Lübkemeier Indra, Bosen Felicitas, Kim Jung-Sun, Sasse Philipp, Malan Daniela, Fleischmann Bernd K, Willecke Klaus
From the Life and Medical Sciences (LIMES) Institute, Molecular Genetics (I.L., F.B., K.W.) and Institute of Physiology I, Life and Brain Center (P.S., D.M., B.K.F.), University of Bonn, Bonn, Germany; and Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (J.-S.K.).
Circ Cardiovasc Genet. 2015 Feb;8(1):21-9. doi: 10.1161/CIRCGENETICS.114.000793. Epub 2014 Dec 10.
Sudden infant death syndrome (SIDS) describes the sudden, unexplained death of a baby during its first year of age and is the third leading cause of infant mortality. It is assumed that ≤20% of all SIDS cases are because of cardiac arrhythmias resulting from mutations in ion channel proteins. Besides ion channels also cardiac gap junction channels are important for proper conduction of cardiac electric activation. In the mammalian heart Connexin43 (Cx43) is the major gap junction protein expressed in ventricular cardiomyocytes. Recently, a novel Connexin43 loss-of-function mutation (Cx43E42K) was identified in a 2-month-old SIDS victim.
We have generated Cx43E42K-expressing mice as a model for SIDS. Heterozygous cardiac-restricted Cx43E42K-mutated mice die neonatally without major cardiac morphological defects. Electrocardiographic recordings of embryonic Cx43+/E42K mice reveal severely disturbed ventricular activation, whereas immunohistochemical analyses show normal localization and expression patterns of gap junctional Connexin43 protein in the Cx43E42K-mutated newborn mouse heart.
Because we did not find heterogeneous gap junction loss in Cx43E42K mouse hearts, we conclude that the Cx43E42K gap junction channel creates an arrhythmogenic substrate leading to lethal ventricular arrhythmias. The strong cardiac phenotype of Cx43E42K expressing mice supports the association between the human Cx43E42K mutation and SIDS and indicates that Connexin43 mutations should be considered in future studies when SIDS cases are to be molecularly explained.
婴儿猝死综合征（SIDS）指婴儿在出生后第一年突然发生的、原因不明的死亡，是婴儿死亡的第三大主要原因。据推测，所有SIDS病例中≤20%是由离子通道蛋白突变导致的心律失常引起的。除离子通道外，心脏缝隙连接通道对心脏电活动的正常传导也很重要。在哺乳动物心脏中，连接蛋白43（Cx43）是心室心肌细胞中表达的主要缝隙连接蛋白。最近，在一名2个月大的SIDS受害者中发现了一种新的连接蛋白43功能丧失突变（Cx43E42K）。
我们构建了表达Cx43E42K的小鼠作为SIDS模型。杂合子心脏限制性Cx43E42K突变小鼠在新生儿期死亡，无明显心脏形态缺陷。对胚胎期Cx43+/E42K小鼠的心电图记录显示心室激活严重紊乱，而免疫组织化学分析显示Cx43E42K突变新生小鼠心脏中缝隙连接连接蛋白43蛋白的定位和表达模式正常。
由于我们在Cx43E42K小鼠心脏中未发现异质性缝隙连接丧失，我们得出结论，Cx43E42K缝隙连接通道产生了致心律失常底物，导致致命性室性心律失常。表达Cx43E42K的小鼠的强烈心脏表型支持了人类Cx43E42K突变与SIDS之间的关联，并表明在未来研究分子解释SIDS病例时应考虑连接蛋白43突变。
