MicroRNA-4516-mediated regulation of relies on 3' UTR -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, 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.

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 of -acting elements in MAPK10 on miR-4516-mediated modulation and cell migration process.

RESULTS

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.

CONCLUSION

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.