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Received: 2013-09-01

Revision Accepted: 2014-02-09

Crosschecked: 2014-04-16

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Journal of Zhejiang University SCIENCE B 2014 Vol.15 No.5 P.474-481

http://doi.org/10.1631/jzus.B1300233


Two unrelated patients with rare Crigler-Najjar syndrome type I: two novel mutations and a patient with loss of heterozygosity of UGT1A1 gene


Author(s):  Yan Li1, Yu-jin Qu1, Xue-mei Zhong2, Yan-yan Cao1, Li-min Jin2, Jin-li Bai1, Xin Ma2, Yu-wei Jin1, Hong Wang1, Yan-ling Zhang2, Fang Song1

Affiliation(s):  1. Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, China; more

Corresponding email(s):   ylzhang7766@126.com

Key Words:  Crigler-Najjar syndrome type I (CN-I), Hyperbilirubinemia, UDP-glycuronosyltransferase gene (UGT1A1), Mutation, Loss of heterozygosity


Yan Li, Yu-jin Qu, Xue-mei Zhong, Yan-yan Cao, Li-min Jin, Jin-li Bai, Xin Ma, Yu-wei Jin, Hong Wang, Yan-ling Zhang, Fang Song. Two unrelated patients with rare Crigler-Najjar syndrome type I: two novel mutations and a patient with loss of heterozygosity of UGT1A1 gene[J]. Journal of Zhejiang University Science B, 2014, 15(5): 474-481.

@article{title="Two unrelated patients with rare Crigler-Najjar syndrome type I: two novel mutations and a patient with loss of heterozygosity of UGT1A1 gene",
author="Yan Li, Yu-jin Qu, Xue-mei Zhong, Yan-yan Cao, Li-min Jin, Jin-li Bai, Xin Ma, Yu-wei Jin, Hong Wang, Yan-ling Zhang, Fang Song",
journal="Journal of Zhejiang University Science B",
volume="15",
number="5",
pages="474-481",
year="2014",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B1300233"
}

%0 Journal Article
%T Two unrelated patients with rare Crigler-Najjar syndrome type I: two novel mutations and a patient with loss of heterozygosity of UGT1A1 gene
%A Yan Li
%A Yu-jin Qu
%A Xue-mei Zhong
%A Yan-yan Cao
%A Li-min Jin
%A Jin-li Bai
%A Xin Ma
%A Yu-wei Jin
%A Hong Wang
%A Yan-ling Zhang
%A Fang Song
%J Journal of Zhejiang University SCIENCE B
%V 15
%N 5
%P 474-481
%@ 1673-1581
%D 2014
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1300233

TY - JOUR
T1 - Two unrelated patients with rare Crigler-Najjar syndrome type I: two novel mutations and a patient with loss of heterozygosity of UGT1A1 gene
A1 - Yan Li
A1 - Yu-jin Qu
A1 - Xue-mei Zhong
A1 - Yan-yan Cao
A1 - Li-min Jin
A1 - Jin-li Bai
A1 - Xin Ma
A1 - Yu-wei Jin
A1 - Hong Wang
A1 - Yan-ling Zhang
A1 - Fang Song
J0 - Journal of Zhejiang University Science B
VL - 15
IS - 5
SP - 474
EP - 481
%@ 1673-1581
Y1 - 2014
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1300233


Abstract: 
crigler-Najjar syndrome type I (CN-I) is the most severe type of hereditary unconjugated hyperbilirubinemia. It is caused by homozygous or compound heterozygous mutations of the UDP-glycuronosyltransferase gene (UGT1A1) on chromosome 2q37. Two patients clinically diagnosed with CN-I were examined in this paper. We sequenced five exons and their flanking sequences, specifically the promoter region of UGT1A1, of the two patients and their parents. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the UGT1A1 gene copy number of one patient. In patient A, two mutations, c.239_245delCTGTGCC (p.Pro80HisfsX6; had not been reported previously) and c.1156G>T (p.Val386Phe), were identified. In patient B, we found that this patient had lost heterozygosity of the UGT1A1 gene by inheriting a deletion of one allele, and had a novel mutation c.1253delT (p.Met418ArgfsX5) in the other allele. In summary, we detected three UGT1A1 mutations in two CN-I patients: c.239_245delCTGTGCC (p.Pro80HisfsX6), c.1253delT (p.Met418ArgfsX5), and c.1156G>T (p.Val386Phe). The former two mutations are pathogenic; however, the pathogenic mechanism of c.1156G>T (p.Val386Phe) is unknown.

