Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021843 (bowel obstruction)
 9,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hirschsprung disease (HSCR) or colonic aganglionosis is a congenital disorder characterized by an absence of intramural ganglia along variable lengths of the colon resulting in intestinal obstruction. The incidence of HSCR is 1 in 5,000 live births. Mutations in the RET gene, which codes for a receptor tyrosine kinase, and in EDNRB which codes for the endothelin-B receptor, have been shown to be associated with HSCR in humans. The lethal-spotted mouse which has pigment abnormalities, but also colonic aganglionosis, carries a mutation in the gene coding for endothelin 3 (Edn3), the ligand for the receptor protein encoded by EDNRB. Here, we describe a mutation of the human gene for endothelin 3 (EDN3), homozygously present in a patient with a combined Waardenburg syndrome type 2 (WS2) and HSCR phenotype (Shah-Waardenburg syndrome). The mutation, Cys159Phe, in exon 3 in the ET-3 like domain of EDN3, presumably affects the proteolytic processing of the preproendothelin to the mature peptide EDN3. The patient's parents were first cousins. A previous child in this family had been diagnosed with a similar combination of HSCR, depigmentation and deafness. Depigmentation and deafness were present in other relatives. Moreover, we present a further indication for the involvement of EDNRB in HSCR by reporting a novel mutation detected in one of 40 unselected HSCR patients.
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PMID:A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). 863 May 3

Hirschsprung's disease (HSCR) is characterized by the absence of autonomic ganglion cells in the terminal bowel and is a relatively common cause of intestinal obstruction in the newborn. The incidence of HSCR is estimated to be 1 in 5000 live births. Recently, the endothelin-B receptor (EDNRB) gene has been shown as a susceptibility gene for HSCR by the production of aganglionic colon in mice with a null mutation of this gene and by demonstrating a missense mutation in a large inbred kindred with a high incidence of HSCR (Mennonite pedigree). However, no further mutations have been demonstrated in other clinical cases. We analysed alterations of the EDNRB gene in 41 isolated patients of HSCR. Two novel mutations were detected: a G to A transition at nucleotide 824 and an insertion of T at nucleotide 878. Both mutations resulted in stop codons, predicted to produce a truncated and non-functional endothelin-B receptor. These observations indicate that dysfunction or loss of function of endothelin-B receptor may be involved in the aetiology of some isolated patients with HSCR.
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PMID:Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung's disease. 885 58

Hirschsprung disease (HSCR), or aganglionic megacolon, is the most common cause of congenital intestinal obstruction. Two different loci have been found to be tightly linked to HSCR on chromosomes 10 and 13, respectively. Recently, mutations in the RET protooncogene on chromosome 10q11.2 were identified in several HSCR patients. In addition, a missense mutation in the endothelin-B receptor (EDNRB) gene on chromosome 13q22 was found in an inbred Mennonite kindred affected by HSCR and associated abnormalities, demonstrating the involvement of EDNRB in HSCR pathogenesis. To test whether mutations in the EDNRB gene could account for Hirschsprung in patients from non-inbred populations, we analysed DNA samples from 17 probands of Italian origin with HSCR. We have identified two novel EDNRB mutations: a missense mutation in a sporadic case, S305N, which leads to a change of a serine to an asparagine, disrupting a putative phosphorylation site; and a single nucleotide deletion in a familial case, N378I, resulting in a truncated protein. Both mutations were found in one of the healthy parents, and neither of these mutations were found in any of the normal individuals tested. These data confirm the involvement of EDNRB in HSCR pathogenesis and demonstrate that EDNRB mutations could contribute to HSCR disease in non-inbred populations.
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PMID:Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. 885 59

Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most common cause of congenital bowel obstruction with an incidence of 1 in 5000 live births. HSCR may be inherited as a single gene disorder with reduced penetrance or as a multigenic trait. HSCR mutations have been identified in the RET receptor tyrosine kinase, endothelin-B receptor (EDNRB) and its physiological ligand, endothelin 3 (EDN3). Although RET's ligand has remained elusive, it is expected to be an extracellular neurotrophic molecule expressed in the developing gut and kidney mesenchyme, based on the phenotypes of intestinal aganglionosis and renal agenesis observed in homozygous RET knockout (Ret -/-) mice. The glial cell line-derived neurotrophic factor (GDNF) is such a molecule. Recently, mice carrying two null alleles for Gdnf were shown to exhibit phenotypes remarkably similar to Ret-/- animals. We screened 106 unrelated HSCR patients for mutations in GDNF by direct sequencing. We identified one familial mutation in a HSCR patient with a known de novo RET mutation and malrotation of the gut. No haplotype sharing was evident in any of 36 HSCR kindreds typed for microsatellite markers surrounding GDNF on human chromosome 5p. Our data suggest that GDNF is a minor contributor to human HSCR susceptibility and that loss of its function in enteric neurogenesis may be compensated for by other neurotrophic factors or via other pathways. However, it may be that in rare instances, RET and GDNF mutations act in concert to produce an enteric phenotype.
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PMID:Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. 889 68

