THE GENETIC-BASIS OF THE REDUCED EXPRESSION OF BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE-1 IN GILBERTS-SYNDROME
THE GENETIC-BASIS OF THE REDUCED EXPRESSION OF BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE-1 IN GILBERTS-SYNDROME
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DOI：
10.1056/nejm199511023331802
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发表时间：
1995-11-02
影响因子：
158.5
通讯作者：
CHOWDHURY, NR
中科院分区：
文献类型：
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作者：
BOSMA, PJ;CHOWDHURY, JR;CHOWDHURY, NR
背景患有吉尔伯特综合征的人在没有肝脏疾病或明显溶血的情况下有轻度慢性非结合型高胆红素血症。肝葡萄糖醛酸化活性，胆红素的有效胆汁排泄所必需的，是减少到约30%的正常。我们对10名无血缘关系的吉尔伯特综合征患者、16名有II型Crigler-Najjar综合征病史的家族成员和55名正常受试者的胆红素UDP-葡萄糖醛酸转移酶1（胆红素/尿苷二磷酸葡萄糖醛酸-葡萄糖醛酸转移酶1）基因的编码区和启动子区进行了测序。10名吉尔伯特综合征患者的酶基因编码区正常。这些患者在该基因的5'启动子区的TATAA元件中的两个额外碱基（TA）是纯合的（A（TA）（7）TAA而不是正常的A（TA）（6）TAA）。的存在。较长的TATAA元件导致在人肝癌细胞系中编码萤火虫荧光素酶的报告基因的表达降低。在正常人中，异常等位基因的频率为40%。对照组中的3名男子谁是纯合子的较长的TATAA元素有显着高于其他52名正常人的血清胆红素水平（P = 0.009）。在有Crigler-Najjar综合征II型病史的亲属中，只有6名在结构正常的等位基因上有较长TATAA元件的杂合子携带者有轻度高胆红素血症，这是吉尔伯特综合征的特征。胆红素UDP-葡萄糖醛酸基转移酶1基因启动子区的异常导致该酶表达减少，这似乎是吉尔伯特综合征所必需的，但不足以完全表现该综合征。
Background. People with Gilbert's syndrome have mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis. Hepatic glucuronidating activity, essential for efficient biliary excretion of bilirubin, is reduced to about 30 percent of normal.Methods. We sequenced the coding and promoter regions of the gene for bilirubin UDP-glucuronosyltransferase 1 (bilirubin/uridine diphosphoglucuronate-glucuronosyltransferase 1) - the only enzyme that contributes substantially to bi[irubin glucuronidation - in 10 unrelated patients with Gilbert's syndrome, 16 members of a kindred with a history of Crigler-Najjar syndrome type II, and 55 normal subjects.Results. The coding region of the gene for the enzyme was normal in the 10 patients with Gilbert's syndrome. These patients were homozygous for two extra bases (TA) in the TATAA element of the 5' promoter region of the gene (A(TA)(7)TAA rather than the normal A(TA)(6)TAA). The presence of the. longer TATAA element resulted in the reduced expression of a reporter gene, encoding firefly luciferase, in a human hepatoma cell line. The frequency of the abnormal allele was 40 percent among the normal subjects. The 3 men in the control group who were homozygous for the longer TATAA element had significantly higher serum bilirubin levels than the other 52 normal subjects (P = 0.009). Among the kindred with a history of Crigler-Najjar syndrome type II, only the six heterozygous carriers who had a longer TATAA element on the structurally normal allele had mild hyperbilirubinemia, characteristic of Gilbert's syndrome.Conclusions. Reduced expression of bilirubin UDP-glucuronosyltransferase 1 due to an abnormality in the promoter region of the gene for this enzyme appears to be necessary for Gilbert's syndrome but not sufficient for the complete manifestation of the syndrome.