Ⅱ型Crigler-Najjar综合征1例报告

正Crigler-Najjar综合征(CNS)是由Crigler和Najjar于1952年首次报道而得名,是由尿苷二磷酸葡萄糖醛酸基转移酶(uridine 5'-diphosphate glucuronosyltransferase,UGT)1A1基因突变使其酶活性完全或部分丧失而导致的遗传性胆红素代谢障碍性疾病,分为Ⅰ型和Ⅱ型,发病率为百万分之一[1-3]。为常染色体     

分子遗传学检查诊断Crigler-Najjar综合征域Ⅱ型3例

目的探讨采用分子遗传学检查诊断Crigler-Najjar综合征Ⅱ型的方法。方法在本科收治的3例高间接胆红素血症患者,抽取外周静脉血,提取基因组DNA,应用PCR法扩增尿苷二磷酸葡萄糖醛酸转移酶1A1基因(UGT1A1)所含5个外显子及其侧翼序列,进行DNA直接测序。结果 3例患者均检出UGT1A1基因5号外显子存在c.1456 TG(p.Y486D)纯合突变;Y486D位于第5外显子上,使1456位胸腺嘧啶(T)突变为鸟嘌呤(G),导致486位氨基酸由酪氨酸(Tyr)变为天冬氨酸(Asp)。结论当临床上高度怀疑Crigler-Najjar综合征Ⅱ型时,应尽早行分子遗传学检查,确定其基因突变位点,以明确诊断。     

兄弟共患Crigler-Najjar综合征

1 病例报告病例1,男,32岁,农民。因皮肤巩膜黄染、尿黄32年,于2002年3月26日入院。患者出生后3～4d 家人发现其皮肤巩膜黄染,尿黄似浓茶色。查血 ALT 正常,BiL 明显高于正常(具体值不详)。患者饮食、生长发育均正常。13岁时黄疸明显加深,TBiL 120μmol/L 左右,肝功正常,无乏力及纳差症状。此后多次复查 ALT 正常,TBiL 120～140μmol/L。2000年-2001年间,因劳累患者出现乏力,肝功异常2次,ALT 600～700U/L,TBiL 160～300μmol/L。2002年2月复查 ALT 正常,TBiL 145μmol/L,DBiL 70μmol/L,因常年多家医院不能确诊来我院。查体:发育正常,养中等,皮肤、巩膜可见明显黄染,未见蜘蛛痣及肝掌。浅表淋     

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。     

Gilbert综合征和Crigler-Najjar综合征相关尿苷二磷酸葡糖醛酸转移酶A1基因突变位点特征分析

目的探讨Gilbert综合征(GS)和Crigler-Najjar综合征(CNS)相关尿苷二磷酸葡糖醛酸转移酶A1(UGT1A1)基因的突变特征及与临床的相关性。方法通过检索PubMed和人类基因突变数据库归纳UGT1A1基因突变位点的特征并分析其临床相关性。结果截至2018年11月16日,共发现UGT1A1基因163个突变位点,上述位点存在以下规律:(1)GS或CNS表型相关的UGT1A1的不同外显子发生的基因突变个数,均与外显子长度呈正相关;(2)无义点突变主要发生在CNS I型;(3)GS、CNS II型的复合杂合突变位点的组合和分布存在一定规律,其中GS的4种复合杂合组成中,均有-3279T>G突变;(4)亚洲地区报道的UGT1A1基因突变位点在c.211-c.558有明显的聚集性。结论UGT1A1基因突变位点不同、报道地区不同及人群不同,其突变特征及临床相关性也不同。本研究对GS和CNS的基础研究和临床诊疗有参考价值。     

Gilbert综合征2例报道

正Gilbert综合征是一种遗传性非结合性高胆红素升高性疾病,是临床上最为常见的一种先天性黄疸。近年,从组织病理学和基因水平诊断该病增多。现就近期我院经肝组织病理学和基因检测确诊的2例患者的临床资料进行分析,并复习了有关文献,现报道如下。1病例摘要例1女,36岁。因"反复眼黄、尿黄、皮肤黄36年"于2016年6月15日入院。缘于出生后即被发现眼黄、皮肤黄,尿黄,饮食等日常生活如常,无皮肤瘙痒。生长发育正常,尿     

