A Homozygous Missense Mutation in the Ciliary Gene TTC21B Causes Familial FSGS
A Homozygous Missense Mutation in the Ciliary Gene TTC21B Causes Familial FSGS
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DOI：
10.1681/asn.2013101126
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发表时间：
2014-11-01
影响因子：
13.6
通讯作者：
Antignac, Corinne
中科院分区：
文献类型：
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作者：
Cong, Evelyne Huynh;Bizet, Albane A.;Antignac, Corinne
几个基因，主要参与足细胞骨架的调节，已牵连在家族形式的原发性FSGS。我们在7个FSGS家系中发现了TTC21B基因的纯合错义突变（p.P209L）。这种纤毛基因的突变以前被报道会引起肾单位萎缩，一种慢性肾小管间质性肾病。值得注意的是，肾小管基底膜增厚，使人想起在肾单位结核中观察到的存在于FSGS和p.P209L突变的患者。我们证明了TTC21 B基因产物IFFT 139，鞭毛内转运蛋白A组分，主要定位于从人胎儿组织和未分化的培养足细胞中发育足细胞的初级纤毛的基部。相反，在无纤毛的成体足细胞和分化的培养细胞中，IFFT 139沿着延伸的微管网络重新定位。我们进一步表明，敲低足细胞中的IFFT 139导致初级纤毛缺陷、异常细胞迁移和细胞骨架改变，这可以通过p.P209L过表达部分挽救，表明其亚形态效应。我们的研究结果表明，纤毛基因参与肾小球疾病，并指出一个关键功能的足细胞中的IFFT 139。总之，这些数据表明，这种纯合子TTC21B p.P209L突变导致一种新的遗传性肾脏疾病，肾小球和肾小管间质损害。
Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS. Mutations in this ciliary gene were previously reported to cause nephronophthisis, a chronic tubulointerstitial nephropathy. Notably, tubular basement membrane thickening reminiscent of that observed in nephronophthisis was present in patients with FSGS and the p.P209L mutation. We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. In contrast, in nonciliated adult podocytes and differentiated cultured cells, IFT139 relocalized along the extended microtubule network. We further showed that knockdown of IFT139 in podocytes leads to primary cilia defects, abnormal cell migration, and cytoskeleton alterations, which can be partially rescued by p.P209L overexpression, indicating its hypomorphic effect. Our results demonstrate the involvement of a ciliary gene in a glomerular disorder and point to a critical function of IFT139 in podocytes. Altogether, these data suggest that this homozygous TTC21B p.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages.