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Pathogenesis of Hirschsprung's disease
G Martucciello1, I Ceccherini, M Lerone
1Department of Pediatric Surgery, G Gaslini Children's Hospital, University of Genoa, Italy.
Journal of Pediatric Surgery
|August 5, 2000
Summary
Hirschsprung's disease involves multiple genes, with RET proto-oncogene mutations being common. Environmental factors and other genetic mutations also contribute to this inherited disorder affecting nerve cell development.
Area of Science:
- Genetics
- Developmental Biology
- Gastroenterology
Background:
- Hirschsprung's disease is an inherited neurocristopathy with incomplete penetrance and variable expressivity.
- Genetic factors are implicated, with mutations in several genes identified as causative.
- The RET proto-oncogene is frequently associated with both familial and sporadic cases.
Purpose of the Study:
- To review the genetic basis of Hirschsprung's disease.
- To highlight the role of various genes and microenvironmental factors in its pathogenesis.
- To discuss the implications of low RET mutation detection rates.
Main Methods:
- Genetic mapping and mutation screening of candidate genes.
- Study of animal models (natural and knockout).
- Review of human genetic studies and molecular mechanisms.
Main Results:
- Six key Hirschsprung genes identified: RET, EDN3, EDNRB, GDNF, ECE1, and SOX10.
- RET mutations account for a significant proportion of cases.
- Microenvironmental factors, such as GDNF and NTN deficits, can arrest neuroblast migration even without genetic mutations.
Conclusions:
- Hirschsprung's disease pathogenesis is complex, involving multiple genes and environmental influences.
- The RET proto-oncogene is a major player, but other genes and factors are crucial.
- Further research into non-genetic factors is warranted to understand the full spectrum of the disease.