Caridi Gianluca, Bertelli Roberta, Carrea Alba, Di Duca Marco, Catarsi Paolo, Artero Mary, Carraro Michele, Zennaro Cristina, Candiano Giovanni, Musante Luca, Seri Marco, Ginevri Fabrizio, Perfumo Francesco, Ghiggeri Gian Marco
*Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
J Am Soc Nephrol. 2001 Dec;12(12):2742-2746. doi: 10.1681/ASN.V12122742.
Podocin mutations (NPHS2 gene) are responsible for the autosomal recessive form of steroid-resistant nephrotic syndrome. As a result of a screening for these gene alterations in a cohort of Italian patients with nonfamilial nephrotic syndrome and histologic focal segmental glomerulosclerosis (FSGS), nine patients with NPHS2 gene homozygous or composite heterozygous mutations were found. In addition to the previously described defects, two novel mutations at exon 4 were identified (frameshift, L169P); four single nucleotide polymorphisms (SNPs) and one dinucleotide repeat were also identified. On the basis of haplotype analysis, a founder effect was suggested for the 419delG mutation, the most frequently observed in the patients studied. Patients carrying NPHS2 mutations and without a family history of nephrotic syndrome were indistinguishable from those with idiopathic FSGS on the basis of the clinical phenotype. Two of the nine patients had normal renal function at 3 and 10 yr of age, despite the presence of the nephrotic syndrome. The other seven had reached end-stage renal failure at a mean age of 9.6 yr (range, 4 to 17 yr) and had received renal allografts. In those presenting with end-stage renal failure, the clinical and laboratory features both before and after transplantation were similar, including the age at onset, the amount of proteinuria, and the absence of any response to steroids and other immunosuppressants. Finally, two children presented recurrence of mild proteinuria after transplantation, which promptly remitted after plasmapheresis combined with cyclophosphamide. These data demonstrate that podocin mutations in nonfamilial cases of steroid-resistant nephrotic syndrome are frequent and may be due in one case to a founder effect. The pretransplantation and posttransplantation outcomes in the group of patients with mutations of the podocin gene are similar to classical idiopathic FSGS, including the possibility of recurrence of proteinuria that is mild and responsive to plasmapheresis. These observations support a role of molecular screening of the podocin gene in patients with nephrotic syndrome before immunosuppressive treatment is started.
足突蛋白突变（NPHS2基因）是常染色体隐性遗传性类固醇抵抗型肾病综合征的病因。在一组患有非家族性肾病综合征和组织学局灶节段性肾小球硬化（FSGS）的意大利患者中筛查这些基因改变时，发现了9例NPHS2基因纯合或复合杂合突变患者。除了先前描述的缺陷外，还在第4外显子上鉴定出两个新突变（移码突变，L169P）；还鉴定出四个单核苷酸多态性（SNP）和一个二核苷酸重复序列。基于单倍型分析，提示在所研究患者中最常观察到的419delG突变存在奠基者效应。携带NPHS2突变且无肾病综合征家族史的患者，根据临床表型与特发性FSGS患者无法区分。9例患者中有2例在3岁和10岁时肾功能正常，尽管存在肾病综合征。其他7例在平均年龄9.6岁（范围4至17岁）时达到终末期肾衰竭并接受了肾移植。在出现终末期肾衰竭的患者中，移植前后的临床和实验室特征相似，包括发病年龄、蛋白尿程度以及对类固醇和其他免疫抑制剂无任何反应。最后，两名儿童在移植后出现轻度蛋白尿复发，在血浆置换联合环磷酰胺治疗后迅速缓解。这些数据表明，在非家族性类固醇抵抗型肾病综合征病例中，足突蛋白突变很常见，在一个病例中可能归因于奠基者效应。足突蛋白基因突变患者组的移植前和移植后结局与经典特发性FSGS相似，包括轻度蛋白尿复发且对血浆置换有反应的可能性。这些观察结果支持在开始免疫抑制治疗前对肾病综合征患者进行足突蛋白基因分子筛查。
