Inhibition of G-protein signaling in cardiac dysfunction of Intellectual Developmental Disorder with Cardiac Arrhythmia (IDDCA) syndrome.

Background: Pathogenic variants of GNB5 encoding the beta5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia. Methods: We used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse. Results: We delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signaling is essential for parasympathetic control of heart rate and maintenance of the sympatho-vagal balance. Gnb5-/- mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/-, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation, resulted in a higher baseline heart rate in Gnb5-/- mice. In contrast, Gnb5-/- mice exhibited profound bradycardia upon treatment with Carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described thirteen affected individuals, increasing the IDDCA cohort to 44 patients. Conclusions: Our data demonstrate that loss of negative regulation of the inhibitory G-protein signaling causes heart rate perturbations in Gnb5-/- mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unraveling the mechanism of Gnb5-signaling in the autonomic control of the heart will pave the way for future drug screening. Six biological replicates of knock-out, heterozygous and control mouse atria and ventricles; six biological replicates of knock-out and control mouse hippocampi, cerebellum and cerebral cortex背景：编码鸟苷酸结合蛋白β5亚基的GNB5基因致病性变异可导致IDDCA综合征，这是一种常染色体隐性遗传神经发育障碍，伴随认知功能障碍与心律失常，尤以严重心动过缓为典型表现。 方法：本研究采用超声心动图及遥测心电图记录技术，探究Gnb5基因缺失对小鼠产生的生物学效应。 结果：本研究阐明了Gnb5在心脏窦房传导中的关键作用，证实Gnb5介导的抑制性G蛋白信号通路对于副交感神经调控心率以及维持交感-迷走神经平衡至关重要。与野生型（Gnb5+/+）及杂合型（Gnb5+/-）小鼠相比，Gnb5纯合敲除（Gnb5-/-）小鼠体型更小，心脏体积也更小，但心脏功能更优。由于副交感神经调控减弱、交感神经调控增强，自主神经系统对心脏的调制作用降低，导致Gnb5-/-小鼠的基础心率升高。与之相反，Gnb5-/-小鼠在给予卡巴胆碱（Carbachol）处理后会出现严重心动过缓，而心脏刺激的交感神经调控并未发生改变。与之相符的是，转录组学研究发现，纯合敲除小鼠的心房与心室中，参与心肌收缩功能的基因表达出现显著异常。Gnb5纯合缺失会显著提高窦性心律失常的发生频率。此外，本研究新增13例IDDCA综合征患者，使该疾病的队列规模扩大至44例。 结论：本研究数据证实，抑制性G蛋白信号通路的负调控缺失会导致Gnb5-/-小鼠出现心率紊乱，该效应主要由副交感神经功能受损介导。我们预期，阐明Gnb5信号通路在心脏自主神经调控中的作用机制，将为后续药物筛选工作奠定坚实基础。 样本信息：敲除型、杂合型与野生型小鼠的心房及心室组织，各6个生物学重复；敲除型与野生型小鼠的海马体、小脑及大脑皮层组织，各6个生物学重复。