Sesti F, Abbott G W, Wei J, Murray K T, Saksena S, Schwartz P J, Priori S G, Roden D M, George A L, Goldstein S A
Departments of Pediatrics and Cellular and Molecular Physiology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.
Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10613-8. doi: 10.1073/pnas.180223197.
Drug-induced long QT syndrome (LQTS) is a prevalent disorder of uncertain etiology that predisposes to sudden death. KCNE2 encodes MinK-related peptide 1 (MiRP1), a subunit of the cardiac potassium channel I(Kr) that has been associated previously with inherited LQTS. Here, we examine KCNE2 in 98 patients with drug-induced LQTS, identifying three individuals with sporadic mutations and a patient with sulfamethoxazole-associated LQTS who carried a single-nucleotide polymorphism (SNP) found in approximately 1.6% of the general population. While mutant channels showed diminished potassium flux at baseline and wild-type drug sensitivity, channels with the SNP were normal at baseline but inhibited by sulfamethoxazole at therapeutic levels that did not affect wild-type channels. We conclude that allelic variants of MiRP1 contribute to a significant fraction of cases of drug-induced LQTS through multiple mechanisms and that common sequence variations that increase the risk of life-threatening drug reactions can be clinically silent before drug exposure.
药物诱导的长QT综合征（LQTS）是一种病因不明的常见疾病，易导致猝死。KCNE2基因编码MinK相关肽1（MiRP1），它是心脏钾通道I(Kr)的一个亚基，此前已与遗传性LQTS相关联。在此，我们对98例药物诱导的LQTS患者进行了KCNE2基因检测，发现了3例携带散发性突变的个体以及1例与磺胺甲恶唑相关的LQTS患者，后者携带一种在普通人群中约1.6%的个体中发现的单核苷酸多态性（SNP）。虽然突变通道在基线时钾通量降低且具有野生型药物敏感性，但携带SNP的通道在基线时正常，但在不影响野生型通道的治疗浓度下会被磺胺甲恶唑抑制。我们得出结论，MiRP1的等位基因变异通过多种机制导致了相当一部分药物诱导的LQTS病例，并且增加危及生命的药物反应风险的常见序列变异在药物暴露前可能在临床上无明显表现。
