Long-QT syndrome: from genetics to management.
Long-QT syndrome: from genetics to management.
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DOI：
10.1161/circep.111.962019
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发表时间：
2012-08-01
期刊：
影响因子：
--
通讯作者：
Insolia R
中科院分区：
文献类型：
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作者：
Schwartz PJ;Crotti L;Insolia R
Schwartz等人的LQTS：从遗传学到管理869 K+通道的跨膜部分，具有轻微的显性-负性功能效应；在这些患者中，我们发现A341V的LQT1携带者的临床严重程度显著高于LQT1非A341V患者，突变要么局限于跨膜区，要么表现出显性-负性效应。13存在LQTS突变的第二个最常见的基因是KCNH2，它编码传导IK整流电流的K+通道的α亚基。快速Ikr(KCNH2)和慢Ik1(KCNQ1)是延迟整流Ik电流的两个独立分量，延迟整流Ik电流是心脏动作电位3相的主要决定因素。KCNH2的突变导致IKR电流的减少，其机制类似于KCNQ1突变对iKS电流的影响。7高达10%的基因分型病例可能在相同或2个主要LQTS基因上存在复合杂合性突变。14、15不足为奇的是，复合突变伴随着更严重的心脏表型。14-16 1995年3月底发现的第三个主要的LQTS基因8是SCN5A，它编码心脏钠通道的α亚基，并传导去极化的钠内向电流。1995年9月Bennett等人的一项突破性的体外表达研究表明，SCN5A-ΔKPQ突变通过增加延迟的Na+内向电流从而延长动作电位时程而产生LQTS表型。几个月后，也就是1995年12月，我们的报告指出，LQTS的遗传缺陷可能与对心率变化和钠离子通道阻滞剂18的不同反应有关，并与美西律减少晚期钠电流的第一个证据有关。这一发现为寻找基因特异性疗法铺平了道路。一些遗传异质性疾病也与钠电流的改变有关，包括Brugada综合征、心房颤动、病态窦房结综合征和Lev-Lenègre病。更复杂的是，一些SCN5A突变表现出多效性，并与>；1表型相关，即所谓的重叠综合征。20当单个突变可能具有相反的功能效应(即，钠电流的增加和减少)时，临床上重要的是表型。鉴于迄今发现的大量且数量不断增加的遗传变异，区分致病突变和罕见变异至关重要。基于近400个明确病例和1300个对照，21错义突变致病的概率似乎在很大程度上取决于位置。一般来说，位于孔区和跨膜区的遗传变异更有可能致病。每当对特定突变进行功能研究时，结果可能有助于评估其临床相关性。当这些数据丢失时，就像通常的情况一样，重要的是确定在家族内突变是否伴随症状或QT延长。一个重要的信息是，实验室发现的氨基酸替代不应该自动被视为致病突变的迹象。
Schwartz et al LQTS: From Genetics to Management 869 transmembrane portion of the K+ channel with a mild dominant-negative functional effect; in these patients, we demonstrated a strikingly higher clinical severity among LQT1 carriers of A341V compared with LQT1 non-A341V patients, with mutations either localized to transmembrane domains or exhibiting a dominant-negative effect. 13 The second most common gene harboring LQTS mutations is KCNH2, encoding the α-subunit of the K+ channel conducting the IK rectifier (IKr) current. The rapid IKr (KCNH2) and the slow IKs (KCNQ1) are 2 independent components of the delayed rectifier IK current, the major determinant of the phase 3 of the cardiac action potential. Mutations in KCNH2 cause a reduction in IKr current, through mechanisms similar to the effects exhibited by KCNQ1 mutations on IKs current. 7 Up to 10% of genotyped cases may harbor compound heterozygous mutations on the same or on 2 of the main LQTS genes. 14, 15 Not surprisingly, a more severe cardiac phenotype accompanies compound mutations. 14–16 The third major LQTS gene, identified at the end of March 1995, 8 is SCN5A, encoding the α-subunit of the cardiac sodium channel and conducting the depolarizing sodium inward current. A ground-breaking in vitro expression study by Bennett et al17 in September 1995 showed that the SCN5A-ΔKPQ mutation produces the LQTS phenotype by increasing the delayed Na+ inward current and, therefore, prolonging the action potential duration. Within a few months, in December 1995, this was followed by our report that the genetic defects in LQTS may be linked to differential responses to heart rate changes and to Na+ channel blockers18 and to the first evidence that mexiletine reduces the late Na+ current. 19 This finding paved the way to the search for gene-specific therapies. Several genetically heterogeneous disorders are also associated with alterations in the sodium current, including Brugada syndrome, atrial fibrillation, sick sinus node syndrome, and the Lev-Lenègre disease. As a further complexity, some SCN5A mutations show a pleiotropic behavior and are associated with> 1 phenotype, the so-called overlap syndrome. 20 When a single mutation can have opposite functional effects (ie, increase and decrease of the Na+ current), what matters clinically is the phenotype.Given the large and growing number of genetic variants identified so far, to distinguish pathogenic mutations from rare variants is critically important. Based on almost 400 definite cases and 1300 controls, 21 the probability for a missense mutation to be pathogenic appears to depend largely on location. In general, genetic variants located in the pore and transmembrane regions are much more likely to be pathogenic. Whenever a functional study of the specific mutation has been performed, the results may help in assessing its clinical relevance. When these data are missing, as is often the case, it is important to establish whether within the family the mutation cosegregates with either symptoms or QT prolongation. An important take-home message is that the laboratory finding of an aminoacidic substitution should not be automatically taken as an indication of a disease-causing mutation.