A novel PKD1 variant demonstrates a disease-modifying role in trans with a truncating PKD1 mutation in patients with Autosomal Dominant Polycystic Kidney Disease
A novel PKD1 variant demonstrates a disease-modifying role in trans with a truncating PKD1 mutation in patients with Autosomal Dominant Polycystic Kidney Disease
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DOI：
10.1186/s12882-015-0015-7
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发表时间：
2015-03-01
期刊：
影响因子：
2.3
通讯作者：
Harris, Peter C.
中科院分区：
文献类型：
--
作者：
Ali, Hamad;Hussain, Naser;Harris, Peter C.
背景：常染色体显性多囊肾病 (ADPKD) 是多囊肾病 (PKD) 最常见的形式，发生频率为 1/800 至 1/1000，影响全世界所有种族群体。 ADPKD 在疾病进展速度和肾外表现方面表现出显着的家族内表型变异，这表明可遗传修饰基因的参与。在这里，我们证明 PKD1 基因可以作为 ADPKD 患者的致病基因和疾病调节基因。方法：对 ADPKD 家族进行临床评估，以诊断和评估每个个体的疾病进展。通过靶向测序对每个个体进行PKD1基因分型。结果：靶向筛查分析显示家系中ADPKD患者存在PKD1：p.Q2243X无义突变。在两名患者中观察到更严重的疾病表型，就估计的肾小球滤过率 (eGFR) 和肾脏总体积而言，除了突变之外，他们还携带一种新的 PKD1 变异 (p. H1769Y)。来自同一家族的其他仅携带 (p.Q2243X) 突变的患者表现出较轻微的疾病表现。结论：ADPKD 显示出显着的家族内表型变异，这通常归因于其他修饰基因。在这种罕见的病例中，我们发现 PKD1 的一个变异体（与 PKD1 突变相反）也可以作为 ADPKD 患者的修饰基因。了解该基因发挥疾病调节作用的分子机制可能有助于我们了解 ADPKD 的发病机制。
Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common form of Polycystic Kidney Disease (PKD) and occurs at a frequency of 1/800 to 1/1000 affecting all ethnic groups worldwide. ADPKD shows significant intrafamilial phenotypic variability in the rate of disease progression and extra-renal manifestations, which suggests the involvement of heritable modifier genes. Here we show that the PKD1 gene can act as a disease causing and a disease modifier gene in ADPKD patients.Methods: Clinical evaluation of a family with ADPKD was performed to diagnose and assess disease progression in each individual. PKD1 was genotyped in each individual by targeted sequencing.Results: Targeted screening analysis showed that the patients with ADPKD in the family had the PKD1: p.Q2243X nonsense mutation. A more severe disease phenotype, in terms of estimated Glomerular Filtration Rate (eGFR) and total kidney volume, was observed in two patients where in addition to the mutation, they carried a novel PKD1 variant (p. H1769Y). Other patients from the same family carrying only the (p.Q2243X) mutation showed milder disease manifestations.Conclusion: ADPKD shows significant intrafamilial phenotypic variability that is generally attributed to other modifier genes. In this rare case, we have shown that a variant at PKD1, in trans with the PKD1 mutation, can also act as a modifier gene in ADPKD patients. Understanding the molecular mechanism through which the gene exerts its disease modifying role may aid our understanding of the pathogenesis of ADPKD.