With Many Different Genetic Abnormalities Conclusion From Animal Models

Congenital neuromuscular disorders of the gut are commonly encountered during the neonatal period. These conditions include, in addition to Hirschsprung's disease (long and short segment varieties), the allied disorders, hypoganglionosis, neuronal intestinal dysplasias (hyper-ganglionosis), ganglion cell immaturity, and dysgangli-onoses. There are also additional defects such as hyper-trophic pyloric stenosis, volvulus, and intussusception, that may also involve abnormalities of the development of the ENS. Hirschsprung's disease is quite common and occurs in up to 1 in 5,000 live births [267]. In some patients, Hirschsprung's disease has been shown to be associated with loss-of-function mutations in the RET pro-tooncogene [267-271]. Only a small minority of patients with Hirschsprung's disease can be accounted for by RET mutations [267-269]. Both long and short segment Hirschsprung's disease can occur in patients with identical Ret abnormalities and patients may also exhibit other problems, including multiple endocrine neoplasia type A (more commonly associated with gain-of-function mutations in RET), maternal deafness, talipes, and malrotation of the gut. Identical mutations in RET may thus give rise to distinctly different phenotypes in affected individuals. Unfortunately, there is no obvious relationship between the RET genotype and the Hirschsprung's phenotype; moreover, the frequency of RET mutations in Hirschsprung's disease is so low that other genetic and/ or environmental conditions must be invoked to explain susceptibility to Hirschsprung's disease in the majority of patients.

Another important genetic defect that has been associated with Hirschsprung's disease involves mutations in EDNRB [187]. Again, many patients with Hirschsprung's disease do not exhibit mutations of EDNRB or RET and there are individuals who carry these mutations (and also those of RET) who do not express the Hirschsprung's disease phenotype [187]. As might be expected, not only are some cases of Hirschsprung's disease linked to mu tations in EDNRB, but mutations of genes encoding the ligand, EDN3, are also associated with Hirschsprung's disease. In the case of the EDN3 mutations, the pheno-type is reminiscent of that which is seen in ls/ls mice. Hirschsprung's disease occurs together with pigmentary abnormalities and is combined with a Waardenburg type 2 phenotype (Shah-Waardenburg syndrome) [272, 273]. Hirschsprung's disease is thus a multigene abnormality and a wide variety of mutations (many of which are still to be identified) predispose toward it [187, 267]. The environmental background within which these mutations operate probably also influences the phenotypic outcome.

Not all of the genetic abnormalities that have been correlated with Hirschsprung's disease are exactly comparable to the analogous mutations in animal models. Knockout of c-ret only leads to aganglionosis in mice when the mutated gene is homozygous [101, 104]. The ENS is not abnormal in the bowel of heterozygous mice that carry only a single mutated c-ret allele. Even when c-ret +/- mice are crossed with animals carrying the ls gene, the double heterozygotes do not exhibit agangli-onosis (Rothman T et al., unpublished observations). In contrast, the RET mutations detected in patients with Hirschsprung's disease have only been heterozygous. This discrepancy in the effects of mutations between humans and mice is difficult to explain and may be due to the effects of additional genes or environmental factors. Despite these discrepancies, animal models provide the best hope of achieving an understanding of the pathogenesis of Hirschsprung's disease. The EDN3/EDNRB-deficient mouse and rat models appear to be especially useful. The resemblance of these models to Hirschsprung's disease are striking both from a genetic and an anatomical point of view. Molecular abnormalities that have been found in the extracellular matrix of the murine models [202] also occur in patients with Hirschsprung's disease [203, 204]. The thickening of the muscularis mucosa and the overabundance of laminin and type IV collagen that characterize the aganglionic gut of ls/ls mice characterize human megacolon as well. In addition, it has been reported that laminin and type IV collagen normally accumulate before neurogenesis begins at the sites where ganglia will form [274]. Observations made on ls/ls [54, 56, 57, 196, 197, 199, 200], sl/sl [194], and Dom [184] mice have been able to demonstrate that the pathogenesis of the agan-glionosis that occurs in these animals is not neural crest autonomous, but involves an intrinsic abnormality of the colon.

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