Keller Dagmar I, Barrane Fatima-Zahara, Gouas Laetitia, Martin Johannie, Pilote Sylvie, Suarez Vivian, Osswald Stefan, Brink Marijke, Guicheney Pascale, Schwick Nicola, Chahine Mohamed
Institut national de la santé et de la recherche médicale U582, Institut Fédératif de Recherche No 14, Pitié-Salpêtrière Hospital, Paris, France.
Can J Cardiol. 2005 Sep;21(11):925-31.
Brugada syndrome (BS) is an electrical cardiac disorder with a right bundle branch block and ST segment elevation in leads V1 to V3 on surface electrocardiograms (ECGs), and is a syndrome that may lead to sudden cardiac death.
The aim of the present study was to screen for mutations in the SCN5A gene in a family with BS, and to characterize the consequences of the mutation on channel function.
A heterozygous nonsense SCN5A mutation (W822X) was identified in the index patient. The mutation was confirmed in the patient's asymptomatic 16-year-old brother and 48-year-old father. The mutation was absent in the index patient's sister and mother. The ECG of the index patient showed a BS type 2 ECG phenotype, which converted into a type 1 ECG phenotype in the presence of flecainide. The ECG of the patient's brother was not typical for BS, but ajmaline treatment unmasked a type 1 ECG phenotype. The ECG of the asymptomatic father was normal at baseline and in the presence of ajmaline. No Na+ currents could be measured in tsA201 cells transfected with W822X mutant channels. Heterozygote expression showed a nearly 50% reduction in Na+ current amplitude with no significant alterations of biophysical properties, indicating a loss of functional Na+ channels, obviously without any dominant-negative activity on wild type channels.
The haploinsufficiency of the Nav1.5 protein is the plausible explanation for the clinical BS phenotype in this family. Because the heterozygous W822X mutation theoretically leads to channel expression at one-half of the normal level, the authors suggest that a modifier gene may influence or rescue the phenotype in the asymptomatic family members.
Brugada综合征（BS）是一种心脏电紊乱疾病，体表心电图（ECG）显示V1至V3导联出现右束支传导阻滞和ST段抬高，是一种可能导致心源性猝死的综合征。
本研究旨在筛查一个BS家系中SCN5A基因的突变，并确定该突变对通道功能的影响。
在索引患者中鉴定出一个杂合的无义SCN5A突变（W822X）。该突变在患者无症状的16岁弟弟和48岁父亲中得到证实。索引患者的妹妹和母亲未检测到该突变。索引患者的心电图显示为2型BS心电图表型，在氟卡尼存在的情况下转变为1型心电图表型。患者弟弟的心电图并非典型的BS表现，但阿义马林治疗揭示出1型心电图表型。无症状父亲的心电图在基线时及阿义马林作用下均正常。用W822X突变通道转染的tsA201细胞中未检测到钠电流。杂合子表达显示钠电流幅度降低近50%，生物物理特性无明显改变，表明功能性钠通道丧失，且对野生型通道无明显显性负性作用。
Nav1.5蛋白的单倍体不足是该家系临床BS表型的合理原因。由于杂合的W822X突变理论上导致通道表达水平为正常水平的一半，作者认为修饰基因可能影响或挽救无症状家庭成员的表型。
