A genetic defect resulting in mild low-renin hypertension
A genetic defect resulting in mild low-renin hypertension
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DOI：
10.1073/pnas.95.17.10200
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发表时间：
1998-08-18
影响因子：
11.1
通讯作者：
New, MI
中科院分区：
文献类型：
--
作者：
Wilson, RC;Dave-Sharma, S;New, MI
严重的低肾素高血压几乎没有已知的原因。表观盐皮质激素过量（AME）是一种遗传性疾病，可导致严重的青少年低肾素高血压、低肾素血症、低醛固酮血症、低钾血症、低出生体重、发育不良、生长不良，在许多情况下还可导致肾钙质沉着症。1995年，研究表明，编码11 β-羟基类固醇脱氢酶2型酶（11 β-HSD 2）的基因（HSD 11B 2）突变导致AME。典型的AME患者具有缺陷的11 β-HSD 2活性，如通过皮质醇与可的松代谢物的异常比率以及通过[11-H-3]皮质醇转化为可的松的能力的极度降低所证明的。最近，我们研究了一个不寻常的病人，轻度低肾素高血压和一个纯合突变的HSD 11B 2基因。这名患者来自一个近亲繁殖的门诺派家族，尽管突变将她确定为AME患者，但她并没有表现出AME的典型特征。生化分析显示，该患者的皮质醇与可的松代谢物的比例中度升高。皮质醇向可的松的转化率为58%，而典型的AME患者为0-6%，而正常转化率为90- 95%。对该患者的HSD 11B 2基因的分子分析搁置了密码子227的第二个核苷酸中的纯合C --> T转换，导致脯氨酸被亮氨酸取代（P227 L）。父母和兄弟姐妹都是这种突变的杂合子。体外表达研究显示K-m（300 nM）高于正常值（54 nM）。由于约40%的原发性高血压患者显示低肾素，我们建议这些患者应该进行基因分析的HSD 11B 2基因。
Severe low-renin hypertension has few known causes. Apparent mineralocorticoid excess (AME) is a genetic disorder that results in severe juvenile low-renin hypertension, hyporeninemia, hypoaldosteronemia, hypokalemic alkalosis, low birth weight, failure to thrive, poor growth, and in many cases nephrocalcinosis. In 1995, it was shown that mutations in the gene (HSD11B2) encoding the 11 beta-hydroxysteroid dehydrogenase type 2 enzyme (11 beta-HSD2) cause AME. Typical patients with AME have defective 11 beta-HSD2 activity, as evidenced by an abnormal ratio of cortisol to cortisone metabolites and by an exceedingly diminished ability to convert [11-H-3]cortisol to cortisone. Recently, we have studied an unusual patient with mild low-renin hypertension and a homozygous mutation in the HSD11B2 gene. The patient came from an inbred Mennonite family, and though the mutation identified her as a patient with AME, she did not demonstrate the typical features of AME. Biochemical analysis in this patient revealed a moderately elevated cortisol to cortisone metabolite ratio. The conversion of cortisol to cortisone was 58% compared with 0-6% in typical patients with AME whereas the normal conversion is 90-95%. Molecular analysis of the HSD11B2 gene of this patient shelved a homozygous C --> T transition in the second nucleotide of codon 227, resulting in a substitution of proline with leucine (P227L). The parents and sibs were heterozygous for this mutation. In vitro expression studies showed an increase in the K-m (300 nM) over normal (54 nM). Because approximate to 40% of patients with essential hypertension demonstrate low renin, we suggest that such patients should undergo genetic analysis of the HSD11B2 gene.