Mice deficient in α-actinin-4 have severe glomerular disease
Mice deficient in α-actinin-4 have severe glomerular disease
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DOI：
10.1172/jci200317988
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发表时间：
2003-06-01
影响因子：
15.9
通讯作者：
Pollak, MR
中科院分区：
文献类型：
--
作者：
Kos, CH;Le, TC;Pollak, MR
编码α -肌动蛋白-4的ACTN4基因的显性遗传突变可导致一种人类局灶性和节段性肾小球硬化（FSGS）。通过ES细胞的同源重组，我们建立了Actn4缺失的小鼠模型。靶等位基因纯合子的小鼠没有检测到α -肌动蛋白-4蛋白的表达。在孟德尔遗传下观察到的纯合子小鼠数量低于预期。靶等位基因纯合子的存活小鼠表现为进行性蛋白尿、肾小球疾病，通常在几个月大时死亡。光镜分析显示广泛的肾小球疾病和蛋白样铸型。电镜检查显示幼鼠足细胞足突消失的病灶区域，老年小鼠足细胞形态弥漫性消失和整体破坏。尽管α -肌动素-4广泛分布，但小鼠的组织学检查仅在肾脏中显示异常。与actn4相关的FSGS显性遗传的人类形式相反，在这里，我们发现α -肌动蛋白4的缺失导致小鼠隐性形式的疾病。通过淋巴细胞趋化性测定，细胞运动性在缺乏a-actin -4的情况下增加。我们得出结论，α -肌动蛋白-4是正常肾小球功能所必需的。我们进一步得出结论，α -肌动蛋白的非肌动蛋白形式（α -肌动蛋白-1和α -肌动蛋白-4）在功能上不是冗余的。此外，这些遗传学研究表明，非肌聚体α -肌动蛋白4参与细胞运动的调节。
Dominantly inherited mutations in ACTN4, which encodes alpha-actinin-4, cause a form of human focal and segmental glomerulosclerosis (FSGS). By homologous recombination in ES cells, we developed a mouse model deficient in Actn4. Mice homozygous for the targeted allele have no detectable alpha-actinin-4 protein expression. The number of homozygous mice observed was lower than expected under mendelian inheritance. Surviving mice homozygous for the targeted allele show progressive proteinuria, glomerular disease, and typically death by several months of age. Light microscopic analysis shows extensive glomerular disease and proteinaceous casts. Electron microscopic examination shows focal areas of podocyte foot-process effacement in young mice, and diffuse effacement and globally disrupted podocyte morphology in older mice. Despite the widespread distribution of alpha-actinin-4, histologic examination of mice showed abnormalities only in the kidneys. In contrast to the dominantly inherited human form of ACTN4-associated FSGS, here we show that the absence of alpha-actinin-4 causes a recessive form of disease in mice. Cell motility, as measured by lymphocyte chemotaxis assays, was increased in the absence of a-actinin-4. We conclude that alpha-actinin-4 is required for normal glomerular function. We further conclude that the nonsarcomeric forms of alpha-actinin (alpha-actinin-1 and alpha-actinin-4) are not functionally redundant. In addition, these genetic studies demonstrate that the nonsarcomeric alpha-actinin-4 is involved in the regulation of cell movement.