Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome.
Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome.
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DOI：
10.1016/j.jacc.2014.04.032
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发表时间：
2014-07-08
影响因子：
24
通讯作者：
Antzelevitch, Charles
中科院分区：
文献类型：
--
作者：
Hu, Dan;Barajas-Martinez, Hector;Pfeiffer, Ryan;Dezi, Fabio;Pfeiffer, Jenna;Buch, Tapan;Betzenhauser, Matthew J.;Belardinelli, Luiz;Kahlig, Kristopher M.;Rajamani, Sridharan;DeAntonio, Harry J.;Myerburg, Robert J.;Ito, Hiroyuki;Deshmukh, Pramod;Marieb, Mark;Nam, Gi-Byoung;Bhatia, Atul;Hasdemir, Can;Haissaguerre, Michel;Veltmann, Christian;Schimpf, Rainer;Borggrefe, Martin;Viskin, Sami;Antzelevitch, Charles
关键词：
本研究的目的是检验SCN 10A变异有助于Brugada综合征（BrS）发展的假设。BrS是一种遗传性心脏性猝死综合征。不到35%的BrS先证者具有遗传鉴定的致病性变体。最近的证据表明，SCN 10A是一种神经元钠通道基因，编码心脏电功能中的Nav1.8。对150名先证者、家族成员和>200名健康对照者进行了BrS易感基因的临床分析和直接测序。进行表达和免疫共沉淀研究以功能性地表征推定的致病突变。我们在25名先证者（20名男性/5名女性）中发现了17个SCN 10A突变; 25名先证者中有23名（92.0%）表现出重叠表型。在16.7%的BrS先证者中发现了SCN 10A突变，接近我们的SCN 5A突变率（20.1%）。与SCN 10A阴性BrS先证者相比，SCN 10A突变的BrS患者症状更明显，PR和QRS间期显著延长。大多数突变位于跨膜区。野生型（WT）SCN 10A与WT-SCN 5A在HEK细胞中的异源共表达导致钠通道电流（INa）与单独的WT-SCN 5A相比接近加倍。相比之下，SCN 10A突变体（R14 L和R1268 Q）与WT-SCN 5A的共表达分别导致INa减少79.4%和84.4%。进行的免疫共沉淀研究提供了Nav1.8和Nav1.5在质膜中共缔合的证据。我们的研究确定了SCN 10A作为BrS的主要易感基因，从而大大提高了我们对先证者和家族成员进行基因分型和风险分层的能力。
The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS). BrS is an inherited sudden cardiac death syndrome. Fewer than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Nav1.8 in the electrical function of the heart. Clinical analysis and direct sequencing of BrS-susceptibility genes were performed on 150 probands, family members and >200 healthy controls. Expression and co-immunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations. We identified 17 SCN10A mutations in 25 probands (20 M/5 F); 23 of the 25 (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). BrS patients with SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals than SCN10A negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous co-expression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current (INa) compared with WT-SCN5A alone. In contrast, co-expression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in INa, respectively. Co-immunoprecipitation studies performed provide evidence for co-association of Nav1.8 and Nav1.5 in the plasma membrane. Our study identifies SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.
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影响因子：
24
作者：
Crotti, Lia;Marcou, Cherisse A.;Tester, David J.;Castelletti, Silvia;Giudicessi, John R.;Torchio, Margherita;Medeiros-Domingo, Argelia;Simone, Savastano;Will, Melissa L.;Dagradi, Federica;Schwartz, Peter J.;Ackerman, Michael J.
通讯作者：
Ackerman, Michael J.
影响因子：
3.5
作者：
Kearney, JA;Yang, Y;Frankel, WN
通讯作者：
Frankel, WN
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
4.5
作者：
Smith JG;Magnani JW;Palmer C;Meng YA;Soliman EZ;Musani SK;Kerr KF;Schnabel RB;Lubitz SA;Sotoodehnia N;Redline S;Pfeufer A;Müller M;Evans DS;Nalls MA;Liu Y;Newman AB;Zonderman AB;Evans MK;Deo R;Ellinor PT;Paltoo DN;Newton-Cheh C;Benjamin EJ;Mehra R;Alonso A;Heckbert SR;Fox ER;Candidate-gene Association Resource (CARe) Consortium
通讯作者：
Candidate-gene Association Resource (CARe) Consortium
影响因子：
1.3
作者：
Antzelevitch, Charles;Yan, Gan-Xin
通讯作者：
Yan, Gan-Xin