Mucha Bettina, Ozaltin Fatih, Hinkes Bernward G, Hasselbacher Katrin, Ruf Rainer G, Schultheiss Michael, Hangan Daniela, Hoskins Bethan E, Everding Anne Schulze, Bogdanovic Radovan, Seeman Thomas, Hoppe Bernd, Hildebrandt Friedhelm
Department of Pediatrics, University of Michigan, Ann Arbor, 48109, USA.
Pediatr Res. 2006 Feb;59(2):325-31. doi: 10.1203/01.pdr.0000196717.94518.f0.
Primary steroid-resistant nephrotic syndrome (SRNS) is characterized by childhood onset of proteinuria and progression to end-stage renal disease. Approximately 10-25% of familial and sporadic cases are caused by mutations in NPHS2 (podocin). Mutations in exons 8 and 9 of the WT1 gene have been found in patients with isolated SRNS and in SRNS associated with Wilms' tumor (WT) or urogenital malformations. However, no large studies have been performed to date to examine whether WT1 mutations in isolated SRNS are restricted to exons 8 and 9. To address this question, we screened a worldwide cohort of 164 cases of sporadic SRNS for mutations in all 10 exons of the WT1 gene by multiplex capillary heteroduplex analysis and direct sequencing. NPHS2 mutations had been excluded by direct sequencing. Fifteen patients exhibited seven different mutations exclusively in exons 8 and 9 of WT1. Although it is possible that pathogenic mutations of WT1 may also reside in the introns, regions of the gene that were not able to be screened in this study, these data together with our previous results (Ruf et al.: Kidney Int 66: 564-570, 2004) indicate that screening of WT1 exons 8 and 9 in patients with sporadic SRNS is sufficient to detect pathogenic WT1 mutations and may open inroads into differential therapy of SRNS.
原发性类固醇抵抗性肾病综合征（SRNS）的特征是儿童期出现蛋白尿并进展为终末期肾病。约10%-25%的家族性和散发性病例由NPHS2（足突蛋白）突变引起。WT1基因第8和9外显子的突变已在孤立性SRNS患者以及与威尔姆斯瘤（WT）或泌尿生殖系统畸形相关的SRNS患者中被发现。然而，迄今为止尚未进行大规模研究来检验孤立性SRNS中的WT1突变是否仅限于第8和9外显子。为解决这个问题，我们通过多重毛细管异源双链分析和直接测序，对来自世界各地的164例散发性SRNS病例队列的WT1基因全部10个外显子进行了突变筛查。已通过直接测序排除NPHS2突变。15例患者仅在WT1基因的第8和9外显子中出现了7种不同的突变。尽管WT1的致病突变也可能存在于本研究无法筛查的基因内含子区域，但这些数据以及我们之前的结果（Ruf等人：《肾脏病国际》66: 564-570, 2004）表明，对散发性SRNS患者筛查WT1基因的第8和9外显子足以检测出致病的WT1突变，并可能为SRNS的差异化治疗开辟道路。
