Special basic science review: Pathogenesis of Hirschsprung's disease

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Abstract

Hirschsprung's disease is an inherited disorder showing incomplete penetrance and variable expressivity. Genetic mapping and mutation screening of candidate genes, together with the study of several natural and knockout animal models, clearly have shown the involvement of several different genes in the pathogenesis of Hirschsprung's disease. Among these genes, the RET proto-oncogene accounts for the highest proportion of both familial and sporadic cases, with a wide range of mutations scattered along its entire coding region. The low detection rate of RET mutations in Hirschsprung patients also led to different hypotheses, such as the existence of additional Hirschsprung genes. Different animal and human genetic studies have identified 6 Hirschsprung genes: RET proto-oncogene (RET), endothelin 3 (EDN3), endothelin B receptor gene (EDNRB), glial-cell-line—derived neurotrophic factor (GDNF), endothelin converting enzyme (ECE1), gene encoding the Sry-related transcription factor SOX10 (SOX10). Microenvironmental factors also can play a role in the pathogenesis of aganglionosis. The developmental process of the crest-derived progenitor cells is sensitive to the level of different molecules. The expression deficit of different factors (GDNF, NTN) in the hindgut, in the absence of genetic mutations, could determine a missed activation of the receptor system, causing enteric neuroblast migration arrest. J Pediatr Surg 35:1017-1025. Copyright © 2000 by W.B. Saunders Company.

Section snippets

The neural crest and the neurocristopathies

The ganglion cells of the ENS derive from the NC, which is a very peculiar structure. “As it originates so early, it has been called one of the primary organs in the development of the vertebrate embryo. But it has only a temporary existence, as it cells are soon dispersed throughout the body, differentiating into many tissues.”2 Although first identified over a century ago, the importance of the neural crest in vertebral development has gained more appreciation over the last 50 years and wide

The major gene for HSCR

The first step toward the understanding of the molecular basis of HSCR as well as of the nature of its genetic transmission was the observation of a young female patient with total colonic aganglionosis (TCA), carrying a de novo interstitial deletion of chromosome 10:46,XX,del 10q11.21-q21.2.16

Following the hypothesis that a major gene responsible for HSCR had to be present in the DNA portion encompassing the deletion, human-hamster somatic cell hybrids retaining the deleted (Hy185-O) and the

Hirschsprung's disease and MEN2

It is well established that receptor tyrosine kinases play important roles in normal differentiation and growth of various types of cells. Binding of growth factors to the receptors results in receptor dimerization and subsequent activation of their intrinsic tyrosine kinases. However, point mutations and rearrangements of these genes may lead to constitutive activation of the corresponding receptors responsible for tumor development. The RET proto-oncogene encodes a receptor tyrosine kinase

GDNF deficit in Hirschsprung's disease

The first identified Ret receptor ligand was the glial cell line—derived neurotrophic factor (GDNF). The GDNF mature protein consists of 134 amino acids with a molecular mass of 32 to 42 kD in dimer form.47 GDNF is proposed to act as a ligand for a multisubunit receptor in which the glycosylphosphatidylinositol-linked protein GDNFR-α provides the ligand binding, and RET provides the signalling component (Fig 3).

. Activation of Retreceptor by GDNF and NTN. (A and B) GDNF ligand binding to GDNFR

Other HSCR genes and syndromic HSCR

The low detection rate of RET mutations in HSCR patients also led to different hypotheses, such as the existence of additional HSCR genes. The availability of animal models of HSCR has played a crucial role in identifying some of these genes (Table 4).

Until today, different animal and human genetic studies have identified 6 HSCR genes: RET proto-oncogene, endothelin 3 (EDN3), endothelin B Receptor genes (EDNRB), GDNF, ECE1, and gene encoding the Sry-related transcription factor SOX10 (SOX10).

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    Address reprint requests to Giuseppe Martucciello, MD, Department of Pediatric Surgery, Giannina Gaslini Children's Hospital, University of Genoa, Largo G. Gaslini, 5 16147 Genoa, Italy.

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