Pediatric Nephrology, Dialysis and Transplant Unit, Department of Pediatrics, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
Clin J Am Soc Nephrol. 2010 Apr;5(4):698-702. doi: 10.2215/CJN.05670809. Epub 2010 Feb 11.
Wilms tumor-suppressor gene-1 (WT1) plays a key role in kidney development and function. WT1 mutations usually occur in exons 8 and 9 and are associated with Denys-Drash, or in intron 9 and are associated with Frasier syndrome. However, overlapping clinical and molecular features have been reported. Few familial cases have been described, with intrafamilial variability. Sporadic cases of WT1 mutations in isolated diffuse mesangial sclerosis or focal segmental glomerulosclerosis have also been reported.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Molecular analysis of WT1 exons 8 and 9 was carried out in five members on three generations of a family with late-onset isolated proteinuria. The effect of the detected amino acid substitution on WT1 protein's structure was studied by bioinformatics tools.
Three family members reached end-stage renal disease in full adulthood. None had genital abnormalities or Wilms tumor. Histologic analysis in two subjects revealed focal segmental glomerulosclerosis. The novel sequence variant c.1208G>A in WT1 exon 9 was identified in all of the affected members of the family.
The lack of Wilms tumor or other related phenotypes suggests the expansion of WT1 gene analysis in patients with focal segmental glomerulosclerosis, regardless of age or presence of typical Denys-Drash or Frasier syndrome clinical features. Structural analysis of the mutated protein revealed that the mutation hampers zinc finger-DNA interactions, impairing target gene transcription. This finding opens up new issues about WT1 function in the maintenance of the complex gene network that regulates normal podocyte function.
Wilms 肿瘤抑制基因-1（WT1）在肾脏发育和功能中发挥关键作用。WT1 突变通常发生在外显子 8 和 9 中，与 Denys-Drash 相关，或在内含子 9 中，与 Fraser 综合征相关。然而，已有报道称两者存在重叠的临床和分子特征。家族内也有少数病例报道，存在家族内变异性。也有散发性 WT1 突变病例报告，涉及孤立性弥漫性系膜硬化或局灶节段性肾小球硬化。
设计、地点、参与者和测量方法：对一个有三代人的家族中的五名成员进行了 WT1 外显子 8 和 9 的分子分析，这些成员患有晚发性孤立性蛋白尿。通过生物信息学工具研究了检测到的氨基酸取代对 WT1 蛋白结构的影响。
三名家族成员在成年后均进展至终末期肾病。他们均无生殖器异常或 Wilms 肿瘤。两名患者的组织学分析显示局灶节段性肾小球硬化。在该家族的所有受影响成员中均发现了 WT1 外显子 9 中的新序列变异 c.1208G>A。
缺乏 Wilms 肿瘤或其他相关表型表明，无论年龄大小或是否存在典型的 Denys-Drash 或 Fraser 综合征临床特征，都应扩大 WT1 基因分析范围，纳入局灶节段性肾小球硬化患者。对突变蛋白的结构分析表明，该突变会干扰锌指-DNA 相互作用，从而损害靶基因转录。这一发现提出了 WT1 在维持调节正常足细胞功能的复杂基因网络中的功能的新问题。
