Mutational analysis of the MRP2 gene and long-term follow-up of Dubin-Johnson syndrome in Japan

Background Recent studies have indicated that dysfunction or loss of the multidrug resistance protein 2 (MRP2) is the molecular basis of Dubin-Johnson syndrome (DJS). To clarify the genetic basis of the disease and the long-term stability of serum bilirubin levels, we conducted a mutational analysis of the MRP2 gene and followed up serum bilirubin levels in Japanese DJS patients 30 years after they were originally diagnosed, based on traditional criteria. Methods. Patients were interviewed by telephone, and blood tests, including a genetic analysis of MRP2, were performed on the patients and family members who gave informed consent. Results. Over the 30 years, hyperbilirubinemia remained unchanged in four of the five patients studied, while it worsened in 1 patient whose DJS was complicated by chronic hepatitis C. From an MRP2 gene mutational analysis, six mutations, including the novel mutation 11.77C > T, were found. Three patients of a consanguineous family were homozygotes for three mutations (298C > T, 1967+2T > C, and 2439+2T > C). Two patients were compound heterozygotes (1177C > T/2302C > T and 1967+2T > C/2026G > C). A familial study showed no difference in serum bilirubin levels between mutant/wild heterozygotes and wild/wild homozygotes. Conclusions. 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.