Genetic variations of HSD11B2 in hypertensive patients and in the general population, six rare Missense/Frameshift mutations
Genetic variations of HSD11B2 in hypertensive patients and in the general population, six rare Missense/Frameshift mutations
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DOI：
10.1291/hypres.29.243
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发表时间：
2006-04-01
影响因子：
5.4
通讯作者：
Miyata, T
中科院分区：
文献类型：
--
作者：
Kamide, K;Kokubo, Y;Miyata, T
编码11β-羟基类固醇脱氢酶2型的基因突变会导致一种罕见的单基因青少年高血压综合征，称为表观盐皮质激素过剩(AME)。在AME中，HSD11B2酶活性缺陷导致皮质醇过度刺激盐皮质激素受体(MR)，导致钠滞留、低钾血症和盐依赖型高血压。在这里，我们研究了HDS11B2基因变异是否与日本高血压患者和普通人群的高血压有关。通过对953例日本高血压患者的HDS11B2全编码区和启动子区进行测序，我们在11例患者中发现了5个错义突变(L14F，n=5；R74H，n=1；R147H，n=3；T156I，n=1；R335H，n=1)和一个新的移码突变(4884Gdel，n=1)，以及19个遗传变异。所有发现的遗传变异都是罕见的，次要等位基因频率低于0.005。在12名错义/移码突变患者中，有4名患者出现了肾功能衰竭。4个错义突变L14F、R74H、R147H和R335H在普通人群中成功地进行了基因分型，样本量为3655人(2,175名正常血压者和1,480名高血压患者)。L14F、R74H、R147H和R335H突变分别在高血压患者(n=6、8、3和0)和正常血压患者(n=8、12、5和0)中发现，频率相近，提示这些错义突变可能不会强烈影响高血压的病因。由于这项研究中发现的所有遗传变异的等位基因频率很少，因此没有进行相关性研究。综上所述，我们的结果表明，HSD11B2错义突变并不是日本人高血压的实质原因。
Mutations in the gene encoding 11 beta-hydroxysteroid dehydrogenase type 2, HSD11B2, cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, defective HSD11B2 enzyme activity results in overstimulation of the mineralocorticoid receptor (MR) by cortisol, causing sodium retention, hypokalemia, and salt-dependent hypertension. Here, we have studied whether genetic variations in HDS11B2 are implicated in essential hypertension in Japanese hypertensives and the general population. By sequencing the entire coding region and the promoter region of HDS11B2 in 953 Japanese hypertensives, we identified five missense mutations in 11 patients (L14F, n = 5; R74H, n = 1; R147H, n = 3; T156I, n= 1; R335H, n = 1) and one novel frameshift mutation (4884Gdel, n = 1) in a heterozygous state, in addition to 19 genetic variations. All genetic variations identified were rare, with minor allele frequencies less than 0.005. Four of 12 patients with the missense/frameshift mutations showed renal failure. Four missense mutations, L14F, R74H, R147H, and R335H, were successfully genotyped in the general population, with a sample size of 3,655 individuals (2,175 normotensives and 1,480 hypertensives). Mutations L14F, R74H, R147H, and R335H were identified in hypertensives (n = 6, 8, 3, and 0, respectively) and normotensives (n = 8, 12, 5, and 0, respectively) with a similar frequency, suggesting that these missense mutations may not strongly affect the etiology of essential hypertension. Since the allele frequency of all of the genetic variations identified in this study was rare, an association study was not conducted. Taken together, our results indicate that missense mutations in HSD11B2 do not substantially contribute to essential hypertension in Japanese.