TAMM41 is required for heart valve differentiation via regulation of PINK-PARK2 dependent mitophagy
TAMM41 is required for heart valve differentiation via regulation of PINK-PARK2 dependent mitophagy
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TAMM41 通过调节 PINK-PARK2 依赖性线粒体自噬来实现心脏瓣膜分化
DOI：
10.1038/s41418-019-0311-z
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发表时间：
2019-11-01
影响因子：
12.4
通讯作者：
Zhu, Jun
中科院分区：
文献类型：
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作者：
Yang, Rui Meng;Tao, Jiong;Zhu, Jun
TAMM41位于3p25缺失综合征的先天性心脏病(CHD)敏感区域，是一种对酵母生存至关重要的线粒体膜维持蛋白，但其在高等脊椎动物中的功能尚不清楚。通过在体斑马鱼模型的建立，我们发现在发育中的心脏组织中，Tamm41基因高度表达，其缺失会导致心脏瓣膜的异常。分子机制研究表明，TAMM41相互作用并调节依赖于PINK1-PARK2的有丝分裂吞噬通路，从而提示TAMM41参与斑马鱼胚胎心脏发生过程中心脏瓣膜的发育。此外，通过在118例散发性房室间隔缺损(AVSD)患者中筛选3p25缺失综合征的先天性心脏病(CHD)敏感区域，我们发现了3例携带TAMM41致病内含子杂合变异的病例。这三个病例都缺乏正常的全长TAMM41转录本，很可能是由于突变等位基因的特定表达。总之，我们的研究强调了TAMM41依赖的有丝分裂在心脏发育中的重要作用，并为AVSD的病因学提供了新的见解。
TAMM41, located within the congenital heart diseases (CHD) sensitive region of 3p25 deletion syndrome, is a mitochondrial membrane maintenance protein critical for yeast survival, but its function in higher vertebrates remains unknown. Via in vivo zebrafish model, we found that tamm41 is highly expressed in the developing heart and deficiency of which led to heart valve abnormalities. Molecular mechanistic studies revealed that TAMM41 interacts and modulates the PINK1-PARK2 dependent mitophagy pathway, thereby implicating TAMM41 in heart valve development during zebrafish embryonic cardiogenesis. Furthermore, through screening of the congenital heart diseases (CHD) sensitive region of 3p25 deletion syndrome among 118 sporadic atrioventricular septal defect (AVSD) patients, we identified three cases carrying heterozygous pathogenic intronic variants of TAMM41. All three cases lacked normal full-length TAMM41 transcripts, most likely due to specific expression of the mutant allele. Collectively, our studies highlight essential roles for TAMM41-dependent mitophagy in development of the heart and provide novel insights into the etiology of AVSD.