Mutations of the gene encoding the tyrosine kinase causes Hirschsprung's disease (HSCR) and medullary thyroid carcinoma (MTC). Current consensus holds that HSCR and MTC are induced by inactivating and activating RET mutations, respectively. However, it remains unknown whether activating mutations in the gene have adverse effects on ENS development We addressed this issue by examining mice engineered to express RET51(C618F), an activating mutation identified in MTC patients. Although mice displayed hyperganglionosis of the ENS, mice exhibited severe intestinal aganglionosis because of premature neuronal differentiation. Reduced levels of glial cell-derived neurotrophic factor (GDNF), a RET-activating neurotrophic factor, ameliorated the ENS phenotype of mice, demonstrating that GDNF-mediated activation of RET51(C618F) is responsible for severe aganglionic phenotype. The allele showed genetic interaction with gene, one of modifier genes for HSCR. These data reveal that proliferation and differentiation of ENS precursors are exquisitely controlled by both the activation levels and total dose of RET. Increased RET activity coupled with a decreased gene dosage can cause intestinal aganglionosis, a finding that provides novel insight into HSCR pathogenesis.
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http://dx.doi.org/10.1523/ENEURO.0534-20.2021 | DOI Listing |
Cureus
November 2024
Pediatric Medicine, New York Institute of Technology (NYIT) College of Osteopathic Medicine, Old Westbury, USA.
Hirschsprung's disease is a congenital condition characterized by the absence of ganglion cells in the intestines, leading to bowel obstruction. The lack of ganglion cells disrupts the normal motility of the intestines, causing a functional obstruction. This can lead to enterocolitis, an inflammation of the intestines, which is a serious complication in infants with Hirschsprung's disease.
View Article and Find Full Text PDFPediatr Surg Int
December 2024
Department of Pediatric Surgery, University of Medicine and Pharmacy at Ho Chi Minh City, 217 Hong Bang, Ward 11, District 5, Ho Chi Minh City, Vietnam.
Background: The efficacy of transanal endorectal pull-through (TERPT) in treating classic Hirschsprung's disease may be enhanced by incorporating laparoscopic-assisted endorectal pull-through (LERPT). This study was done to compare the long-term outcomes of TERPT and LERPT in the treatment of classic segment Hirschsprung's disease.
Methods: Longitudinal study.
Pediatr Surg Int
December 2024
Department of Neonatal Surgery, National Center for Children's Health, Beijing Children Hospital, Capital Medical University, 56 Nanlishi Road, Beijing, 100045, China.
World J Pediatr Surg
November 2024
Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Hirschsprung disease (HSCR) is a congenital enteric neuropathy in which the enteric nervous system (ENS) fails to develop along variable lengths of the distal gastrointestinal (GI) tract. This aganglionosis results in a functional bowel obstruction and requires surgical resection of the aganglionic segment. Despite surgery, however, long-term bowel dysfunction affects many patients.
View Article and Find Full Text PDFChildren (Basel)
November 2024
Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-970, São Paulo, Brazil.
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