Gilbert综合征UGT1 A1基因突变特征及对肝脏和肝外系统的影响

Gilbert综合征是最常见的遗传性高胆红素血症,发病率较高。简述了Gilbert综合征的流行病学特征、常见的尿苷二磷酸葡萄糖醛酸转移酶(UGT) 1A1基因突变位点以及Gilbert综合征对肝脏本身及肝外疾病的影响进展,并认为这对Gilbert综合征的诊疗及某些肝脏及肝外疾病的防治具有重要意义。     

Gilbert综合征与Crigler-Najjar综合征Ⅱ型患者UGT1A1基因多态性分析

目的 分析Gilbert综合征（GS）与Crigler-Najjar综合征Ⅱ型（CN-2）患者UGT1A1基因突变位点、单倍型及双倍型的差异。方法 回顾性分析2010年1月1日—2019年12月31日就诊于首都医科大学附属北京佑安医院的138例GS与CN-2患者临床资料,其中GS组109例,CN-2组29例,分析两种表型在突变位点上的差异。计量资料两组间比较采用Mann-Whitney U检验。计数资料两组间比较采用χ²检验或Fisher精确检验。使用SNPStats软件对突变位点进行连锁不平衡（LD）分析及单倍型分析。强LD被定义为|D′|和r²均>0.8,中度LD被定义为|D′|>0.8且r²>0.4。结果 138例患者均进行了UGT1A1基因检测,突变主要发生在启动子上游苯巴比妥反应增强元件（PBREM）区域-3279T>G突变（104例,75.36%）、-3152G>A突变（82例,59.42%）和启动子TATA 盒TA插入突变（88例,63.77%）,以及编码区1号外显子上的c.2...     

尿苷二磷酸葡萄糖醛酸转移酶在肝脏疾病中的作用及其转录调控机制

尿苷二磷酸葡萄糖醛酸转移酶（UDP-glucuronosyltransferases,UGTs）是机体重要的Ⅱ相代谢酶,在肝脏中高表达,在物质代谢和清除中发挥重要作用。肝脏疾病状态下机体对于UGTs的转录调控在疾病的发生发展中具有重要作用。本文对UGTs的一般家族及其与代谢的关系进行综述,探讨了UGTs在肝脏疾病中的表达和转录调控,UGTs在疾病机制中的研究以及UGTs在肝脏疾病临床治疗中的意义。     

Regulation of uridine diphosphate glucuronosyltransferase during the acute-phase response

The acute-phase response is associated with profound effects on oxidative drug metabolism. However, the effects on glucuronidation are poorly characterized. The aim of the present study was to determine the role of mediators of the acute-phase response in the regulation of hepatic uridine diphosphate glucuronosyltransferase (UGT) expression. Family 1 and family 2 UGT isoforms were studied in turpentine-injected rats and in primary hepatocyte cultures exposed to cytokines and/or dexamethasone. In the in vivo model, glucuronidation of p-nitrophenol was unaffected, while testosterone glucuronidation was reduced to 65% of control (P < 0.01). In contrast, the mRNA level of UGT1*1 (which metabolizes bilirubin, not phenols) was depressed to 16% of control (P < 0.002), while the mRNA level of UGT2B3 (which metabolizes testosterone) was reduced to 53% (P < 0.05). In primary hepatocyte culture, dexamethasone treatment resulted in a 3.4-fold induction of UGT1*1 mRNA levels (P < 0.001) but only a 1.5-fold induction of UGT2B3 (P=0.1). Interleukin-6 in the presence of dexamethasone resulted in a marked dose-dependent suppression of both UGT1*1 and UGT2B3, although to different degrees. Interleukin-1 had no effect on UGT mRNA levels. Thus, inflammatory mediators, such as cytokines and glucocorticoids, may be important determinants of both oxidative and conjugative drug metabolism by the liver.     

Crigler-Najjar syndrome type II

Summary The inheritance of Crigler-Najjar syndrome type II (CNS II) is still unclear. Both autosomal dominant transmission with variable penetrance and autosomal recessive transmission have been reported. We describe the diagnosis of CNS II in an adult patient with unconjugated serum bilirubin levels up to 19.6 mg/dl and no detectable activity of bilirubin UDP-glucuronosyltransferase in the liver biopsy. Serum bilirubin levels decreased markedly on phenobarbital treatment. The parents of our patient are first cousins. The mother and three of the patient's five sibs were jaundiced within a few days of birth. Our patient and her jaundiced siblings have 11 children, all healthy and anicteric. We conclude from these data that the inheritance of this very rare disease follows an autosomal recessive pattern, with pseudodominance in this family.     

