Resistance genes to collagen disease in a wild mice-derived inbred strain MSM/Ms

本研究试图阐明野生小鼠衍生的近交菌株MSM/Ms对MRL/Mp-lpr/lpr （MRL- fas ^<lpr>）狼疮小鼠肾小球肾炎的多基因遗传抗性，从而了解狼疮肾炎发展的控制步骤。利用MRL-Fas^<lpr> x (MRL-Fas^<lpr> x MSM/Ms) F1回交小鼠，对显性遗传形式的肾小球肾炎耐药位点进行全基因组扫描。3个MSM/Ms抗性优势位点分别位于染色体2、13和4上。Agnmrl位点的候选基因之一是Cd59a，它编码一种糖基磷脂酰肌醇锚定的糖蛋白，抑制补体的膜攻击复合物。MSM/Ms患者肾小球中Cd59a的表达高于MRL-Fas^<lpr>。Cd59a启动子区的转录活性在亲本系小鼠之间存在差异。然后，新建立了小鼠MRL-Fas^<lpr>-Cd59a^<MSM>重组基因株，其肾小球肾炎和肾血管炎的严重程度均明显降低。

This study attempted to elucidate the polygenic genetic resistance of a wild mice-derived inbred strain MSM/Ms, having a larger gene pools than commonly used laboratory mouse strains, to glomerulonephritis in an MRL/Mp-lpr/lpr (MRL-Fas^<lpr>) lupus strain of mice and thereby to understand the steps controlling development of lupus nephritis. A genome wide scan for glomerulonephritis resistance loci in a dominant inheritance form was carried out by using MRL-Fas^<lpr> x (MRL-Fas^<lpr> x MSM/Ms) F1 backcross mice. Three dominant MSM/Ms resistance loci were mapped on chromosomes 2, 13 and 4. One of the candidate genes for the locus Agnmrl was Cd59a, encoding an glycosyl phosphatidylinositol-anchored glycoprotein inhibiting the membrane attack complex of complement. Expression of Cd59a in the glomeruli was higher in MSM/Ms than in MRL-Fas^<lpr>. Different transcriptional activity of the Cd59a promoter region was observed between the parental strains of mice. Then, the recombinant congenic strain of mice MRL-Fas^<lpr>-Cd59a^<MSM> was newly established, which was significantly decreased in severity of glomerulonephritis and also renal vasculitis.