Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Department of Pediatric Gastroenterology, Shanghai Institute for Pediatric Research, Shanghai, China.
J Med Genet. 2020 Sep;57(9):634-642. doi: 10.1136/jmedgenet-2019-106615. Epub 2020 Feb 17.
Hirschsprung disease (HSCR) is a life-threatening congenital disorder in which the enteric nervous system is completely missing from the distal gut. Recent studies have shown that miR-4516 markedly inhibits cell migration, and as one of its potential targets, functions as a modifier for developing HSCR. We thus aimed to evaluate the role of miR-4516 and in HSCR and how they contribute to the pathogenesis of HSCR.
We examined 13 genetic variants using the MassArray system in a case-control study (n=1015). We further investigated miR-4516-mediated regulation of MAPK10 in HSCR cases and human neural cells, the effects of -acting elements in MAPK10 on miR-4516-mediated modulation and cell migration process.
Three positive 3' UTR variants in were associated with altered HSCR susceptibility. We also showed that miR-4516 directly regulates expression, and this regulatory mechanism is significantly affected by the 3' UTR -acting elements of . In addition, knock-down of rescued the effect of miR-4516 on the migration of human neural cells.
Our findings indicate a key role of miR-4516 and its direct target in HSCR risk, and highlight the general importance of - and posttranscriptional modulation for HSCR pathogenesis.
先天性巨结肠（HSCR）是一种危及生命的先天性疾病，其肠神经系统完全缺失。最近的研究表明，miR-4516 显著抑制细胞迁移，作为其潜在靶点之一， 作为发育性 HSCR 的修饰因子。因此，我们旨在评估 miR-4516 和 在 HSCR 中的作用以及它们如何导致 HSCR 的发病机制。
我们使用 MassArray 系统在病例对照研究中检查了 13 个遗传变异（n=1015）。我们进一步研究了 miR-4516 在 HSCR 病例和人神经细胞中对 MAPK10 的调节作用，MAPK10 的 - 作用元件对 miR-4516 介导的调节和细胞迁移过程的影响。
中的三个阳性 3'UTR 变异与改变的 HSCR 易感性相关。我们还表明，miR-4516 直接调节 表达，这种调节机制受 的 3'UTR - 作用元件显著影响。此外， 敲低挽救了 miR-4516 对人神经细胞迁移的影响。
我们的研究结果表明，miR-4516 及其直接靶标 在 HSCR 风险中起关键作用，并强调了 - 和转录后调节对 HSCR 发病机制的普遍重要性。
