From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
Circ Res. 2017 May 12;120(10):e33-e44. doi: 10.1161/CIRCRESAHA.116.310112. Epub 2017 Feb 20.
Familial sinus node and atrioventricular conduction dysfunction is a rare disorder that leads to paroxysmal dizziness, fatigue, and syncope because of a temporarily or permanently reduced heart rate. To date, only a few genes for familial sinus and atrioventricular conduction dysfunction are known, and the majority of cases remain pathogenically unresolved.
We aim to identify the disease gene in a large 3-generation family (n=25) with autosomal dominant sinus node dysfunction (SND) and atrioventricular block (AVB) and to characterize the mutation-related pathomechanisms in familial SND+AVB.
Genome-wide linkage analysis mapped the SND+AVB disease locus to chromosome 7q21.1-q31.1 (2-point logarithm of the odds score: 4.64; θ=0); in this region, targeted exome sequencing identified a novel heterozygous mutation (p.Arg52Leu) in the gene that strictly cosegregated with the SND+AVB phenotype. encodes the β subunit (Gβ) of the heterotrimeric G-protein complex that is being released from G-protein-coupled receptors on vagal stimulation. In 2 heterologous expression systems (HEK-293T cells and oocytes), an enhanced activation of the G-protein-activated K channel (GIRK; Kir3.1/Kir3.4) was shown when mutant Gβ was coexpressed with Gγ; this was in contrast to coexpression of mutant Gβ-Gγ with other cardiac ion channels (HCN4, HCN2, and Cav1.2). Molecular dynamics simulations suggested a reduced binding property of mutant Gβ to cardiac GIRK channels when compared with native Gβ.
A gene mutation is associated with familial SND+AVB and leads to a sustained activation of cardiac GIRK channels, which is likely to hyperpolarize the myocellular membrane potential and thus reduces their spontaneous activity. Our findings describe for the first time a role of a mutant G-protein in the nonsyndromic pacemaker disease because of GIRK channel activation.
家族性窦房结和房室传导功能障碍是一种罕见的疾病，由于心率暂时或永久性降低，导致阵发性头晕、疲劳和晕厥。迄今为止，已知的家族性窦房结和房室传导功能障碍的基因只有少数几个，大多数病例的发病机制仍未得到解决。
我们旨在鉴定一个大型三代家族（n=25）中与常染色体显性窦房结功能障碍（SND）和房室传导阻滞（AVB）相关的疾病基因，并对家族性 SND+AVB 的突变相关发病机制进行特征描述。
全基因组连锁分析将 SND+AVB 疾病基因座定位在染色体 7q21.1-q31.1（两点对数优势得分：4.64；θ=0）；在该区域，靶向外显子组测序发现了一个新的杂合突变（p.Arg52Leu），位于 基因中，该突变与 SND+AVB 表型严格共分离。 编码异三聚体 G 蛋白复合物的β亚基（Gβ），该复合物在迷走神经刺激时从 G 蛋白偶联受体上释放。在 2 种异源表达系统（HEK-293T 细胞和 卵母细胞）中，当突变 Gβ与 Gγ共表达时，G 蛋白激活的 K 通道（GIRK；Kir3.1/Kir3.4）的激活增强；这与突变 Gβ-Gγ与其他心脏离子通道（HCN4、HCN2 和 Cav1.2）共表达形成对比。分子动力学模拟表明，与天然 Gβ相比，突变 Gβ与心脏 GIRK 通道的结合能力降低。
基因突变与家族性 SND+AVB 相关，并导致心脏 GIRK 通道持续激活，这可能使心肌膜电位超极化，从而降低其自发活动。我们的研究结果首次描述了一种突变 G 蛋白在非综合征性起搏疾病中的作用，原因是 GIRK 通道激活。
