Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CMAP, Fyn, and synaptopodin
Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CMAP, Fyn, and synaptopodin
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DOI：
10.1172/jci27400
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发表时间：
2006-05-01
影响因子：
15.9
通讯作者：
Shaw, AS
中科院分区：
文献类型：
--
作者：
Huber, TB;Kwoh, C;Shaw, AS
局灶节段性肾小球硬化症（FSGS）是导致终末期肾病的最常见的原发性肾小球诊断。多种足细胞蛋白的缺陷与 FSGS 的病因有关，包括足细胞蛋白、α-肌动蛋白-4、CD2 相关蛋白 (CD2AP) 和 TRPC6。尽管我们对局灶节段性硬化症发病机制的基因了解不断加深，但绝大多数患有这种疾病的患者，即使是那些有家族联系的患者，也缺乏明确的基因诊断。在这里，我们测试了单独不会导致临床肾脏疾病的遗传杂合性（双基因杂合性）的组合是否可以共同作用以增强对肾小球损伤和 FSGS 的易感性。 Cd2ap 杂合性和突触足蛋白 (Synpo) 或 Fyn 原癌基因 (Fyn) 杂合性的组合，但不包括 IRRE 类似 1 (Neph1) 的亲属，导致自发性蛋白尿和 FSGS 样肾小球损伤。这些遗传相互作用也反映在功能水平上，因为我们发现 CD2AP 与 Fyn 和 Synpo 相关，但与 Neph1 不相关。这表明双基因杂合性可导致 FSGS，并表明 2 个或多个足细胞基因的组合突变可能是肾小球疾病的常见病因。
Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular diagnosis resulting in end-stage renal disease. Defects in several podocyte proteins have been implicated in the etiology of FSGS, including podocin, alpha-actinin-4, CD2-associated protein (CD2AP), and TRPC6. Despite our growing understanding of genes involved in the pathogenesis of focal segmental sclerosis, the vast majority of patients with this disease, even those with a familial linkage, lack a clear genetic diagnosis. Here, we tested whether combinations of genetic heterozygosity (bigenic heterozygosity) that alone do not result in clinical kidney disease could function together to enhance susceptibility to glomerular damage and FSGS. Combinations of Cd2ap heterozygosity and heterozygosity of either synaptopodin (Synpo) or Fyn proto-oncogene (Fyn) but not kin of IRRE like 1 (Neph1) resulted in spontaneous proteinuria and in FSGS-like glomerular damage. These genetic interactions were also reflected at a functional level, as we found that CD2AP associates with Fyn and Synpo but not with Neph1. This demonstrates that bigenic heterozygosity can lead to FSGS and suggests that combined mutations in 2 or multiple podocyte genes may be a common etiology for glomerular disease.