Disease relevance of Megacolon

• Enx (Hox11L1)-deficient mice develop myenteric neuronal hyperplasia and megacolon [1].
• METHODS: Colonic specimens obtained from patients with slow-transit constipation (n = 11), patients with megacolon (n = 6), and a control group (n = 13, nonobstructing neoplasia) were stained with antibodies against c-kit (marker for interstitial cells of Cajal) and protein gene product 9.5 (neuronal marker) [2].
• Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease [3].
• A similar condition of aganglionic megacolon, postaxial polydactyly, and ventricular septal defect with a presumed autosomal recessive (AR) inheritance was reported by Laurence in two sibs [Laurence et al.; J Med Genet 12: 334-338, 1975] [4].
• In order to evaluate the effect of pentagastrin on the motor activity of the sigmoid and rectum in patients with Chagas' disease, manometric studies were performed on 22 chagasic patients, 11 without and 11 with megacolon, and 11 control subjects [5].

High impact information on Megacolon

• This 1-kb enhancer is activated as the ENS precursors approach the colon, and partial deletion of this enhancer at the endogenous Ednrb locus results in pigmented mice that die postnatally from megacolon [6].
• Tlx1-deficient and Enx-deficient mice display phenotypes in tissues where the mutated gene is singularly expressed, resulting in asplenogenesis and hyperganglionic megacolon, respectively [7].
• WS and HSCR are associated in patients with Waardenburg-Shah syndrome (WS4), whose symptoms are reminiscent of the white coat-spotting and aganglionic megacolon displayed by the mouse mutants Dom (Dominant megacolon), piebald-lethal (sl) and lethal spotting (ls) [8].
• Defects in the gene encoding the endothelin-B receptor produce aganglionic megacolon and pigmentary disorders in mice and humans [9].
• Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice [10].

Chemical compound and disease context of Megacolon

• The megacolon was unresponsive to nasogastric suction, corticosteroids, antibiotics, and total parenteral nutrition [11].
• In situ hybridization experiments carried out in the dominant megacolon (DOM:) mouse, confirmed that SOX10 dysfunction impairs MITF: expression as well as melanocytic development and survival [12].
• Lower oesophageal sphincter response to pentagastrin in chagasic patients with megaoesophagus and megacolon [13].
• Loss of interstitial cells and a fibromuscular layer on the luminal side of the colonic circular muscle presenting as megacolon in an adult patient [14].
• An increase of at least 2-fold in distal colon wall thickness confirmed the induction of megacolon in BAC-treated rats [15].

Biological context of Megacolon

• Germline mutations of RET cause a dominantly inherited dysgenesis of the enteric nervous system known as Hirschsprung's disease (HSCR; aganglionosis megacolon) [16].
• A high-resolution genetic map of mouse chromosome 15 encompassing the Dominant megacolon (Dom) locus [17].
• Mice with megacolon absorb alanine and Na at a greater rate than N mice and the enhanced amino acid absorptive rate can be explained by an increased alanine influx, probably due to an increased number of active transport carriers [18].
• Comparing between UL144 sequences and the corresponding symptoms showed that genotype 2 did not exist in megacolon isolates [19].
• Hirschsprung disease (HSCR, aganglionic megacolon) is the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births [20].

Anatomical context of Megacolon

• Mutation of the Sox10 gene leads to neural crest defects in the Dominant megacolon mouse mutant and to combined Waardenburg-Hirschsprung syndrome in humans [21].
• Potential explanations include depletion of tissue L-Arginine, decreased capacity to recycle citrulline to arginine, or decreased release of vasoactive intestinal peptide from circular smooth muscle in acquired megacolon [22].
• We report on a 46-year-old man with striking resemblance to the children described by Harrod who also has secondary megacolon and varicose veins, suggesting a connective tissue disorder [23].
• In chagasic patients with megacolon, pentagastrin had no effect on sigmoid or rectum motility, probably as a result of the intrinsic denervation known to occur in this disease [5].
• Respiratory muscle paralysis, megacolon, and nocturnal delirium observed in this patient might have partially resulted from the use of dantrolene administered during the course of the treatment [24].

Gene context of Megacolon

• WS-HSCR mimicks the megacolon and white coat-spotting observed in Ednrb mouse mutants [25].
• Mice that are homozygous for a null mutation in the Ednrb gene are almost completely white and die as juveniles from megacolon [26].
• Inactivation of both Foxf2 alleles, or one allele each of Foxf1 and Foxf2, cause a range of defects, including megacolon, colorectal muscle hypoplasia and agangliosis [27].
• The mutation, called dominant megacolon, symbol Dom, is located on chromosome (chr) 15, 20.6 +/- 1.6 units proximal to Ca [28].
• Second, they found that disruption of the ET-3 peptide and ETB receptor genes result in homozygous mice that share identical phenotypic traits (i.e., coloration changes and aganglionic megacolon) which are similar to a previously known natural mutation, the Piebald-Lethal mouse (Hosoda et al., 1994; Baynash et al., 1994) [29].

References