Jeunemaitre X, Bassilana F, Persu A, Dumont C, Champigny G, Lazdunski M, Corvol P, Barbry P
Laboratoire de Biologie Moléculaire de l'Assistance Publique-Hôpitaux de Paris, Hôpital Broussais, France.
J Hypertens. 1997 Oct;15(10):1091-100. doi: 10.1097/00004872-199715100-00007.
To investigate the clinical, biologic, and molecular abnormalities in a family with Liddle's syndrome and analyze the short- and long-term efficacies of amiloride treatment.
The pedigree consisted of one affected mother and four children, of whom three suffered from early-onset and moderate-to-severe hypertension.
In addition to the biochemical and hormonal measurements, genetic analysis of the carboxy terminus of the beta subunit of the epithelial sodium channel (beta ENaC) was conducted through single-strand conformation analysis and direct sequencing. The functional properties of the mutation were analyzed using the Xenopus expression system and compared with one mutation affecting the proline-rich sequence of the beta ENaC.
Mild hypokalemia and suppressed levels of plasma renin and aldosterone were observed in all affected subjects. Administration of 10 mg/day amiloride for 2 months normalized the blood pressure and plasma potassium levels of all of the affected subjects, whereas their plasma and urinary aldosterone levels remained surprisingly low. A similar pattern was observed after 11 years of follow-up, but a fivefold increase in plasma aldosterone was observed under treatment with 20 mg/day amiloride for 2 weeks. Genetic analysis of the beta ENaC revealed a deletion of 32 nucleotides that had modified the open reading frame and introduced a stop codon at position 582. Expression of this beta 579del32 mutant caused a 3.7 +/- 0.3-fold increase in the amiloride-sensitive sodium current, without modification of the unitary properties of the channel. A similar increase was elicited by one mutation affecting the carboxy terminus of the beta ENaC.
This new mutation leading to Liddle's syndrome highlights the importance of the carboxy terminus of the beta ENaC in the activity of the epithelial sodium channel. Small doses of amiloride are able to control the blood pressure on a long-term basis in this monogenic form of hypertension.
研究一家利德尔综合征患者的临床、生物学和分子异常情况，并分析氨氯吡咪治疗的短期和长期疗效。
该家系包括一位患病母亲和四个孩子，其中三个患有早发性中重度高血压。
除进行生化和激素检测外，通过单链构象分析和直接测序对上皮钠通道β亚基（βENaC）的羧基末端进行基因分析。利用非洲爪蟾表达系统分析该突变的功能特性，并与一个影响βENaC富含脯氨酸序列的突变进行比较。
所有患病个体均出现轻度低钾血症，血浆肾素和醛固酮水平受到抑制。给予每日10毫克氨氯吡咪治疗2个月后，所有患病个体的血压和血钾水平恢复正常，而其血浆和尿醛固酮水平仍出奇地低。随访11年后观察到类似模式，但在每日20毫克氨氯吡咪治疗2周后，血浆醛固酮增加了五倍。对βENaC的基因分析显示，有32个核苷酸缺失，这改变了开放阅读框，并在第582位引入了一个终止密码子。这种β579del32突变体的表达使氨氯吡咪敏感的钠电流增加了3.7±0.3倍，而通道的单一特性未发生改变。一个影响βENaC羧基末端的突变也引发了类似的增加。
这种导致利德尔综合征的新突变凸显了βENaC羧基末端在上皮钠通道活性中的重要性。小剂量氨氯吡咪能够长期控制这种单基因形式高血压的血压。
