Zheng Fang-Fang, Zhu Li-Min, Nie Ai-Fang, Li Xiao-Ying, Lin Jing-Rong, Zhang Ke, Chen Jing, Zhou Wen-Long, Shen Zhou-Jun, Zhu Yi-Chun, Wang Ji-Guang, Zhu Ding-Liang, Gao Ping-Jin
From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (F.-F.Z., L.-M.Z., J.C., J.-G.W., D.-L.Z., P.-J.G.); Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (F.-F.Z., J.-R.L., K.Z., P.-J.G.); Shanghai Institute of Hypertension (F.-F.Z., L.-M.Z., J.C., J.-G.W., D.-L.Z., P.-J.G.), Shanghai Institute of Endocrinology and Metabolism (A.-F.N., X.-Y.L.), and Department of Urology, Ruijin Hospital (W.-L.Z., Z.-J.S.), Shanghai Jiao Tong University School of Medicine, Shanghai, China; and Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China (Y.-C.Z.).
Hypertension. 2015 Mar;65(3):622-8. doi: 10.1161/HYPERTENSIONAHA.114.03346. Epub 2015 Jan 26.
Recent studies have shown that somatic mutations in the KCNJ5, ATP1A1, ATP2B3, and CACNA1D genes are associated with the pathogenesis of aldosterone-producing adenoma. Clinical profile and biochemical characteristics of the mutations in Chinese patients with aldosterone-producing adenoma remain unclear. In this study, we performed DNA sequencing in 168 Chinese patients with aldosterone-producing adenoma and found 129 somatic mutations in KCNJ5, 4 in ATP1A1, 1 in ATP2B3, and 1 in CACNA1D. KCNJ5 mutations were more prevalent in female patients and were associated with larger adenomas, higher aldosterone excretion, and lower minimal serum K(+) concentration. More interestingly, we identified a novel somatic KCNJ5 mutation (c.445-446insGAA, p.T148-T149insR) that could enhance CYP11B2 mRNA upregulation and aldosterone release. This mutation could also cause membrane depolarization and intercellular Ca(2+) increase. In conclusion, somatic KCNJ5 mutations are conspicuously more popular than mutations of other genes in aldosterone-producing adenomas of Chinese patients. The T148-T149insR mutation in KCNJ5 may influence K(+) channel selectivity and autonomous aldosterone production.
近期研究表明，KCNJ5、ATP1A1、ATP2B3和CACNA1D基因的体细胞突变与醛固酮瘤的发病机制相关。中国醛固酮瘤患者突变的临床特征和生化特性仍不明确。在本研究中，我们对168例中国醛固酮瘤患者进行了DNA测序，发现KCNJ5有129个体细胞突变，ATP1A1有4个，ATP2B3有1个，CACNA1D有1个。KCNJ5突变在女性患者中更常见，且与更大的腺瘤、更高的醛固酮排泄量以及更低的血清最低钾离子浓度相关。更有趣的是，我们鉴定出一种新的体细胞KCNJ5突变（c.445 - 446insGAA，p.T148 - T149insR），它可增强CYP11B2 mRNA上调和醛固酮释放。该突变还可导致膜去极化和细胞间钙离子增加。总之，在中国患者醛固酮瘤中，体细胞KCNJ5突变明显比其他基因突变更常见。KCNJ5中的T148 - T149insR突变可能影响钾离子通道选择性和醛固酮自主分泌。
