Hirschsprung’s disease: genetic mutations in mice and men

Abstract

Hirschsprung’s 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 3The pathogenesis of the aganglionosis is often attributed to a failure of migration of neural crest cells, although this has not been proven.Recently, mutations in a developmentally regulated receptor tyrosine kinase gene, ret, and mutations in the endothelin receptor-B gene (ENDR-B) have both been linked to familial Hirschsprung’s disease in humans.4-6 Moreover, certain mutant mouse strains—namely piebald lethal and lethal spotted—exhibit 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 Two transgenic mouse lines have been developed which also reflect the human disease: ret-k−, which has aloss of function mutation of the retgene,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 “Hirschsprung’s-like” 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.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’s disease. Disruption of these genes in the mouse, either by transgenic “knockout” approaches or in mutant mouse lines, offers the prospect of greater understanding of both the cellular and developmental bases of the human disease.

Molecular etiology of gut malformations and diseases

“…In HSCR patients, the colon proximal to the aganglionic portion becomes distended, and its wall thickens markedly, showing muscular hypertrophy. HSCR occurs in 1 of 5,000 live births [Robertson et al, 1997]. Symptoms usually begin at birth with delayed passage of meconium.…”

Signal transduction pathways in the mitogenic response to G protein-coupled neuropeptide receptor agonists

“…For example, mice deficient in either the CCK B /gastrin receptor or its ligand, gastrin, show a striking atrophy of the gastric mucosa (Langhans et al, 1997;Nagata et al, 1996) and reduced thymidine labeling index of the colon (Koh et al, 1997). Targeted disruption of endothelin B signaling in mice results in aganglionic mega colon and pigmentary alterations (Hosoda et al, 1994;Robertson et al, 1997), whereas mice deficient in endothelin A have morphological abnormalities of the craniofacial tissues and cardiovascular system (Clouthier et al, 1998;Kurihara et al, 1997). It is also increasingly recognized that multiple neuropeptides, including those of the bombesin family, play an important role as autocrine/paracrine growth factors for small cell lung cancer and other human cancer cells .…”

Glial Cell Line–Derived Neurotrophic Factor Family Receptors Are Abnormally Expressed in Aganglionic Bowel of a Subpopulation of Patients with Hirschsprung's Disease

“…In aganglionic colon, the plexus remnants consisted of hypertrophic nerve trunks and glial cells. The hypertrophied nerve trunks consist of cholinergic nerve fibers that have been shown to be extrinsic parasympathetic nerve fibers of sacral origin (Kobayashi et al, 1994;Robertson et al, 1997;Tam and Boyd, 1990). Our result that shows that both the extrinsic parasympathetic nerves and the abnormal hypertrophied nerves are negative for GFRA1 is in line with the suggestion that hypertrophied nerve trunks are derived from the extrinsic parasympathetic nerve fibers.…”