Maruo Y, Poon K K-H, Ito M, Iwai M, Takahashi H, Mori A, Sato H, Takeuchi Y
Department of Pediatrics, Shiga University of Medical Science, Seta, Otsu, Japan.
Clin Genet. 2003 Nov;64(5):420-3. doi: 10.1034/j.1399-0004.2003.00136.x.
Crigler-Najjar syndrome type I is a severe form of hereditary unconjugated hyperbilirubinemia and is caused by homozygous or compound heterozygous mutations of the bilirubin UDP-glucuronosyltransferase gene (UGT1A1). We analyzed the bilirubin UDP-glucuronosyltransferase gene in a female Chinese patient with Crigler-Najjar syndrome type I. Relatives of the patient were also analyzed. The patient was homozygous for a nonsense mutation of R341X. The patient's father, sister and brother, all diagnosed with Gilbert's syndrome, were compound heterozygotes of R341X, P229Q, and an insertion mutation of the TATA box [A(TA)7TAA]. Heterozygotes of nonsense mutations (Q331X and C280X) in our previous study had either Crigler-Najjar syndrome type II or Gilbert's syndrome, but heterozygotes of R341X (mother and grandmothers) were normal. An in vitro expression study of homozygous and heterozygous models of R341X showed 0 and 58%, respectively, of normal enzyme activity. Therefore, the present results indicate that carriers of the nonsense mutation could be normal for plasma bilirubin concentration, Gilbert's syndrome and Crigler-Najjar syndrome type II. The results also suggest the importance of the accumulation of prevalent or polymorphic mutation in the etiology of Gilbert's syndrome and Crigler-Najjar syndrome type II.
Ⅰ型克里格勒-纳贾尔综合征是一种严重的遗传性非结合胆红素血症，由胆红素UDP-葡萄糖醛酸基转移酶基因（UGT1A1）的纯合或复合杂合突变引起。我们分析了一名患有Ⅰ型克里格勒-纳贾尔综合征的中国女性患者的胆红素UDP-葡萄糖醛酸基转移酶基因。对该患者的亲属也进行了分析。该患者为R341X无义突变的纯合子。患者的父亲、姐姐和哥哥均被诊断为吉尔伯特综合征，他们是R341X、P229Q和TATA框插入突变[A(TA)7TAA]的复合杂合子。在我们之前的研究中，无义突变（Q331X和C280X）的杂合子患有Ⅱ型克里格勒-纳贾尔综合征或吉尔伯特综合征，但R341X的杂合子（母亲和祖母）是正常的。R341X纯合和杂合模型的体外表达研究分别显示正常酶活性的0%和58%。因此，目前的结果表明，无义突变的携带者血浆胆红素浓度、吉尔伯特综合征和Ⅱ型克里格勒-纳贾尔综合征可能正常。结果还提示了常见或多态性突变的积累在吉尔伯特综合征和Ⅱ型克里格勒-纳贾尔综合征病因学中的重要性。
