COL4A6 is dispensable for autosomal recessive Alport syndrome.
COL4A6 is dispensable for autosomal recessive Alport syndrome.
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DOI：
10.1038/srep29450
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发表时间：
2016-07-05
影响因子：
4.6
通讯作者：
Ito M
中科院分区：
文献类型：
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作者：
Murata T;Katayama K;Oohashi T;Jahnukainen T;Yonezawa T;Sado Y;Ishikawa E;Nomura S;Tryggvason K;Ito M
Alport综合征由编码α3、α4或α5（IV）链的基因突变引起。与X连锁Alport小鼠不同，在常染色体隐性Alport小鼠的肾小球基底膜中检测到α5和α6（IV）链，然而，该发现的意义仍有待研究。因此，我们产生了缺乏α3和α6（IV）链的小鼠，并将其肾功能和存活率与129 × 1/Sv背景的Col 4a 3敲除小鼠进行了比较。在两组的肾功能或存活率方面，或当小鼠与C57 BL/6背景回交一次时，未观察到显著差异。但回交双基因敲除小鼠的存活时间明显长于129 × 1/Sv背景的小鼠，这表明其他修饰基因参与了这一现象。在进一步的研究中，我们确定了两名Alport患者，他们在COL 4A 4的内含子46中有纯合突变。α5和α6（IV）链在这些患者的肾小球基底膜中检测到局灶性。这些结果表明，虽然α5和α6（IV）链在常染色体隐性遗传性Alport综合征的肾小球基底膜中被诱导，但它们的诱导似乎并不起主要的代偿作用。
Alport syndrome is caused by mutations in the genes encoding α3, α4, or α5 (IV) chains. Unlike X-linked Alport mice, α5 and α6 (IV) chains are detected in the glomerular basement membrane of autosomal recessive Alport mice, however, the significance of this finding remains to be investigated. We therefore generated mice lacking both α3 and α6 (IV) chains and compared their renal function and survival with Col4a3 knockout mice of 129 × 1/Sv background. No significant difference was observed in the renal function or survival of the two groups, or when the mice were backcrossed once to C57BL/6 background. However, the survival of backcrossed double knockout mice was significantly longer than that of the mice of 129 × 1/Sv background, which suggests that other modifier genes were involved in this phenomenon. In further studies we identified two Alport patients who had a homozygous mutation in intron 46 of COL4A4. The α5 and α6 (IV) chains were focally detected in the glomerular basement membrane of these patients. These findings indicate that although α5 and α6 (IV) chains are induced in the glomerular basement membrane in autosomal recessive Alport syndrome, their induction does not seem to play a major compensatory role.