State Key Laboratory of Cardiovascular Disease, Sino-German Laboratory for Molecular Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China.
Mol Biol Rep. 2014 Mar;41(3):1569-75. doi: 10.1007/s11033-013-3003-7. Epub 2014 Jan 29.
The families with Liddle syndrome show marked phenotypic variation in blood pressure, serum potassium and other clinical manifestations. Here we analyzed the correlation of genotype-phenotype in two Chinese families with Liddle syndrome. The sequence of C-terminus of SCNN1B and SCNN1G were screened in the two families with likely Liddle syndrome. In addition to hypertension and hypokalemia, one of the two pedigrees had sudden death in their family members, so the exons of 428 reported genes-related to cardiovascular diseases were screened as well in the family. A heterozygous βR566X nonsense mutation was found in the proband-1 in the first pedigree, and the proband's sister and father. They showed mild phenotype with hypertension under control. In contrast, two of the four previous studies report that the mutation causes severe phenotype. A heterozygous βR597PfrX607 frameshift mutation was identified in the proband-2 in the second pedigree, showing malignant phenotype including resistant hypertension, hypokalemia, higher PRA and plasma angiotensin II levels. Both the proband-2 and the proband-2's father had sudden death in their twenties, but no meaningful mutations were found by screening of the exons in 428 cardiovascular disease-related genes. However, the same mutation has been related to moderate phenotype in previous studies. Our results confirmed that the phenotypes of Liddle syndrome are varied significantly even with the same mutation. The mechanisms why the same mutation causes very different phenotype need to be explored because intervention of these modifiers may change the disease course and prognosis accordingly.
具有莱顿综合征的家族在血压、血清钾和其他临床表现方面表现出明显的表型变异。在这里，我们分析了两个中国莱顿综合征家族的基因型-表型相关性。在两个可能具有莱顿综合征的家族中，筛选了 SCNN1B 和 SCNN1G 的 C 末端序列。除了高血压和低钾血症外，两个家系中的一个还有家族成员猝死，因此也筛选了与心血管疾病相关的 428 个报告基因的外显子。在第一个家系中，先证者-1 及其姐妹和父亲均发现 SCNN1B 基因的βR566X 无义突变杂合子，表现为轻度高血压。相比之下，之前的四项研究中有两项报告该突变导致严重表型。在第二个家系中，先证者-2 发现 SCNN1B 基因的βR597PfrX607 移码突变杂合子，表现为恶性高血压、低钾血症、较高的 PRA 和血浆血管紧张素 II 水平。先证者-2 和先证者-2 的父亲都在二十多岁时猝死，但通过 428 个心血管疾病相关基因的外显子筛选未发现有意义的突变。然而，相同的突变在之前的研究中与中度表型有关。我们的结果证实，即使具有相同的突变，莱顿综合征的表型也有很大差异。相同突变导致非常不同表型的机制需要进一步探讨，因为这些修饰因子的干预可能会相应地改变疾病的进程和预后。
