Bosma P J, Chowdhury J R, Bakker C, Gantla S, de Boer A, Oostra B A, Lindhout D, Tytgat G N, Jansen P L, Oude Elferink R P
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
N Engl J Med. 1995 Nov 2;333(18):1171-5. doi: 10.1056/NEJM199511023331802.
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.
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 bilirubin 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.
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)7TAA rather than the normal A(TA)6TAA). 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.
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.
吉尔伯特综合征患者在无肝脏疾病或明显溶血的情况下，存在轻度慢性非结合性高胆红素血症。肝脏葡萄糖醛酸化活性对于胆红素的有效胆汁排泄至关重要，其活性降低至正常水平的约30%。
我们对10例无关的吉尔伯特综合征患者、16例有Ⅱ型克里格勒 - 纳贾尔综合征病史的家族成员以及55名正常受试者的胆红素UDP - 葡萄糖醛酸基转移酶1（胆红素/尿苷二磷酸葡萄糖醛酸 - 葡萄糖醛酸基转移酶1）基因的编码区和启动子区进行了测序，该酶是唯一对胆红素葡萄糖醛酸化有显著贡献的酶。
10例吉尔伯特综合征患者该酶基因的编码区正常。这些患者在该基因5'启动子区的TATAA元件中存在两个额外碱基（TA）的纯合子（A(TA)7TAA而非正常的A(TA)6TAA）。较长的TATAA元件的存在导致在人肝癌细胞系中编码萤火虫荧光素酶的报告基因表达降低。正常受试者中异常等位基因的频率为40%。对照组中3名较长TATAA元件纯合子男性的血清胆红素水平显著高于其他52名正常受试者（P = 0.009）。在有Ⅱ型克里格勒 - 纳贾尔综合征病史的家族中，只有6名在结构正常的等位基因上有较长TATAA元件的杂合携带者有轻度高胆红素血症，这是吉尔伯特综合征的特征。
由于该酶基因启动子区异常导致的胆红素UDP - 葡萄糖醛酸基转移酶1表达降低似乎是吉尔伯特综合征所必需的，但不足以完全表现出该综合征。
