Lehnhardt Anja, Karnatz Claartje, Ahlenstiel-Grunow Thurid, Benz Kerstin, Benz Marcus R, Budde Klemens, Büscher Anja K, Fehr Thomas, Feldkötter Markus, Graf Norbert, Höcker Britta, Jungraithmayr Therese, Klaus Günter, Koehler Birgit, Konrad Martin, Kranz Birgitta, Montoya Carmen R, Müller Dominik, Neuhaus Thomas J, Oh Jun, Pape Lars, Pohl Martin, Royer-Pokora Brigitte, Querfeld Uwe, Schneppenheim Reinhard, Staude Hagen, Spartà Giuseppina, Timmermann Kirsten, Wilkening Frauke, Wygoda Simone, Bergmann Carsten, Kemper Markus J
Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
Clin J Am Soc Nephrol. 2015 May 7;10(5):825-31. doi: 10.2215/CJN.10141014. Epub 2015 Mar 27.
The Wilms tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1, including patients without proteinuria or WT.
DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012.
Median age was 12.4 (interquartile range [IQR], 6-19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1-1.5] years) than in those with truncating (9.7 [IQR, 5.7-11.9]; P<0.001) and splice site (4.0 [IQR, 2.6-6.6]; P=0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy-three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01-9.3] years) than those with truncating mutations (16.5 [IQR, 16.5-16.8]; P<0.001) and splice site mutations (12.3 [IQR, 7.9-18.2]; P=0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations (n=19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations.
Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases.
肾母细胞瘤抑制基因1（WT1）在泌尿生殖系统和肾脏发育中起关键作用。在全球范围内患有肾病综合征或肾母细胞瘤（WT）的队列研究中，已观察到WT1突变的基因型/表型与肾功能和蛋白尿之间的相关性。本研究分析了欧洲中部已知WT1基因杂合突变的患者，包括无蛋白尿或WT的患者。
设计、地点、参与者与测量：对2010年至2012年期间来自德国、奥地利和瑞士所有儿科肾脏病中心的53例WT1突变患者的基因型、表型和治疗情况进行回顾性分析。
中位年龄为12.4岁（四分位间距[IQR]，6 - 19岁）。53例患者中有44例（83%）发生外显子突变（36例错义突变，8例截短突变），53例中有9例（17%）发生内含子赖氨酸 - 苏氨酸 - 丝氨酸（KTS）剪接位点突变。53例患者中有50例（94%）出现蛋白尿，错义突变患者蛋白尿出现的年龄较早（0.6岁[IQR，0.1 - 1.5岁]），低于截短突变患者（9.7岁[IQR，5.7 - 11.9岁]；P<0.001）和剪接位点突变患者（4.0岁[IQR，2.6 - 6.6岁]；P = 0.004）。50例中有13例（26%）接受了类固醇治疗但仍无反应，5例中有3例对环孢素A部分反应。所有患者中有73%需要肾脏替代治疗（RRT），错义突变患者需要RRT的时间明显早于截短突变患者（1.1岁[IQR，0.01 - 9.3岁]）和剪接位点突变患者（12.3岁[IQR，7.9 - 18.2岁]；P = 0.002）。弥漫性系膜硬化仅见于错义突变患者，而局灶节段性硬化在所有组中均有发生。WT仅发生在外显子突变患者中（n = 19）。53例患者中有50例（94%）进行了核型分析：31例（62%）为XY染色体，19例（38%）为XX染色体，96%的男性核型存在泌尿生殖系统畸形。
WT1突变的类型和位置对蛋白尿、肾功能不全和WT的发生具有预测价值。XY核型更为常见，且在大多数情况下与泌尿生殖系统畸形相关。
