundice in a patient with Dubin-Johnson syndrome complicated by hepatitis C virus-positive chronic liver disease and iron overload was partially improved by iron-reduction therapy.