Variants in the 3' untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner.
Variants in the 3' untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner.
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DOI：
10.1093/eurheartj/ehr473
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发表时间：
2012-03
影响因子：
39.3
通讯作者：
Pinto YM
中科院分区：
文献类型：
--
作者：
Amin AS;Giudicessi JR;Tijsen AJ;Spanjaart AM;Reckman YJ;Klemens CA;Tanck MW;Kapplinger JD;Hofman N;Sinner MF;Müller M;Wijnen WJ;Tan HL;Bezzina CR;Creemers EE;Wilde AA;Ackerman MJ;Pinto YM
KCNQ1的杂合突变导致1型长QT综合征（LQT1），这是一种以心率校正QT间期（QTc）延长和危及生命的心律失常为特征的疾病。目前还不清楚为什么疾病的表现率和表达率在携带相同突变的个体之间如此可变。我们的目的是研究这是否可以解释为KCNQ1的3′非翻译区（3′UTR）的单核苷酸多态性（SNPs）。本研究在阿姆斯特丹学术医学中心的84名LQT 1患者中进行，并在罗切斯特的马约诊所的84名LQT 1患者中进行了验证。所有患者均进行了KCNQ1基因3′UTR的SNPs分型，共发现6个SNPs，单核苷酸多态性rs2519184、rs8234和rs10798与QTc间期和症状发生呈等位基因特异性相关。在突变的KCNQ1等位基因上具有衍生SNP变体的患者具有较短的QTc和较少的症状，而相反的情况也是如此：在正常的KCNQ1等位基因上具有衍生SNP变体的患者具有显著较长的QTc和更多的症状。荧光素酶报告基因分析表明，KCNQ1的3′UTR与衍生的SNP变体的表达低于3′UTR与祖先的SNP变体的表达。我们的数据表明，3′UTR SNP有效地改变LQT1的疾病严重程度。SNP对疾病严重程度和基因表达的等位基因特异性作用强烈表明它们是直接改变它们所驻留的等位基因的表达的功能性变体，从而影响源自正常或突变KCNQ1等位基因的蛋白质之间的平衡。
Heterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1's 3′ untranslated region (3′UTR). This study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1's 3′UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1's 3′UTR with the derived SNP variants was lower than the expression of the 3′UTR with the ancestral SNP variants. Our data indicate that 3′UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele.
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影响因子：
37.8
作者：
Crotti, Lia;Monti, Maria Cristina;George, Alfred L., Jr.
通讯作者：
George, Alfred L., Jr.
影响因子：
11.2
作者：
Saetrom P;Biesinger J;Li SM;Smith D;Thomas LF;Majzoub K;Rivas GE;Alluin J;Rossi JJ;Krontiris TG;Weitzel J;Daly MB;Benson AB;Kirkwood JM;O'Dwyer PJ;Sutphen R;Stewart JA;Johnson D;Larson GP
通讯作者：
Larson GP
影响因子：
64.8
作者：
Sanguinetti, MC;Curran, ME;Keating, MT
通讯作者：
Keating, MT
影响因子：
9.8
作者：
Tan, Zheng;Randall, Glenn;Ober, Carole
通讯作者：
Ober, Carole
影响因子：
37.8
作者：
Splawski, I;Shen, JX;Keating, MT
通讯作者：
Keating, MT