MicroRNA-4516-mediated regulation of MAPK10 relies on 3' UTR cis -acting variants and contributes to the altered risk of Hirschsprung disease.

Background 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,MAPK10functions as a modifier for developing HSCR. We thus aimed to evaluate the role of miR-4516 andMAPK10in HSCR and how they contribute to the pathogenesis of HSCR. Methods 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 ofcis-acting elements in MAPK10 on miR-4516-mediated modulation and cell migration process. Results Three positive 3 ' UTR variants inMAPK10were associated with altered HSCR susceptibility. We also showed that miR-4516 directly regulatesMAPK10expression, and this regulatory mechanism is significantly affected by the 3 ' UTRcis-acting elements ofMAPK10. In addition, knock-down ofMAPK10rescued the effect of miR-4516 on the migration of human neural cells. Conclusion Our findings indicate a key role of miR-4516 and its direct targetMAPK10in HSCR risk, and highlight the general importance ofcis- and posttranscriptional modulation for HSCR pathogenesis.