{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T10:45:58Z","timestamp":1781174758633,"version":"3.54.1"},"reference-count":0,"publisher":"BMJ","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gut"],"published-print":{"date-parts":[[1997,10,1]]},"abstract":"<jats:p>Hirschsprung\u2019s disease is a neuronal dysplasia of the hindgut, characterised by a loss of neurones, which affects about 1 in 5000 live births.1 Genetic factors have been implicated in the aetiology of this disease in about 20% of cases and a dominant pattern of inheritance has been revealed in several families.2\n3The pathogenesis of the aganglionosis is often attributed to a failure of migration of neural crest cells, although this has not been proven.<\/jats:p><jats:p>Recently, mutations in a developmentally regulated receptor tyrosine kinase gene, <jats:italic>ret<\/jats:italic>, and mutations in the endothelin receptor-B gene (ENDR-B) have both been linked to familial Hirschsprung\u2019s disease in humans.4-6 Moreover, certain mutant mouse strains\u2014namely piebald lethal and lethal spotted\u2014exhibit striking similarities to the human condition. The mutation which gives rise to piebald lethal has now been found to be in the ENDR-B gene,7 and the mutation associated with lethal spotted occurs in the gene for endothelin-3 (ET-3), a ligand for ENDR-B.8\n<\/jats:p><jats:p>Two transgenic mouse lines have been developed which also reflect the human disease: <jats:italic>ret-k<jats:sup>\u2212<\/jats:sup><\/jats:italic>, which has a<jats:italic>loss of function<\/jats:italic> mutation of the <jats:italic>ret<\/jats:italic>gene,9 and ENDR-B null.10 In addition, the introduction of a Lac-Z reporter gene into neural crest cells of aganglionic mice has made it possible to study directly the fate of enteric neuroblasts which are affected by \u201cHirschsprung\u2019s-like\u201d mutations.11 Here, we review the possible roles of RET and endothelin in the normal development of the enteric nervous system, and the significance of their mutated forms in the pathogenesis of familial aganglionosis.<\/jats:p><jats:p>This review focuses on recent advances in our understanding of the genetic basis of the lesions which have been implicated in congenital forms of Hirschsprung\u2019s disease. Disruption of these genes in the mouse, either by transgenic \u201cknockout\u201d approaches or in mutant mouse lines, offers the prospect of greater understanding of both the cellular and developmental bases of the human disease.<\/jats:p>","DOI":"10.1136\/gut.41.4.436","type":"journal-article","created":{"date-parts":[[2010,6,30]],"date-time":"2010-06-30T16:46:12Z","timestamp":1277916372000},"page":"436-441","source":"Crossref","is-referenced-by-count":80,"title":["Hirschsprung\u2019s disease: genetic mutations in mice and men"],"prefix":"10.1136","volume":"41","author":[{"given":"K","family":"ROBERTSON","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I","family":"MASON","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"HALL","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[1997,10,1]]},"container-title":["Gut"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/gut.41.4.436","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,9,26]],"date-time":"2020-09-26T03:31:28Z","timestamp":1601091088000},"score":1,"resource":{"primary":{"URL":"https:\/\/gut.bmj.com\/lookup\/doi\/10.1136\/gut.41.4.436"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,10,1]]},"references-count":0,"journal-issue":{"issue":"4","published-online":{"date-parts":[[1997,10,1]]},"published-print":{"date-parts":[[1997,10,1]]}},"alternative-id":["10.1136\/gut.41.4.436"],"URL":"https:\/\/doi.org\/10.1136\/gut.41.4.436","relation":{},"ISSN":["0017-5749","1468-3288"],"issn-type":[{"value":"0017-5749","type":"print"},{"value":"1468-3288","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,10,1]]}}}