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Blau综合征患者NOD2基因突变及临床特点分析

Mutations of NOD2 gene and clinical features in Chinese Blau syndrome patients

摘要:

目的 通过对临床疑似Blau综合征(BS)患儿进行NOD2基因分析以确诊,了解BS的基因突变类型及临床特点,并试图寻找区分BS的临床指征.方法 2006-2014年于北京协和医院就诊的18例BS临床疑似患儿,其中男7例、女11例,就诊年龄1岁8个月~9岁6个月.取患儿及父母抗凝外周血4 ml,常规提取DNA,对NOD2基因进行PCR扩增,2%凝胶电泳分离PCR产物,纯化,测序.对于新发现错义突变,应用SIFT软件分析其致病性,并对50名健康对照进行测序验证.进而分析基因确诊的BS组患儿临床资料,并与未发现突变的非BS组进行比较.x2检验进行组间比较.结果 (1)12例患儿经基因诊断确诊为BS,其余6例被除外.共发现7种错义突变,4种为已报道突变:c.1000C >T,p.Arg 334Trp;c.1001G> A,p.Arg334Gln;c.1538T>C,p.Met513Thr;c.1759C>T,p.Arg587Cys.3种为新突变c.1147 G>C,p.Glu383Gln;c.1471A >T,p.Met491 Leu;c.2006A>G,p.His669Arg.(2)12例基因确诊BS患儿均有关节炎表现并伴多关节周围的囊肿,囊肿无压痛,有波动感.7例患儿具有典型的皮疹、虹膜睫状体炎及关节炎三联征症状;3例无皮疹;1例无眼部症状;1例仅表现为关节炎及关节周围囊肿而无其他症状.4例患儿有家族史,为经父遗传.(3)基因确诊的BS患儿全部有沿关节周围的多发囊肿,基本无反复发热出现,多数不伴有C反应蛋白(CRP)升高;而无突变患儿少见关节囊肿,多数有反复发热,全部出现CRP升高;两组比较,差异均有统计学意义(P均<0.05).结论 共确诊12例BS患儿,检测到7种致病突变,3种为新突变,为人类的基因突变库增添了新的成员.虽然三联征为BS的典型症状,但并非所有患者三种症状都出现.关节炎及多关节周围囊肿是BS的常见表现.BS全部具有沿关节周围囊肿,通常不伴有反复发热,CRP多数不升高;或许可作为临床区分BS的指征.

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abstracts:

Objective Blau syndrome (BS),an autosomal dominant inherited autoinflammatory disease,is caused by NOD2 mutations.This study aimed to analyze NOD2 gene of suspected BS patients to make definite diagnosis,find NOD2 mutation types and clinical features of Chinese BS cases,and find some clinical indications to identify BS by comparing BS and non-BS cases.Method Eighteen suspected BS children (7 boys and 11 girls,age of first visit was from 1 y 8 m to 9 y 6 m) who visited Peking Union Medical College Hospital from 2006 to 2014 and their parents's DNA were extracted from 4 ml blood specimens.PCR was performed for exon 4 of NOD2 and PCR products were purified by 2% gel electrophoresis and sequenced directly.Role of novel missense mutations in pathogenicity was analyzed by SIFT and sequencing NOD2 of fifty normal controls.Clinical data of BS children diagnosed by NOD2 analysis were summarized and compared with the data of non-BS group.Result (1) Twelve of eighteen suspected BS children were diagnosed as BS by NOD2 analysis,and the remaining 6 were excluded.Seven missense mutations were detected,4 were reported before:c.1000C > T,p.Arg 334Trp; c.1001G > A,p.Arg334Gln;c.1538T > C,p.Met513Thr;c.1759C > T,p.Arg587Cys.Three novel mutations were found:c.1147 G >C,p.Glu383Gln; c.1471A >T,p.Met491Leu; c.2006A >G,p.His669Arg.(2) Chronic symmetric arthritis and multi-joints periarticular hydatoncus,which were painless with fluctuation,were found in all 12 BS children with NOD2 mutations.Skin rash,chronic symmetric arthritis,and recurrent uveitis were identified in 7 patients.Three patients had no skin rash,while 1 had no uveitis,1 only had symmetric arthritis and multi-joints periarticular hydatoncus.Four children inherited the disease from father.(3) Compared with other 6 non-BS children,BS children had such different clinical characteristic (P < 0.05):All the BS cases had multiple periarticular hydatoncus,which always had no persistent fever,most had no elevated CRP,while non-BS group always had no hydatoncus,most had persistent fever,all had elevated CRP.Conclusion The 12 BS children were diagnosed by NOD2 analysis; 7 missense mutations were detected,3 were novel mutations,adding new findings to human NOD2 mutations.Although classic BS was characterized by skin rash,arthritis,and eye involvement,some presented with less than 3 of the classic features.Chronic symmetric arthritis and multi-joints periarticular hydatoncus were the most comment fetures.Comparing with non-BS group,all BS cases had multi hydatoncus surrounding multi-joints,always had no persistent fever,most had no elevated CRP.Those features may distinguish BS in clinical settings.

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作者: 王薇 [1] 魏珉 [1] 宋红梅 [1] 邱正庆 [1]
期刊: 《中华儿科杂志》2014年52卷12期 896-901页 MEDLINEISTICPKUCSCD
栏目名称: 免疫疾病研究
DOI: 10.3760/cma.j.issn.0578-1310.2014.12.004
发布时间: 2015-01-07
基金项目:
2014年度公益性行业科研专项
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