Spectrum of UGT1A1 Mutations in Crigler-Najjar (CN) Syndrome Patients: Identification of Twelve Novel Alleles and Genotype-Phenotype Correlation
Spectrum of UGT1A1 Mutations in Crigler-Najjar (CN) Syndrome Patients: Identification of Twelve Novel Alleles and Genotype-Phenotype Correlation
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DOI：
10.1002/humu.9322
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发表时间：
2005-03-01
期刊：
影响因子：
3.9
通讯作者：
Iolascon, Achille
中科院分区：
文献类型：
--
作者：
Servedio, Veronica;d'Apolito, Maria;Iolascon, Achille
Crigler-Najjar综合征I型和II型（CN 1和CN2）通常作为常染色体隐性遗传疾病遗传，其特征为非溶血性非结合型高胆红素血症。CN 1是最严重的形式，与肝胆红素-尿苷二磷酸葡萄糖醛酸葡萄糖醛酸转移酶（UGT 1A 1）活性缺失相关。由于肝脏UGT 1A 1活性不完全缺乏，CN 2呈现中等水平的高胆红素血症。本文对31例无血缘关系的Crigler-Najjar（CN）综合征患者进行UGT 1A 1基因分析。这项分析使我们能够鉴定出22种突变，其中12种以前没有描述过，将已知的UGT 1突变谱扩展到77种。在UGT 1A 1基因的编码外显子和侧翼内含子中发现了被认为是致病性的新突变，包括1个无义突变、2个改变的剪接位点、1个单碱基缺失和9个错义突变。几个新的错义突变定位于UGT 1A 1酶的关键结构域。此外，对Crigler-Najjar（CN）综合征患者中UGT 1A 1的Gilbert型启动子进行了评价。启动子区的多态性可以改变UGT 1A 1突变表型。这项研究代表了迄今为止研究的最大的意大利Crigler-Najjar吉尔伯特综合征患者队列的分子特征;增加了全球UGT 1A 1等位基因变体的突变谱，并为临床诊断和遗传咨询提供了新的见解。(C)2005 Wiley-Liss，Inc.
Crigler-Najjar syndrome types I and II (CN1 and CN2) are usually inherited as autosomal recessive conditions and are characterized by non-hemolytic unconjugated hyperbilirubinaemia. CN1 is the most severe form, associated with the absence of hepatic bilirubin-uridinediphosphoglucuronate glucuronosyltransferase (UGT1A1) activity. CN2 presents intermediate levels of hyperbilirubinaemia as a result of an incomplete deficiency of hepatic UGT1A1 activity. Here, we present the analysis of UGT1A1 gene in 31 unrelated Crigler-Najjar (CN) syndrome patients. This analysis allowed us to identify 22 mutations, 12 of which were no previously described, expanding the spectrum of known UGT1 mutations to 77. Novel mutations, considered pathogenic, including one nonsense mutation, two altered splice sites, one single base deletion and nine missense mutations were identified in coding exons of the UGT1A1 gene and flanking introns. Several novel missense mutations localize in critical domain of UGT1A1 enzyme. In addition, the evaluation of Gilbert-type promoter of UGT1A1 in Crigler-Najjar (CN) syndrome patients was performed. The polymorphisms of the promoter region can modify the UGT1A1 mutation phenotype. This study represents the molecular characterization of the largest cohort of Italian Crigler-Najjar Gilbert syndrome patients studied so far; increase the mutational spectrum of UGT1A1 allelic variants worldwide and provide a new insight useful for clinical diagnosis and genetic counseling. (C) 2005 Wiley-Liss, Inc.