LRP5 variants may contribute to ADPKD
LRP5 variants may contribute to ADPKD
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DOI：
10.1038/ejhg.2015.86
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发表时间：
2016-02-01
影响因子：
5.2
通讯作者：
Drenth, Joost P. H.
中科院分区：
文献类型：
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作者：
Cnossen, Wybrich R.;Morsche, Rene H. M. te;Drenth, Joost P. H.
多囊肾病蛋白（PKD 1或PKD 2）的突变是常染色体显性多囊肾病（ADPKD）的病因。然而，一小部分ADPKD先证者在任何已知基因中都没有突变。低密度脂蛋白受体相关蛋白5（LRP 5）最近与孤立性多囊肝病（PCLD）的肝囊肿形成有关。在这里，我们证明了该基因也可能在非连锁和散发性ADPKD患者中发挥作用。在79例不相关的成人型ADPKD患者队列中，我们通过计算机工具确定了总共4种不同的LRP 5变异体，这些变异体被预测为致病性。1例ADPKD患者有ADPKD和变异LRP 5 c阳性家族史。1680G>T; p.（Trp 560 Cys）与疾病分离。虽然还鉴定了可能影响蛋白质功能的两种PKD 1变体，但针对三种LRP 5变体的荧光素酶活性测定显著降低了经典Wnt信号传导的信号激活。这项研究有助于ADPKD的遗传谱。经典Wnt信号通路的引入为研究其病理生理机制提供了新的途径。
Mutations in Polycystic Kidney Disease proteins (PKD1 or PKD2) are causative for autosomal dominant polycystic kidney disease (ADPKD). However, a small subset of ADPKD probands do not harbor a mutation in any of the known genes. Low density lipoprotein Receptor-related Protein 5 (LRP5) was recently associated with hepatic cystogenesis in isolated polycystic liver disease (PCLD). Here, we demonstrate that this gene may also have a role in unlinked and sporadic ADPKD patients. In a cohort of 79 unrelated patients with adult-onset ADPKD, we identified a total of four different LRP5 variants that were predicted to be pathogenic by in silico tools. One ADPKD patient has a positive family history for ADPKD and variant LRP5 c. 1680G>T; p.(Trp560Cys) segregated with the disease. Although also two PKD1 variants probably affecting protein function were identified, luciferase activity assays presented for three LRP5 variants significant decreased signal activation of canonical Wnt signaling. This study contributes to the genetic spectrum of ADPKD. Introduction of the canonical Wnt signaling pathway provides new avenues for the study of the pathophysiology.