The molecular basis of complete complement C4A and C4B deficiencies in a systemic lupus erythematosus patient with homozygous C4A and C4B mutant genes
The molecular basis of complete complement C4A and C4B deficiencies in a systemic lupus erythematosus patient with homozygous C4A and C4B mutant genes
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DOI：
10.4049/jimmunol.169.3.1570
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发表时间：
2002-08-01
影响因子：
4.4
通讯作者：
Yu, CY
中科院分区：
文献类型：
--
作者：
Rupert, KL;Moulds, JM;Yu, CY
对美国一名完全缺乏 C4 的患者的病程进行了长达 18 年的跟踪调查。该患者经历了多次感染，9岁时被诊断出患有系统性红斑狼疮。 23 岁时，该疾病进展为 WHO III 级轻度狼疮性肾炎，并发展为致命的中枢神经系统血管炎。免疫化学实验显示，患者及其兄弟姐妹完全缺乏C4A和C4B蛋白，并且Rodgers和Chido血型Ags呈阴性。分离和最终的 RFLP 分析表明，患者和他的兄弟姐妹遗传了两个相同的单倍型：HLA A2 B12 DR6，每个单倍型都携带有缺陷的长 C4A 基因和有缺陷的短 C4B 基因。 PCR 和 DNA 测序显示，突变体 C4A 在外显子 29 密码子 1213 序列处包含 2 bp 插入。突变体 C4B 中不存在相同的突变。通过长距离PCR选择性扩增C4B突变基因，并对其41个外显子进行了完整测序。 C4B 突变体在外显子 13 的密码子 522 序列处有一个新的单 C 核苷酸缺失，导致移码突变和过早终止。因此，设计了多重PCR，通过它可以方便地阐明C4A和C4B中的已知突变。在 28 名报告完全缺乏 C4 的个体中，75-96% 的受试者（取决于纳入标准）患有自身免疫或免疫复合物疾病。因此，C4 完全缺乏是人类系统性红斑狼疮最常见的遗传危险因素之一。
The disease course of a complete C4-deficient patient in the U.S. was followed for 18 years. The patient experienced multiple episodes of infection, and he was diagnosed with systemic lupus erythematosus at age 9 years. The disease progressed to WHO class III mild lupus nephritis and to fatal CNS vasculitis at age 23 years. Immunochemical experiments showed that the patient and his sibling had complete absence of C4A and C4B proteins and were negative for the Rodgers and Chido blood group Ags. Segregation and definitive RFLP analyses demonstrated that the patient and his sibling inherited two identical haplotypes, HLA A2 B12 DR6, each of which carries a defective long C4A gene and a defective short C4B gene. PCR and DNA sequencing revealed that the mutant C4A contained a 2-bp insertion in exon 29 at the sequence for codon 1213. The identical mutation was absent in the mutant C4B. The C4B mutant gene was selectively amplified by long range PCR, and its 41 exons were completely sequenced. The C4B mutant had a novel single C nucleotide deletion at the sequence for codon 522 in exon 13, leading to frame-shift mutation and premature termination. Thus, a multiplex PCR is designed by which known mutations in C4A and C4B can be elucidated conveniently. Among the 28 individuals reported with complete C4 deficiency, 75-96% of the subjects (dependent on the inclusion criteria) were afflicted with autoimmune or immune complex disorders. Hence, complete C4 deficiency is one of the most penetrant genetic risk factors for human systemic lupus erythematosus.