Caridi Gianluca, Bertelli Roberta, Di Duca Marco, Dagnino Monica, Emma Francesco, Onetti Muda Andrea, Scolari Francesco, Miglietti Nunzia, Mazzucco Gianna, Murer Luisa, Carrea Alba, Massella Laura, Rizzoni Gianfranco, Perfumo Francesco, Ghiggeri Gian Marco
Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, 16148 Genoa, Italy.
J Am Soc Nephrol. 2003 May;14(5):1278-86. doi: 10.1097/01.asn.0000060578.79050.e0.
A total of 179 children with sporadic nephrotic syndrome were screened for podocin mutations: 120 with steroid resistance, and 59 with steroid dependence/frequent relapses. Fourteen steroid-resistant patients presented homozygous mutations that were associated with early onset of proteinuria and variable renal lesions, including one case with mesangial C3 deposition. Single mutations of podocin were found in four steroid-resistant and in four steroid-dependent; five patients had the same mutation (P20L). Among these, two had steroid/cyclosporin resistance, two had steroid dependence, and one responded to cyclosporin. The common variant R229Q of podocin, recently associated with late-onset focal segmental glomerulosclerosis, had an overall allelic frequency of 4.2% versus 2.5% in controls. To further define the implication of R229Q, a familial case was characterized with two nephrotic siblings presenting the association of the R229Q with A297V mutation that were inherited from healthy mother and father, respectively. Immunohistochemistry with anti-podocin antibodies revealed markedly decreased expression of the protein in their kidneys. All carriers of heterozygous coding podocin mutation or R229Q were screened for nephrin mutation that was found in heterozygosity associated with R229Q in one patient. Finally, podocin loss of heterozygosity was excluded in one heterozygous child by characterizing cDNA from dissected glomeruli. These data outline the clinical features of sporadic nephrotic syndrome due to podocin mutations (homozygous and heterozygous) in a representative population with broad phenotype, including patients with good response to drugs. The pathogenetic implication of single podocin defects per se in proteinuria must be further investigated in view of the possibility that detection of a second mutation could have been missed. A suggested alternative is the involvement of other gene(s) or factor(s).
共对179例散发性肾病综合征患儿进行了足突蛋白突变筛查：其中120例为激素抵抗型，59例为激素依赖/频繁复发型。14例激素抵抗型患者出现纯合突变，这些突变与蛋白尿的早期发作及多样的肾脏病变相关，其中1例伴有系膜C3沉积。在4例激素抵抗型和4例激素依赖型患者中发现了足突蛋白的单突变；5例患者具有相同的突变（P20L）。其中，2例对激素/环孢素耐药，2例为激素依赖型，1例对环孢素有效。足突蛋白的常见变异体R229Q最近与迟发性局灶节段性肾小球硬化相关，其总体等位基因频率在患者中为4.2%，而在对照组中为2.5%。为进一步明确R229Q的影响，对一个家族病例进行了特征分析，该家族中有两名肾病患儿，分别从健康的父母那里遗传了R229Q与A297V突变的组合。用抗足突蛋白抗体进行免疫组化显示，他们肾脏中该蛋白的表达明显降低。对所有携带杂合性编码足突蛋白突变或R229Q的患者进行了nephrin突变筛查，在1例患者中发现nephrin突变与R229Q杂合存在。最后，通过对分离的肾小球cDNA进行特征分析，排除了1例杂合子患儿的足突蛋白杂合性缺失。这些数据概述了在具有广泛表型的代表性人群中，由足突蛋白突变（纯合和杂合）导致的散发性肾病综合征的临床特征，包括对药物反应良好的患者。鉴于可能漏检了第二个突变，单个足突蛋白缺陷本身在蛋白尿发病机制中的影响必须进一步研究。一种可能的替代解释是其他基因或因素的参与。
