Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus.
Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus.
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DOI：
10.1038/gene.2009.10
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发表时间：
2009-07
影响因子：
5
通讯作者：
Yu, C. Y.
中科院分区：
文献类型：
--
作者：
Wu, Y. L.;Hauptmann, G.;Viguier, M.;Yu, C. Y.
关键词：
补体C4完全缺乏是人类SLE最强的遗传危险因素之一。C4是HLA中RP-C4-CYP 21-TNX（RCCX）模块的组成部分，表现出个体间拷贝数和基因大小的差异。在这里，我们研究了两个北非家庭完全C4缺乏症和SLE。第一组包括一名摩洛哥男性SLE患者（1 P）和一名同胞，他们都是HLA-A*02 B*17 DRB 1 *07纯合子。第二例为阿尔及利亚女性SLE患者（2 P），HLA-A*01 B*17 DRB 1 *13纯合子。SLE发病早、出现光敏性皮疹、抗Ro/SSA抗体和肾脏疾病是C4完全缺乏的常见特征。Southern印迹分析显示，1 P具有长C4 A的单模块RCCX;而2 P具有长C4 A和短C4 B的双模块RCCX。对这些突变基因的基因组DNA片段进行扩增和测序。在1 P中发现了一个C>T转换，导致C4 A中的R540 X无义突变。在2 P的C4 A和C4 B中发现了一个相同的4-bp插入，产生移码和Y1537 X无义突变。在非DR 3和非DR 2单倍型患者中，SLE和完全C4缺乏的高度一致性强调了C4蛋白在预防SLE中的重要性。
Complete deficiency of complement C4 is among the strongest genetic risk factors for human SLE. C4 is a constituent of the RP-C4-CYP21-TNX (RCCX) module in the HLA that exhibits inter-individual copy-number and gene-size variations. Here we studied two North-African families with complete C4 deficiency and SLE. The first included a Moroccan male SLE patient (1P) and a sibling who were both homozygous for HLA-A*02 B*17 DRB1*07. The second had an Algerian female SLE patient (2P) homozygous for HLA-A*01 B*17 DRB1*13. Early SLE disease onset, the presence of photosensitive rashes, anti-Ro/SSA and renal disease were common features of complete C4 deficiency. Southern blot analyses revealed that 1P had monomodular-RCCX with a long C4A; while 2P had bimodular-RCCX with one long C4A and one short C4B. Genomic DNA fragments for these mutant genes were amplified and sequenced. A C>T transition that created the R540X nonsense mutation in C4A was found in 1P. An identical 4-bp insertion that generated frameshift and the Y1537X nonsense mutation was discovered in both C4A and C4B of 2P. The high concordance of SLE and complete C4 deficiency among patients with non-DR3 and non-DR2 haplotypes underscores the importance of C4 proteins in the protection against SLE.
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