No association between cyclooxygenase-2 and uridine diphosphate glucuronosyltransferase 1A6 genetic polymorphisms and colon cancer risk

AIM：To investigate the association of variations in the cyclooxygenase-2 （COX2） and uridine diphosphate glucuronosyltransferase 1A6 （UGTIA6） genes and non-steroidal anti-inflammatory drugs （NSAIDs） use with risk of colon cancer.METHODS： NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly,enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGTIA6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms （SNPs） in the COX2 and UGTIA6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls.RESULTS： No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk （P 〉 0.05）,and we did not observe that these variants modify the protective effect of NSAIDs （P 〉 0.05）. We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas.CONCLUSION： Our study does not support a role of COX2 and UGTIA6 genetic variations in the development of colon cancer.     

A homozygous mutation in a Chinese man with Crigler-Najjar syndrome type II and a family genetic analysis

OBJECTIVE: To investigate the family genetic background of a 22-year-old man with Crigler-Najjar syndrome type II (CN-II). METHODS: After the proband (patient) with CN-II was diagnosed by liver function tests, a low calorie intake test and an oral phenobarbital enzyme-induction trial, blood samples were collected from 11 family members for identifying DNA gene groups. Exons 1-5 of the UGT1A1 gene were amplified by polymerase chain reaction (PCR) and mutations of the UGT1A1 gene were screened by a direct DNA sequencing. RESULTS: The serum unconjugated bilirubin increased in the proband from 156.4 micromol/L to 243.5 micromol/L after he started a low calorie intake, and it decreased to 51.8 micromol/L within a month of taking oral phenobarbital daily. Both functional tests and ultrasonographic images of the liver were normal except for the unconjugated hyperbilirubinemia. A missense mutation of Tyr486Asp at exon 5 in the UGT1A1 gene and a homozygous mutation were confirmed in the proband. Heterozygous mutations were found in his parents, his younger sister and three great-uncles, while no mutation of the UGT1A1 gene was detected in the remaining four family members. CONCLUSION: A missense mutation of Tyr486Asp is considered to be the cause of the CN-II in this patient. It is a recessive trait that is autosomally inherited in this family. No influence of the mutation was found on the response elements for phenobarbital in the promoter region.     

Genetic polymorphisms of the uridine diphosphate glucuronosyltransferase 1A7 and colorectal cancer risk in relation to cigarette smoking and alcohol drinking in a Chinese population

BACKGROUND: The impact of uridine diphosphate glucuronosyltransferase 1A7 (UGT1A7) polymorphisms on genetic susceptibility to digestive system cancer has received close attention since the discovery by Guillemette, the polymorphisms of which may alter enzyme activity. To clarify the allele frequency distribution and its association with risk of colorectal cancer, a population-based case-control study was carried out in Chinese population. METHODS: A total of 140 patients with colorectal cancer and 280 cancer-free frequency-matched controls from a follow-up cohort population established in 1989, were enrolled. For the UGT1A7 polymorphisms analysis, polymerase chain reaction (PCR)-based genotyping techniques including semi-nested PCR, allele-specific PCR and PCR-restriction fragment length polymorphism (RFLP) were developed. RESULTS: The variant allele frequencies in patients and controls were 50.0% and 38.6%, respectively, which were significantly associated with risk of colorectal cancer (odds ratio [OR]: 1.59; 95% confidence interval [CI]: 1.19-2.13). For the variant genotypes analysis, *2/*2 and *3/*3 exhibited a significant association with risk of colorectal cancer (OR: 7.80, 95%CI: 2.66-22.87; OR: 3.47, 95%CI: 1.51-7.97, respectively). Stratification analysis indicated that in previous-current cigarette smoking (cigarette smoking history), current cigarette smoking (current cigarette smoking status), previous-current alcohol drinking (alcohol drinking history) or current alcohol drinking individuals (current alcohol drinking status), the risk developing colorectal cancer increased: OR (95%CI), 2.81 (0.97-8.11), 3.39 (1.19-9.67), 2.89 (0.99-8.46) and 3.14 (1.09-9.09), respectively. CONCLUSIONS: UGT1A7 polymorphisms may have a significant modifying effect on colorectal cancer risk, which may interact with environmental factors, cigarette smoking and alcohol drinking in colorectal carcinogenesis.     

