Broadening the spectrum of diseases related to podocin mutations
Broadening the spectrum of diseases related to podocin mutations
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DOI：
10.1097/01.asn.0000060578.79050.e0
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发表时间：
2003-05-01
影响因子：
13.6
通讯作者：
Ghiggeri, GM
中科院分区：
文献类型：
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作者：
Caridi, G;Bertelli, R;Ghiggeri, GM
共有179名散发性肾病综合征儿童接受了podocin突变筛查：120名类固醇耐药，59名类固醇依赖/频繁复发。14例类固醇耐药患者出现了与蛋白尿早期发作和可变肾脏病变相关的纯合子突变，包括1例系膜C3沉积。在4例类固醇耐药和4例类固醇依赖患者中发现了podocin的单突变; 5例患者有相同的突变（P20 L）。其中，两个有类固醇/环孢菌素耐药，两个有类固醇依赖，一个对环孢菌素有反应。podocin的常见变体R229 Q最近与晚发性局灶节段性肾小球硬化症相关，其总体等位基因频率为4.2%，而对照组为2.5%。为了进一步确定R229 Q的含义，一个家族性病例的特征是两个肾病兄弟姐妹呈现R229 Q与A297 V突变的关联，分别从健康的母亲和父亲遗传。抗podocin抗体的免疫组织化学显示，在他们的肾脏蛋白质的表达显着下降。所有携带杂合编码podocin突变或R229 Q的携带者都筛查了nephrin突变，该突变在1例患者中与R229 Q相关的杂合性中发现。最后，podocin的杂合性丢失被排除在一个杂合子的孩子，从解剖肾小球的cDNA特征。这些数据概述了广泛表型的代表性人群（包括对药物反应良好的患者）中podocin突变（纯合子和杂合子）引起的散发性肾病综合征的临床特征。考虑到第二个突变的检测可能被遗漏，蛋白尿中单个podocin缺陷本身的致病意义必须进一步研究。一种建议的替代方法是其他基因或因子的参与。
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).