Machida Ikuo, Wakusawa Shinya, Sanae Fujiko, Hayashi Hisao, Kusakabe Atsushi, Ninomiya Hiroshi, Yano Motoyoshi, Yoshioka Kentaro
Department of Medicine, Faculty of Pharmaceutical Sciences of Hokuriku University, Ho-3, Kanagawa-machi, Kanazawa 920-1181, Japan.
J Gastroenterol. 2005 Apr;40(4):366-70. doi: 10.1007/s00535-004-1555-y.
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.
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.
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 1177C>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.
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.
最近的研究表明，多药耐药蛋白2（MRP2）功能障碍或缺失是杜宾-约翰逊综合征（DJS）的分子基础。为了阐明该疾病的遗传基础以及血清胆红素水平的长期稳定性，我们对MRP2基因进行了突变分析，并根据传统标准对日本DJS患者最初诊断30年后的血清胆红素水平进行了随访。
通过电话采访患者，并对给予知情同意的患者及其家庭成员进行血液检查，包括MRP2的基因分析。
在30年的时间里，所研究的5名患者中有4名的高胆红素血症保持不变，而1名DJS合并慢性丙型肝炎的患者病情恶化。通过MRP2基因突变分析，发现了6种突变，包括新突变1177C>T。一个近亲家庭的3名患者为3种突变（298C>T、1967+2T>C和2439+2T>C）的纯合子。2名患者为复合杂合子（1177C>T/2302C>T和1967+2T>C/2026G>C）。一项家族研究表明，突变/野生杂合子和野生/野生纯合子之间的血清胆红素水平没有差异。
4名日本DJS患者的高胆红素血症未随年龄增长而恶化，其中1名患者的MRP2基因有新突变1177C>T。
