Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome
Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome
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DOI：
10.1016/j.ajhg.2014.11.014
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发表时间：
2015-01-08
影响因子：
9.8
通讯作者：
Majumdar, Arindam
中科院分区：
文献类型：
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作者：
Ebarasi, Lwaki;Ashraf, Shazia;Majumdar, Arindam
肾病综合征（NS）是由大量蛋白尿、低白蛋白血症、水肿和高脂血症引起的，临床上可分为类固醇敏感型（SSNS）和类固醇抵抗型（SRNS）。 SRNS 通常进展为终末期肾衰竭。通过纯合性作图和全外显子组测序，我们在受 SRNS 影响的四个不同家族中鉴定了 Crumbs 同源物 2 (CRB2) 的隐性突变。此前，我们确定了斑马鱼 crb2b（一种上皮极性的保守调节因子）在足细胞形态发生中的需求。通过对斑马鱼 crb2b 功能丧失突变的表征，我们现在表明斑马鱼 crb2b 是足细胞足突树枝化、裂隙隔膜形成和适当的去氧肾上腺素运输所必需的。此外，通过斑马鱼的互补实验，我们证明 CRB2 突变会导致功能丧失，因此构成导致人类 NS 的致病突变。这些结果表明 NS 发病机制中足细胞顶端-基底极性的缺陷。
Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.