Hirschsprung's disease (HD) is one of the commonest gastrointestinal malformations, as it affects one child out of 5,000 births. It classically induces severe neonatal intestinal obstruction requiring surgical treatment which currently ensures a favourable prognosis for most of the affected children. Although the great majority of cases are sporadic, the existence of familial forms (10% of cases) has allowed localization and then identification of an autosomal dominant gene on chromosome 10, the RET proto-oncogene, responsible for 50% of familial forms and 15% of sporadic cases. A second gene has been recently localized on chromosome 13, the endothelium beta receptor (EDNRB) gene. Two homozygous mutations of the EDNRB gene have been identified in two consanguineous families, in which HD is associated with Waardenburg's syndrome (WS). Other heterozygous mutations have been identified in patients presenting with isolated HD and an 5% of cases of HD can be considered to present mutations of this gene. Finally, the authors have recently identified a mutation of the endothelium gene 3 (EDN3), one of the EDNRB ligands in a patient presenting with a combination of HD and WS. This mutation, present at the homozygous state in this patient, is predictive of complete absence of EDN3 protein: this is therefore the third known gene responsible for HD.
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PMID:[Genetics of Hirschsprung disease]. 903 23

Hirschsprung disease (HD) is one of the commonest gastro-intestinal malformations, as it affects one child out of 5,000 births. It classically induces severe neonatal intestinal obstruction requiring surgical treatment which currently ensures a favourable prognosis for most of the affected children. Although the great majority of cases are sporadic, the existence of familial forms (10% of cases) has allowed the localization and then the identification of an autosomal dominant gene on chromosome 10, the RET proto-oncogene, responsible for 50% of familial forms and 15% of sporadic cases. A second gene has been recently localized on chromosome 13, the endothelin beta receptor (EDNRB) gene. Two homozygous mutations have been identified in two consanguineous families, in which HD is associated with Waardenburg syndrome (WS). Other heterozygous mutations have been identified in patients presenting with isolated HD and 5% of cases can be considered to present mutations of this gene. Finally the authors have recently identified a mutation of the endothelin 3 gene (EDN3), one of EDNRB ligands in a patient presenting a combination of HD and WS. This mutation, present at the homozygous state in this patient, is predictive of complete absence of EDN3 protein: this is therefore the third known gene responsible for HD.
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PMID:[Genetics of Hirschsprung disease]. 907 20

Hirschsprung's disease (HD) is a relatively common cause of intestinal obstruction in the newborn, characterized by the absence of autonomic ganglion cells in the terminal bowel. Existence of familial cases indicates that genetic factors may be involved in the etiology of some cases of HD. Different inheritance patterns observed in subsets of HD families or kindreds, and the detection of different chromosome aberrations in some HD patients, suggest genetic heterogeneity of HD. Recent expansion of molecular genetics has identified multiple susceptibility genes of HD. These include the RET gene, the glial cell-derived neurotrophic factor gene, the endothelin-B receptor gene, and endothelin-3 gene. Furthermore, some other genes or genetic factors are speculated to be implicated in the development of HD, and it is believed that multiple factors play a role in disease development in some cases. Taken together, these data suggest and may explain the complexity of the etiology of HD. This review focuses on recent advances in our understanding of the genetic aspects of HD.
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PMID:Genetic aspects of Hirschsprung's disease. 971 52

Hirschsprung's disease, affecting one in 5000 live newborns, is the most common cause of neonatal intestinal obstruction. The obstruction or, later in life, constipation arises from the lack of enteric ganglia in the hindgut, thus resulting in poor coordination of peristalsis. Mutations in Hirschsprung patients have so far been reported in five genes associated in two different receptor-ligand systems, RET-GDNF/NTN and EDNRB-EDN-3, and an additional gene with yet unknown precise function, SOX10. We report the results of single-stranded conformation polymorphism screening of the endothelin-3 gene in a Swedish population-based material of 66 sporadic and nine familial Hirschsprung's disease cases. We have found a novel heterozygous mutation in exon 2, c.262insG, in a patient with sporadic short segment Hirschsprung's disease without any Waardenburg features. This frameshift results in a premature stop two codons further on. Because this stop is introduced 5' of the biologically active protein, this mutation can hence be predicted to result in haplo-insufficiency.
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PMID:A heterozygous frameshift mutation in the endothelin-3 (EDN-3) gene in isolated Hirschsprung's disease. 1023 70

Hirschsprung disease (HSCR) is a congenital disorder characterised by intestinal obstruction due to an absence of intramural ganglia along variable lengths of the intestine. RET is the major gene involved in HSCR. Mutations in the GDNF gene, and encoding one of the RET ligands, either alone or in combination with RET mutations, can also cause HSCR, as can mutations in four other genes (EDN3, EDNRB, ECE1, and SOX10). The rare mutations in the latter four genes, however, are more or less restricted to HSCR associated with specific phenotypes. We have developed a novel comprehensive mutation detection system to analyse all but three amplicons of the RET and GDNF genes, based on denaturing gradient gel electrophoresis. We make use of two urea-formamide gradients on top of each other, allowing mutation detection over a broad range of melting temperatures. For the three remaining (GC-rich) PCR fragments we use a combination of DGGE and constant denaturing gel electrophoresis (CDGE). These two dual gel systems substantially facilitate mutation scanning of RET and GDNF, and may also serve as a model to develop mutation detection systems for other disease genes. In a screening of 95 HSCR patients, RET mutations were found in nine out of 17 familial cases (53%), all containing long segment HSCR. In 11 of 78 sporadic cases (14%), none had long segment HSCR. Only one GDNF mutation was found, in a sporadic case.
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PMID:RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. 1079 Feb 3

Hirschsprung disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence. The gene at 10q11 is probably RET, supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in only 40% of linked families, suggesting the importance of noncoding variation. Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. This study demonstrates by a complete genetic dissection why the inheritance pattern of S-HSCR is nonmendelian.
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PMID:Segregation at three loci explains familial and population risk in Hirschsprung disease. 1195 48


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