两例罕见I型Crigler-Najjar综合征患者

研究目的:I型Crigler-Najjar综合征(CN-I)为先天性间接胆红素血症的最严重的一种,是由位于染色体2q37的葡萄糖醛酸转移酶基因(UGT1A1)的纯合或复合杂合突变引起的一种罕见的遗传性疾病。本研究对来自两个无关家庭的两例临床诊断为CN-I的患儿及父母进行UGT1A1基因分子遗传学分析。
研究方法:经知情同意后,采集两例患儿及父母外周血;聚合酶链式反应(PCR)扩增UGT1A1基因5个外显子及外显子-内含子交界处,进行测序分析。应用实时定量PCR(qRT-PCR)测定其中一例患者UGT1A1基因的拷贝数。
重要结论:本研究在两例CN-I型患儿中检测到3个UGT1A1基因突变:c.239_245delCTGTGCC (p.Pro80HisfsX6)、c.1253delT (p.Met418ArgfsX5)和c.1156G>T (p.Val386Phe)。前两个突变均为新发的移码突变,预测提前出现终止密码或诱发RNA降解;而突变c.1156G>T (p.Val386Phe)的致病机制尚需进一步研究。

关键词:I型Crigler-Najjar综合征(CN-I);高胆红素血症;UDP-葡萄糖醛酸转移酶基因(UGT1A1);突变;杂合性缺失

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References

[1] Basu, N.K., Ciotti, M., Hwang, M.S., 2004. Differential and special properties of the major human UGT1-encoded gastrointestinal UDP-glucuronosyltransferases enhance potential to control chemical uptake. J Biol Chem, 279(2):1429-1441. 


[2] Bortolussi, G., Zentilin, L., Baj, G., 2012. Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer. FASEB J, 26(3):1052-1063. 


[3] Bosma, P.J., Chowdhury, J.R., Bakker, C., 1995. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med, 333(18):1171-1175. 


[4] Canu, G., Minucci, A., Zuppi, C., 2013. Gilbert and Crigler-Najjar syndromes: an update of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation database. Blood Cells Mol Dis, 50(4):273-280. 


[5] Costa, E.V., Vieira, E., Lopes, A.I., 2009. Identification of a novel deletion in UDP-glucuronosyltransferase gene in a patient with Crigler-Najjar syndrome type I. Blood Cells Mol Dis, 42(3):265-266. 


[6] Crigler, J.F., Najjar, V.A., 1952. Congenital familial nonhemolytic jaundice with kernicterus. Pediatrics, 10(2):169-180. 


[7] Kadakol, A., Ghosh, S.S., Sappal, B.S., 2000. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and gilbert syndromes: correlation of genotype to phenotype. Hum Mutat, 16(4):297-306. 


[8] Lucey, J.F., Suresh, G.K., Kappas, A., 2000. Crigler-Najjar syndrome, 1952–2000: learning from parents and patients about a very rare disease and using the Internet to recruit patients for studies. Pediatrics, 105(5):1152-1153. 


[9] Lysy, P.A., Najimi, M., Stephenne, X., 2008. Liver cell transplantation for Crigler-Najjar syndrome type I: update and perspectives. World J Gstroenterol, 14(22):3464-3470. 


[10] Maruo, Y., Nishizawa, K., Sato, H., 1999. Association of neonatal hyperbilirubinemia with bilirubin UDP-glucuronosyltransferase polymorphism. Pediatrics, 103(6):1224-1227. 


[11] Maruo, Y., Ozgenc, F., Mimura, Y., 2011. Compound heterozygote of a novel missense mutation (p.K402T) and a double missense mutation (p.[G71R;Y486D]) in type II Crigler-Najjar syndrome. J Pediatr Gastroenterol Nutr, 52(3):362-365. 


[12] Petit, F.M., Gajdos, V., Francoual, J., 2004. Allelic heterogeneity of Crigler-Najjar type I syndrome: a study of 24 cases. Clin Genet, 66(6):571-572. 


[13] Petit, F.M., Bzieau, S., Gajdos, V., 2008. The Tunisian population history through the Crigler-Najjar type I syndrome. Eur J Hum Genet, 16(7):848-853. 


[14] Sambrook, J., Fitsch, E.F., Maniatis, T., 1989.  Molecular Cloning: A Laboratory Manual+Cold Spring Harbor. Cold Spring Harbor Laboratory Press,NY, USA :

[15] Sneitz, N., Bakker, C.T., de Knegt, R.J., 2010. Crigler-Najjar syndrome in the Netherlands: identification of four novel UGT1A1 alleles, genotype-phenotype correlation, and functional analysis of 10 missense mutants. Hum Mutat, 31(1):52-59. 


[16] Tukey, R.H., Strassburg, C.P., 2001. Genetic multiplicity of the human UDP-glucuronosyltransferases and regulation in the gastrointestinal tract. Mol Pharmacol, 59(3):405-414. 


[17] Wilke, K., Duman, B., Horst, J., 2000. Diagnosis of haploidy and triploidy based on measurement of gene copy number by real-time PCR. Hum Mutat, 16(5):431-436. 



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