Maury Philippe, Moreau Adrien, Hidden-Lucet Francoise, Leenhardt Antoine, Fressart Veronique, Berthet Myriam, Denjoy Isabelle, Bennamar Nawal, Rollin Anne, Cardin Christelle, Guicheney Pascale, Chahine Mohamed
Unité de Rythmologie et de Stimulation Cardiaque, Fédération de Cardiologie, University Hospital Rangueil, 31059, Toulouse, Cedex 09, France.
J Interv Card Electrophysiol. 2013 Aug;37(2):131-40. doi: 10.1007/s10840-013-9805-7. Epub 2013 Apr 24.
Brugada syndrome (BrS) is an inherited cardiac disease characterized by ST segment elevation in V1-V3 ECG leads. Mutations SCN5A gene encoding for the cardiac voltage-gated Na(+) channel are found in some BrS patients, but also in family members with isolated conduction disturbances. However, some patients show coved ST elevation in the inferior or lateral leads whose association with SCN5A and familial conduction disturbances are poorly known.
Two novel SCN5A mutations, D1430N and Q1476X, were identified in two unrelated families comprising patients with Brugada-like ST elevation located in the inferior leads or isolated conduction disturbances. Wild-type (WT) and D1430N mutant channels were expressed in tsA201 cells. Patch clamp electrophysiological experiments revealed total absence of Na(+) current resulting from Nav1.5 mutant when compared to WT channels. Treatments known to restore trafficking defect (incubation at low temperature, with mexiletine or lidocaine) did not restore Na(+) current supporting that Nav1.5 mutation is not a defective trafficking mutation. Furthermore, immunocytolabelling indicates the membrane localisation of both WT and mutant channels confirming what we observed in our patch clamp experiments. This suggests that the mutation may induce a complete block of Na(+) permeation. The nonsense mutation Q1476X was leading to a premature stop codon and was not expressed.
Brugada-like ST elevation in the inferior ECG leads or isolated conduction disturbances were found in two unrelated families and associated with two novel SCN5A mutations. The missense and nonsense mutations are both resulting in a complete loss of ventricular Na(+) current explaining the phenotypes.
Brugada综合征（BrS）是一种遗传性心脏病，其特征为心电图V1-V3导联ST段抬高。在一些BrS患者中发现了编码心脏电压门控钠通道的SCN5A基因突变，在仅有传导障碍的家庭成员中也有发现。然而，一些患者在下壁或侧壁导联出现穹窿型ST段抬高，其与SCN5A及家族性传导障碍的关系尚不清楚。
在两个不相关的家族中鉴定出两个新的SCN5A突变，D1430N和Q1476X，这些家族中的患者在下壁导联有类似Brugada综合征的ST段抬高或仅有传导障碍。野生型（WT）和D1430N突变通道在tsA201细胞中表达。膜片钳电生理实验显示，与WT通道相比，Nav1.5突变体导致钠电流完全缺失。已知可恢复转运缺陷的处理方法（低温孵育、使用美西律或利多卡因）不能恢复钠电流，这支持Nav1.5突变不是转运缺陷突变。此外，免疫细胞化学标记显示WT和突变通道均定位于细胞膜，证实了我们在膜片钳实验中的观察结果。这表明该突变可能导致钠通透完全阻断。无义突变Q1476X导致提前终止密码子，未表达。
在两个不相关的家族中发现了下壁导联类似Brugada综合征的ST段抬高或仅有传导障碍，并与两个新的SCN5A突变相关。错义突变和无义突变均导致心室钠电流完全丧失，解释了这些表型。
