Partial and complete loss of myosin binding protein H-like cause cardiac conduction defects.
Partial and complete loss of myosin binding protein H-like cause cardiac conduction defects.
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DOI：
10.1016/j.yjmcc.2022.04.012
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发表时间：
2022-08
影响因子：
5
通讯作者：
McNally, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Barefield, David Y.;Yamakawa, Sean;Tahtah, Ibrahim;Sell, Jordan J.;Broman, Michael;Laforest, Brigitte;Harris, Sloane;Alvarez-Arce, Alejandro;Araujo, Kelly N.;Puckelwartz, Megan J.;Wasserstrom, J. Andrew;Fishman, Glenn I.;McNally, Elizabeth M.
关键词：
人的MYBPHL过早截短和小鼠的Mybphl缺失与扩张型心肌病、房性和室性心律失常以及心房扩大有关。MYBPHL编码肌球蛋白结合蛋白H样（MyBP-HL）。先前在小鼠中的工作间接鉴定了Mybphl在心房和整个心室的小斑点中的表达。由于其与人类和小鼠心脏传导系统疾病的遗传关联，我们评估了MyBP-HL的解剖定位和MyBP-HL缺失对传导系统功能的影响。正常成年小鼠心室的免疫荧光显微镜鉴定了MyBP-HL阳性心室心肌细胞，其与房室结附近的心室传导系统标记物contactin-2和浦肯野纤维的子集共定位。与对照相比，Mybphl杂合心室的MyBP-HL阳性细胞显著减少。正常围产期第5天小鼠心脏的光片显微镜检查显示，MyBP-HL阳性细胞在contactin-2阳性心室传导系统内和紧邻处富集，但这种关联在Mybphl杂合子心脏中不明显。Mybphl基因敲除小鼠的体表遥测显示房室传导阻滞和心房二联律，而心内起搏显示较短的心房相对不应期和房性心动过速。分离的Mybphl-空心房心肌细胞的钙瞬变分析表明，与野生型对照相比，钙释放的异质性增加，钙释放速率更快。Mybphl杂合和纯合无效心房心肌细胞的超分辨率显微镜显示与野生型对照相比ryanodine受体紊乱。在Mybphl无效而非野生型对照心脏中观察到的异常钙释放、较短的心房不应期和心房扩张与观察到的房性心律失常、二联律和房性心动过速一致，而MyBP-HL阳性细胞与心室传导系统的接近提供了对心房主要表达的基因如何促成室性心律失常和心室功能障碍的深入了解。
A premature truncation of MYBPHL in humans and a loss of Mybphl in mice is associated with dilated cardiomyopathy, atrial and ventricular arrhythmias, and atrial enlargement. MYBPHL encodes myosin binding protein H-like (MyBP-HL). Prior work in mice indirectly identified Mybphl expression in the atria and in small puncta throughout the ventricle. Because of its genetic association with human and mouse cardiac conduction system disease, we evaluated the anatomical localization of MyBP-HL and the consequences of loss of MyBP-HL on conduction system function. Immunofluorescence microscopy of normal adult mouse ventricles identified MyBP-HL-positive ventricular cardiomyocytes that co-localized with the ventricular conduction system marker contactin-2 near the atrioventricular node and in a subset of Purkinje fibers. Mybphl heterozygous ventricles had a marked reduction of MyBP-HL-positive cells compared to controls. Lightsheet microscopy of normal perinatal day 5 mouse hearts showed enrichment of MyBP-HL-positive cells within and immediately adjacent to the contactin-2-positive ventricular conduction system, but this association was not apparent in Mybphl heterozygous hearts. Surface telemetry of Mybphl-null mice revealed atrioventricular block and atrial bigeminy, while intracardiac pacing revealed a shorter atrial relative refractory period and atrial tachycardia. Calcium transient analysis of isolated Mybphl-null atrial cardiomyocytes demonstrated an increased heterogeneity of calcium release and faster rates of calcium release compared to wild type controls. Super-resolution microscopy of Mybphl heterozygous and homozygous null atrial cardiomyocytes showed ryanodine receptor disorganization compared to wild type controls. Abnormal calcium release, shorter atrial refractory period, and atrial dilation seen in Mybphl null, but not wild type control hearts, agree with the observed atrial arrhythmias, bigeminy, and atrial tachycardia, whereas the proximity of MyBP-HL-positive cells with the ventricular conduction system provides insight into how a predominantly atrial expressed gene contributes to ventricular arrhythmias and ventricular dysfunction.
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影响因子：
20.1
作者：
Alyonycheva, T;CohenGould, L;Mikawa, T
通讯作者：
Mikawa, T
影响因子：
9.7
作者：
Lee, Seung-Pyo;Ashley, Euan A.;Perez, Marco V.
通讯作者：
Perez, Marco V.
DOI：
10.1016/s0735-1097(02)01724-2
发表时间：
2002-03-20
影响因子：
24
作者：
Arbustini, E;Pilotto, A;Tavazzi, L
通讯作者：
Tavazzi, L
DOI：
10.1111/j.1540-8159.2008.01199.x
发表时间：
2008-11-01
影响因子：
1.8
作者：
Brembilla-Perrot, Beatrice;Alla, Francois;Juilliere, Yves
通讯作者：
Juilliere, Yves
影响因子：
9.7
作者：
Aubert, Gregory;Barefield, David Y.;McNally, Elizabeth M.
通讯作者：
McNally, Elizabeth M.