Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Technical University of Denmark, Lyngby, Denmark.
Ann Rheum Dis. 2022 Aug;81(8):1151-1161. doi: 10.1136/annrheumdis-2021-221714. Epub 2022 Apr 25.
Neonatal lupus erythematosus (NLE) may develop after transplacental transfer of maternal autoantibodies with cardiac manifestations (congenital heart block, CHB) including atrioventricular block, atrial and ventricular arrhythmias, and cardiomyopathies. The association with anti-Ro/SSA antibodies is well established, but a recurrence rate of only 12%-16% despite persisting maternal autoantibodies suggests that additional factors are required for CHB development. Here, we identify fetal genetic variants conferring risk of CHB and elucidate their effects on cardiac function.
A genome-wide association study was performed in families with at least one case of CHB. Gene expression was analysed by microarrays, RNA sequencing and PCR and protein expression by western blot, immunohistochemistry, immunofluorescence and flow cytometry. Calcium regulation and connectivity were analysed in primary cardiomyocytes and cells induced from pleuripotent stem cells. Fetal heart performance was analysed by Doppler/echocardiography.
We identified as a novel fetal susceptibility gene, with decreased cardiac expression of associated with the disease risk genotype. We further demonstrate that fetal cardiomyocytes deficient in auxilin, the protein encoded by , have abnormal connectivity and Ca homoeostasis in culture, as well as decreased cell surface expression of the Ca1.3 calcium channel. Doppler echocardiography of auxilin-deficient fetal mice revealed cardiac NLE abnormalities in utero, including abnormal heart rhythm with atrial and ventricular ectopias, as well as a prolonged atrioventricular time intervals.
Our study identifies auxilin as the first genetic susceptibility factor in NLE modulating cardiac function, opening new avenues for the development of screening and therapeutic strategies in CHB.
新生儿红斑狼疮（NLE）可能是由于母体自身抗体通过胎盘转移而引起的，其心脏表现包括先天性心脏传导阻滞（CHB），包括房室传导阻滞、心房和心室心律失常以及心肌病。与抗 Ro/SSA 抗体的关联已得到充分证实，但尽管存在持续的母体自身抗体，复发率仅为 12%-16%，这表明 CHB 发展还需要其他因素。在这里，我们确定了赋予 CHB 风险的胎儿遗传变异，并阐明了它们对心脏功能的影响。
对至少有一个 CHB 病例的家族进行了全基因组关联研究。通过微阵列、RNA 测序和 PCR 分析基因表达，通过 Western blot、免疫组织化学、免疫荧光和流式细胞术分析蛋白表达。通过钙调节和连接性分析原代心肌细胞和多能干细胞诱导的细胞。通过多普勒/超声心动图分析胎儿心脏功能。
我们确定了 作为一种新的胎儿易感性基因，与疾病风险基因型相关的 心脏表达降低。我们进一步证明，辅助蛋白缺失的胎儿心肌细胞 ，在培养中具有异常的连接性和钙稳态，以及钙通道 1.3 的细胞表面表达减少。辅助蛋白缺失的胎儿小鼠的多普勒超声心动图显示胎儿 NLE 异常，包括心律失常伴心房和心室异位，以及房室时间间隔延长。
我们的研究确定了辅助蛋白作为 NLE 调节心脏功能的第一个遗传易感性因素，为 CHB 的筛查和治疗策略的发展开辟了新的途径。
