In:
Journal of Medical Genetics, BMJ, Vol. 57, No. 9 ( 2020-09), p. 634-642
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0022-2593
,
1468-6244
DOI:
10.1136/jmedgenet-2019-106615
Language:
English
Publisher:
BMJ
Publication Date:
2020
detail.hit.zdb_id:
2009590-9
SSG:
12
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