Autosomal dominant polycystic kidney disease in absence of renal cyst formation illustrates genetic interaction between WT1 and PKD1
Autosomal dominant polycystic kidney disease in absence of renal cyst formation illustrates genetic interaction between WT1 and PKD1
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DOI：
10.1136/jmedgenet-2019-106633
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发表时间：
2020-05
影响因子：
4
通讯作者：
Johannes Münch;K. Kirschner;H. Schlee;C. Kraus;Ria Schönauer;W. Jin;D. Le Duc;H. Scholz;J. Halbritter
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文献类型：
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作者：
Johannes Münch;K. Kirschner;H. Schlee;C. Kraus;Ria Schönauer;W. Jin;D. Le Duc;H. Scholz;J. Halbritter
目的常染色体显性多囊肾病（Autosomal dominant polycystic kidney disease，ADPKD）是由PKD 1或PKD 2的致病性变异体引起的一种疾病，具有广泛的家族间和家族内表型变异性。本研究旨在确定ADPKD家族成员显著临床变异性的分子基础，并试图分析编码基因表达调节因子的WT 1（Wilms tumor 1）的改变是否可能对肾囊肿形成产生影响。方法对ADPKD家系成员进行临床和分子生物学评价。在功能上，Pkd 1的mRNA和蛋白表达Wt 1敲低后，在小鼠胚胎肾脏和中肾M15细胞进行了评估。结果通过肾脏基因组分析，我们在一个有ADPKD母亲病史，但没有囊肿肾但有多囊肝疾病的个体中发现了两种致病性变异：一种已知的PKD 1错义变异（c.8311G>A，p.Glu2771Lys）和一种已知的从头WT 1剪接位点变异（c.1432+4C>T）。后者以前与WT 1的+/−KTS亚型比例失衡有关。在离体小鼠胚胎肾脏器官培养中，Wt 1敲低导致Pkd 1在mRNA和蛋白水平上的表达降低。结论虽然WT 1在肾小球疾病中的作用已经得到很好的证实，但本报告通过说明WT 1与PKD 1的遗传相互作用，提出WT 1是ADPKD的潜在修饰剂。
Purpose Autosomal dominant polycystic kidney disease (ADPKD), caused by pathogenic variants of either PKD1 or PKD2, is characterised by wide interfamilial and intrafamilial phenotypic variability. This study aimed to determine the molecular basis of marked clinical variability in ADPKD family members and sought to analyse whether alterations of WT1 (Wilms tumour 1), encoding a regulator of gene expression, may have an impact on renal cyst formation. Methods ADPKD family members underwent clinical and molecular evaluation. Functionally, Pkd1 mRNA and protein expression upon Wt1 knockdown was evaluated in mouse embryonic kidneys and mesonephric M15 cells. Results By renal gene panel analysis, we identified two pathogenic variants in an individual with maternal history of ADPKD, however, without cystic kidneys but polycystic liver disease: a known PKD1 missense variant (c.8311G>A, p.Glu2771Lys) and a known de novo WT1 splice site variant (c.1432+4C>T). The latter was previously associated with imbalanced +/−KTS isoform ratio of WT1. In ex vivo organ cultures from mouse embryonic kidneys, Wt1 knockdown resulted in decreased Pkd1 expression on mRNA and protein level. Conclusion While the role of WT1 in glomerulopathies has been well established, this report by illustrating genetic interaction with PKD1 proposes WT1 as potential modifier in ADPKD.