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

  1. Yang Wang1,2,
  2. Qian Jiang3,
  3. Aravinda Chakravarti4,
  4. Hao Cai1,5,
  5. Ze Xu1,5,
  6. Wenjie Wu1,5,
  7. Beilin Gu1,
  8. Long Li6,
  9. Wei Cai1,2
  1. 1
    Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  2. 2
    Department of Pediatric Gastroenterology, Shanghai Institute for Pediatric Research, Shanghai, China
  3. 3
    Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China
  4. 4
    Center for Human Genetics and Genomics, New York University School of Medicine, New York, New York, USA
  5. 5
    Department of Pediatric Gastroenterology, Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
  6. 6
    Department of General Surgery, Capital Institute of Pediatrics Affiliated Children’s Hospital, Beijing, China
  1. Correspondence to
    Dr Wei Cai, Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; caiw204{at}sjtu.edu.cn; Dr Yang Wang, Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; wangyang{at}xinhuamed.com.cn; Dr Long Li, Department of General Surgery, Capital Institute of Pediatrics Affiliated Children’s Hospital, Beijing 100020, China; lilong23{at}126.com

Abstract

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, MAPK10 functions as a modifier for developing HSCR. We thus aimed to evaluate the role of miR-4516 and MAPK10 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 cis-acting elements in MAPK10 on miR-4516-mediated modulation and cell migration process.

Results Three positive 3? UTR variants in MAPK10 were associated with altered HSCR susceptibility. We also showed that miR-4516 directly regulates MAPK10 expression, and this regulatory mechanism is significantly affected by the 3? UTR cis-acting elements of MAPK10. In addition, knock-down of MAPK10 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 MAPK10 in HSCR risk, and highlight the general importance of cis– and posttranscriptional modulation for HSCR pathogenesis.

  • gastroenterology
  • genetics

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