SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del.
SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del.
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家族性扩张型心肌病中的 SCN5A 罕见变异体根据常见多态性 H558R 和常见剪接变异体 Q1077del 降低峰值钠电流
DOI：
10.1111/j.1752-8062.2010.00249.x
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发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Hershberger RE
中科院分区：
文献类型：
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作者：
Cheng J;Morales A;Siegfried JD;Li D;Norton N;Song J;Gonzalez-Quintana J;Makielski JC;Hershberger RE
获得新鉴定的罕见变异的功能数据增加了确定性，即鉴定的变异与扩张型心肌病（DCM）病因相关。两个新的SCN 5A罕见变异体，R222 Q和I1835 T，与DCM分离在两个家庭中，受影响的个人纯合或杂合的共同SCN 5A多态性H558 R。在具有和不具有H558 R多态性的常见Q1077 del或Q1077剪接变体背景中构建具有每种罕见变体的cDNA，并在HEK 293细胞中表达。使用全细胞电压钳研究每种细胞的钠电流（INa）。在Q1077 del背景中，R222 Q和I1835 T的INa密度与野生型没有差异，但R222 Q/H558 R、I1835 T/H558 R的组合变体分别引起约35%和约30%的降低，并且各自显示出从失活的较慢恢复。在Q1077 del背景中，R222 Q和R222 Q/H558 R也在激活和失活中表现出显著的负偏移，而I1835 T/H558 R在失活中表现出显著的负偏移，其倾向于降低窗口电流。相比之下，Q1077背景中的表达显示，对于R222 Q/H558 R和I1835 T/H558 R，峰值INa密度、衰减或从失活恢复没有变化。我们的结论是，生物物理学研究结果，依赖于常见的SCN 5A变异，提供了进一步的证据，这些新的SCN 5A罕见变异与DCM有关。《临床和跨科学》2010年;第3卷：287-294
Obtaining functional data with newly identified rare variants increases certainty that the variant identified is relevant for dilated cardiomyopathy (DCM) causation. Two novel SCN5A rare variants, R222Q and I1835T, segregated with DCM in two families with affected individuals homozygous or heterozygous for the common SCN5A polymorphism H558R. cDNAs with each rare variant were constructed in the common Q1077del or Q1077 splice variant backgrounds with and without the H558R polymorphism and expressed in HEK293 cells. Sodium current (INa) was studied for each using whole‐cell voltage clamp. In the Q1077del background INa densities of R222Q and I1835T were not different from wild type, but the combined variants of R222Q/H558R, I1835T/H558R caused approximately 35% and approximately 30% reduction, respectively, and each showed slower recovery from inactivation. In the Q1077del background R222Q and R222Q/H558R also exhibited a significant negative shift in both activation and inactivation while I1835T/H558R showed a significant negative shift in inactivation that tended to decrease window current. In contrast, expression in the Q1077 background showed no changes in peak INa densities, decay, or recovery from inactivation for R222Q/H558R and I1835T/H558R. We conclude that the biophysical findings, dependent upon common SCN5A variants, provide further evidence that these novel SCN5A rare variants are relevant for DCM. Clin Trans Sci 2010; Volume 3: 287–294