Cebecauerova Dita, Jirasek Tomas, Budisova Lucie, Mandys Vaclav, Volf Vladimir, Novotna Zorka, Subhanova Iva, Hrebicek Martin, Elleder Milan, Jirsa Milan
Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Gastroenterology. 2005 Jul;129(1):315-20. doi: 10.1053/j.gastro.2004.10.009.
BACKGROUND & AIMS: Dubin-Johnson syndrome is recessively inherited, conjugated hyperbilirubinemia induced by mutations in the ABCC2/MRP2 gene encoding the canalicular transporter for conjugated bilirubin. Gilbert's syndrome is recessively inherited, unconjugated hyperbilirubinemia caused by decreased conjugation rate of bilirubin associated mostly with homozygous A(TA) 7 TAA variant of the TATAA-box in the UGT1A1 gene promoter. Our aim was to establish the molecular diagnosis in a 3-year-old male with atypical, intermittent, predominantly unconjugated, hyperbilirubinemia.
99m Tc-HIDA cholescintigraphy was used for imaging the biliary tree. Expression of ABCC2/MRP2 protein in hepatocytes was investigated immunohistochemically. UGT1A1 and ABCC2/MRP2 genes were sequenced from genomic DNA, and the mutations were verified by fragment analysis, sequencing the cloned exons, and restriction fragment length polymorphism.
Cholescintigraphy revealed delayed visualization of the gallbladder. A brown granular lipopigment differing from melanin-like pigment reported in Dubin-Johnson syndrome was present in hepatocytes, but, otherwise, liver histology was normal. ABCC2/MRP2 protein was not detected on the canalicular membrane of hepatocytes, and 2 novel mutations were found in the ABCC2/MRP2 gene: a heterozygous in-frame insertion-deletion mutation 1256insCT/delAAACAGTGAACCTGATG in exon 10 inherited from the father and a heterozygous deletion 4292delCA in exon 30 inherited from the mother. In addition, the patient was homozygous for -3279T>G and A(TA) 7 TAA mutations in the UGT1A1 gene promoter.
Our patient represents a case of digenic mixed hyperbilirubinemia-a distinct type of constitutive jaundice resulting from coinherited defects in ABCC2/MRP2 and UGT1A1 genes.
杜宾-约翰逊综合征是一种隐性遗传性结合胆红素血症，由编码结合胆红素小管转运体的ABCC2/MRP2基因突变引起。吉尔伯特综合征是一种隐性遗传性非结合胆红素血症，主要由UGT1A1基因启动子中TATAA盒的纯合A(TA)7TAA变异导致胆红素结合率降低所致。我们的目的是对一名3岁男性的非典型、间歇性、主要为非结合胆红素血症进行分子诊断。
采用99mTc-HIDA肝胆闪烁显像对胆道系统进行成像。采用免疫组织化学方法研究肝细胞中ABCC2/MRP2蛋白的表达。从基因组DNA中对UGT1A1和ABCC2/MRP2基因进行测序，并通过片段分析、克隆外显子测序和限制性片段长度多态性对突变进行验证。
肝胆闪烁显像显示胆囊显影延迟。肝细胞中存在一种棕色颗粒状脂色素，与杜宾-约翰逊综合征中报道的黑色素样色素不同，但肝脏组织学检查其他方面正常。在肝细胞的胆小管膜上未检测到ABCC2/MRP2蛋白，并且在ABCC2/MRP2基因中发现了2个新的突变：一个是从父亲遗传的外显子10中的杂合框内插入缺失突变1256insCT/delAAACAGTGAACCTGATG，另一个是从母亲遗传的外显子30中的杂合缺失4292delCA。此外，该患者在UGT1A1基因启动子中-3279T>G和A(TA)7TAA突变为纯合子。
我们的患者代表了一种双基因混合性高胆红素血症病例——一种由ABCC2/MRP2和UGT1A1基因共同遗传缺陷导致的独特类型的先天性黄疸。
