Department of Immunology, Genetics, and Pathology, Uppsala University, 751 85 Uppsala, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden.
Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Am J Hum Genet. 2015 Jan 8;96(1):153-61. doi: 10.1016/j.ajhg.2014.11.014. Epub 2014 Dec 31.
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.
肾病综合征（NS）是大量蛋白尿、低白蛋白血症、水肿和高脂血症的联合表现，临床上可分为激素敏感型（SSNS）和激素抵抗型（SRNS）。SRNS 常进展为终末期肾衰竭。通过纯合子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发现了 Crumb 同源物 2（CRB2）的隐性突变。此前，我们确定了斑马鱼 crb2b 在足细胞形态发生中的上皮极性保守调节因子的作用。通过对斑马鱼 crb2b 功能丧失突变的特征描述，我们现在表明斑马鱼 crb2b 是足细胞足突分支、裂孔隔膜形成和nephrin 正确运输所必需的。此外，通过在斑马鱼中的互补实验，我们证明 CRB2 突变导致功能丧失，因此构成导致人类 NS 的致病突变。这些结果表明足细胞顶底极性缺陷在 NS 的发病机制中起作用。
