Kalluri R, Weber M, Netzer K O, Sun M J, Neilson E G, Hudson B G
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City.
Kidney Int. 1994 Mar;45(3):721-6. doi: 10.1038/ki.1994.96.
Mutations in the COL4A5 gene encoding the alpha 5(IV) chain of type IV collagen have been implicated as the primary defect in X-linked Alport syndrome. Several kinds of mutations have been reported so far, spanning point mutations to complete gene deletions. About 5% of Alport patients, who undergo renal transplantation, develop anti-glomerular basement membrane (GBM) nephritis, causing loss of allograft function. In one such patient, COL4A5 gene deletion was recently identified. In the present study, the GBM constituent, targeted by the anti-GBM alloantibodies from the patient who had complete COL4A5 gene deletion was identified. Its identity was determined on the basis of circulating antibody binding to various GBM constituents, domains of bovine type IV collagen and recombinant NC1 domain of human type IV collagen. These results establish, for the first time, the absence of the alpha 5(IV) chain in Alport GBM and, in the same patient, the production of an alloantibody that is targeted to a different chain of type IV collagen, the alpha 3(IV) chain. These findings provide further support for the hypothesis that: (1) anti-alpha 3(IV) collagen alloantibodies mediate the allograft glomerulonephritis; and (2) COL4A5 gene mutations cause defective assembly of the alpha 3(IV) collagen alloantibodies mediate the allograft glomerulonephritis; and (2) COL4A5 gene mutations cause defective assembly of the alpha 3(IV) chain in Alport GBM, as reflected by the production of anti-alpha 3(IV) alloantibodies.
编码IV型胶原α5(IV)链的COL4A5基因突变被认为是X连锁Alport综合征的主要缺陷。迄今为止已报道了几种类型的突变，范围从点突变到整个基因缺失。约5%接受肾移植的Alport患者会发生抗肾小球基底膜（GBM）肾炎，导致移植肾功能丧失。在其中一名此类患者中，最近发现了COL4A5基因缺失。在本研究中，确定了来自完全缺失COL4A5基因患者的抗GBM同种抗体所靶向的GBM成分。根据循环抗体与各种GBM成分、牛IV型胶原结构域和人IV型胶原重组NC1结构域的结合情况确定了其身份。这些结果首次证实Alport GBM中不存在α5(IV)链，且在同一患者中产生了靶向IV型胶原不同链即α3(IV)链的同种抗体。这些发现为以下假说提供了进一步支持：（1）抗α3(IV)胶原同种抗体介导移植肾肾小球肾炎；（2）COL4A5基因突变导致Alport GBM中α3(IV)链组装缺陷，这通过抗α3(IV)同种抗体的产生得以体现。