二磷酸尿苷葡萄糖苷转移酶1A7基因多态性与国人结直肠癌的相关性研究

目的探讨二磷酸尿苷葡萄糖苷转移酶(UGT)1A7基因第1外显子3处单核苷酸多态性与国人结直肠癌(CRC)的相关性,及其在我国自然人群中的分布频率。方法采用人群为基础的成组匹配病例对照研究,以半巢式聚合酶链反应(PCR)、等位基因特异PCR和PCR-限制性内切酶片段长度多态性(RFLP)联用分析技术对140例CRC患者和280例正常对照者的UGT1A7基因型进行检测分析。结果CRC患者携带变异等位基因(~*2,~*3,~*4)频率明显高于对照组(50．0%比38．6%,P＜0．01)。CRC患者携带变异纯合基因型频率(28．6%)明显高于对照组(14．3%),差异有统计学意义(P＜0．01)。与野生型相比,变异杂合型及纯合型OR比值增高趋势有统计学意义(X~2=12．15,P＜0．01)。红烧熏炸食品摄入与CRC发病有关,与低摄人量组(≤5．40 kg/年)相比,中(≤14．35kg/年)、高(＞14．35kg/年)摄入量组风险明显增高,在中摄入量组风险增高差异有统计学意义(P＜0．05,OR=1．84,95% CI∶1．09～3．11)。以红烧熏炸、腌制食品摄人以及吸烟、饮酒状况为分层因素,分析UGT1A7基因多态性与CRC发病的相关性,仅在吸烟个体观察到有相关效应,差异有统计学意义(P＜0．05,OR=3．13,95%CI∶1．03～9．52),在饮酒个体观察到的相关效应临界于显著性水平(P=0．05,OR=2．89,95%CI∶0．99～8．46)。结论UGT1A7基因多态性与CRC的发病呈正相关关系,同时与吸烟、饮酒等环境危险因素可能存在一定的协同作用。     

Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects

BACKGROUND AND AIM: Numerous mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with familial unconjugated hyperbilirubinemia. The UGT1A1 mutation appears to be considerably different among ethnic groups. To clarify the incidence of this gene mutation in the Japanese population, the presence of UGT1A1 mutation was investigated in a group of Japanese patients with Crigler-Najjar syndrome type 2 (CNS2) and Gilbert's syndrome (GS), as well as in healthy anicteric subjects. METHODS: Four patients with CNS2, 63 patients with GS, and 71 healthy subjects were enrolled in the study. The promoter and coding regions of UGT1A1 were amplified by polymerase chain reaction (PCR) from genomic DNA isolated from leukocytes. The PCR products were directly sequenced by a dye terminating method. The UGT1A1 enzyme activity was determined in COS7 cells transfected with wild or P364L (1091 C > T) mutant DNA. RESULTS: Homozygous Y486D was observed in all four patients with CNS2. The GS patients had UGT1A1 mutations with 13 different genotypes in the promoter and coding region. Homozygous TA insertion in the TATA box (TA7) of the promoter region (TA7/7; 33%), homozygous G71R (9%), and combination of TA7/6 and heterozygous G71R (17%) were the most frequent findings in GS patients. Homozygous or heterozygous Y486D (8%) and P229Q (8%) were also observed in GS. A novel mutation, heterozygous P364L, was also identified in a GS patient. In addition to GS patients, homozygous or heterozygous TA7, G71R, and heterozygous Y486D were also observed in healthy subjects. The allele frequency of G71R and TA7 was 0.183 and 0.113 in healthy subjects, respectively. The P364L UGT1A1 enzyme activity was 64.4% lower than the wild-type enzyme activity. CONCLUSIONS: Polymorphisms in the coding region of UGT1A1 were commonly observed in Japanese patients with GS and in healthy subjects. The genetic basis of hyperbilirubinemia appears to be different between the Japanese and Caucasian populations.