1例中国Gilbert综合征家系UGT1A1基因遗传分析

背景:国内关于遗传性非结合性高胆红素血症(Gilbert综合征)的基因研究极少见。目的:通过分析1例中国Gilbert综合征患者及其家系成员的尿苷二磷酸葡萄糖醛酸转移酶(UGT)1A1基因突变位点,研究其遗传方式。方法:根据肝功能试验和低热量试验结果确诊Gilbert综合征患者1例,追踪并抽取该先证者及其5名家系成员的外周静脉血,提取基因组DNA,应用聚合酶链反应(PCR)扩增UGT1A1基因5对外显子以及上游苯巴比妥反应增强元件(PBREM)和启动子TATA盒,以直接DNA测序法鉴定UGT1A1基因突变位点。结果:先证者及其4名家系成员PBREM发生T-3279G突变,TATA盒发生TA插入突变,形成A(TA)7TAA,其中先证者及其胞妹之一为突变纯合子。通过血清非结合胆红素水平检测证实了基因型与表现型的关系。结论:T-3279G与A(TA)7TAA共同作用是导致Gilbert综合征家系发病的原因,A(TA)7TAA对胆红素代谢的影响更为显著,两者高度连锁。Gilbert综合征的遗传方式符合常染色体隐性遗传。该家系UGT1A1基因T-3279G和A(TA)7TAA突变为国内首例报道。

Genetic Analysis of UGT1A1 Gene in a Chinese Family with Gilbert Syndrome

Background:There are only few studies on the genetic analysis of inherited unconjugated hyperbilirubinemia(Gilbert syndrome) in China.Aims:To analyze the mutation locus of bilirubin uridine diphosphate glucurono-syltransferase(UGT)1A1 gene in a Chinese patient with Gilbert syndrome and his first degree relatives,and a pedigree analysis of heredity was made.Methods:The patient(proband) was diagnosed as having Gilbert syndrome by liver function test and low calorie test.Blood samples were collected from the proband and his five first degree relatives,and the genomic DNA was extracted.The phenobarbital-responsive enhancer module(PBREM),TATA box and 5 exons of the UGT1A1 gene were amplified by polymerase chain reaction(PCR) and mutations of the UGT1A1 gene were screened by direct DNA sequencing.Results:A T-3279G mutation in PBREM and a TA insertion in TATA box were observed in this family.The proband and one of his sisters were homozygous of these two mutations.The correlation between genotype and phenotype with high serum unconjugated bilirubin level was confirmed.Conclusions:Both T-3279G and A(TA)7TAA are essential for the pathogenesis of Gilbert syndrome in this family,especially A(TA)7TAA.A highly significant linkage disequilibrium is noted between these two mutations.Gilbert syndrome in this family is inherited in an autosomal recessive manner.This is the first report of T-3279G and A(TA)7TAA mutations in UGT1A1 gene in China.