Kalluri R, van den Heuvel L P, Smeets H J, Schroder C H, Lemmink H H, Boutaud A, Neilson E G, Hudson B G
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, USA.
Kidney Int. 1995 Apr;47(4):1199-204. doi: 10.1038/ki.1995.170.
The X-linked Alport syndrome is associated with mutations and deletions in COL4A5 gene, one of six genes which constitute the alpha-chains of type IV collagen in basement membranes. The autosomal recessive form of Alport syndrome is characterized by mutations and deletions in the COL4A3 and COL4A4 genes. A fraction of Alport patients who undergo renal transplantation develop anti-glomerular basement membrane (GBM) nephritis, which results in loss of the renal allograft function. Recently, the target for alloantibodies from an X-linked Alport patient with complete COL4A5 gene deletion was determined to be the alpha 3 chain of type IV collagen. The present study characterized the post-transplant alloantibodies from an autosomal recessive Alport patient with anti-GBM glomerulonephritis and a COL4A3 gene mutation which predicted a loss of 85% of the alpha 3(IV) NC1 domain. The specificity of these new antibodies were studied using glomerular basement membrane constituents and recombinant type IV collagen domains. The results establish the target for the alloantibodies from an autosomal recessive Alport patient with COL4A3 deletion as principally the alpha 3(IV) collagen chain, similar to the post-transplant alloantibodies from X-linked Alport patients with COL4A5 gene deletions. The absence of alpha 3(IV) chain in the GBM of patients with both these forms of Alport syndrome, due either to a failure of synthesis or a failure of assembly, presumably leads to a loss of immunologic tolerance for the alpha 3(IV) NC1 domain in transplanted allografts.
X连锁遗传性Alport综合征与COL4A5基因突变和缺失有关，COL4A5基因是构成基底膜IV型胶原α链的六个基因之一。常染色体隐性遗传型Alport综合征的特征是COL4A3和COL4A4基因突变和缺失。一部分接受肾移植的Alport患者会发生抗肾小球基底膜（GBM）肾炎，导致移植肾失去功能。最近，一名完全缺失COL4A5基因的X连锁遗传性Alport患者的同种异体抗体靶抗原被确定为IV型胶原的α3链。本研究对一名患有抗GBM肾小球肾炎且COL4A3基因突变（预计α3(IV)NC1结构域缺失85%）的常染色体隐性遗传型Alport患者的移植后同种异体抗体进行了特征分析。使用肾小球基底膜成分和重组IV型胶原结构域研究了这些新抗体的特异性。结果表明，一名COL4A3基因缺失的常染色体隐性遗传型Alport患者的同种异体抗体靶抗原主要是α3(IV)胶原链，这与COL4A5基因缺失的X连锁遗传性Alport患者移植后的同种异体抗体相似。这两种形式的Alport综合征患者的GBM中缺乏α3(IV)链，可能是由于合成失败或组装失败，大概导致了移植同种异体肾中对α3(IV)NC1结构域免疫耐受的丧失。
