A new experimental approach is required in the molecular analysis of intestinal neuronal dysplasia type B patients

Sánchez-Mejías,Avencia; Fernández,Raquel   M.; Antiñolo,Guillermo; Borrego,Salud

doi:10.3892/etm.2010.140

A new experimental approach is required in the molecular analysis of intestinal neuronal dysplasia type B patients

Authors:
- Avencia Sánchez-Mejías
- Raquel M. Fernández
- Guillermo Antiñolo
- Salud Borrego
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Affiliations: Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal, Instituto de Biomedicina de Sevilla (IBIS), Hospitales Universitarios Virgen del Rocío/CSIC/Universidad de Sevilla
Published online on: August 26, 2010 https://doi.org/10.3892/etm.2010.140
Pages: 999-1003

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Abstract

Intestinal neuronal dysplasia type B (INDB) is characterized by the malformation of the parasympathetic submucous plexus of the gut. It is generally accepted that INDB has a genetic basis, and several genes produce an INDB-like phenotype in mice when disrupted, such as EDNRB. However, no mutations associated with this disease have been identified in several series analysed. In the present studu, we sought to determine whether the EDNRB/EDN3 signalling pathway plays a role in the pathogenesis of INDB in humans. Denaturing high performance liquid chromatography (dHPLC) techniques were employed to screen the EDNRB and EDN3 coding regions in 23 INDB patients. In addition, association studies were performed on these genes with single nucleotide polymorphisms strategically selected and genotyped by TaqMan technology. Although several novel variants were detected in both genes, none of these variants appeared to play a functional role in protein function or expression. Our results indicate that additional screening of other candidate genes in larger patient series is required to elucidate the molecular basis of INDB. Additionally, the systematic lack of positive results in the screening of candidate genes for INDB reported in the literature, together with our results, leads us to propose that INDB may alternatively arise as a consequence of gain of function mutations in genes related to enteric nervous system development. Therefore, the use of different molecular approaches, such as screening for genetic duplication or enhancer mutations, is recommended for future studies on the genetic basis of INDB.

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1.	Puri P and Shinkai T: Pathogenesis of Hirschsprung’s disease and its variants: recent progress. Semin Pediatr Surg. 13:18–24. 2004.
2.	Meier-Ruge WA, Bruder E and Kapur RP: Intestinal neuronal dysplasia type B: one giant ganglion is not good enough. Pediatr Dev Pathol. 9:444–452. 2006. View Article : Google Scholar : PubMed/NCBI
3.	Galvez Y, Skaba R, Vajtrova R, Frantlova M and Herget J: Evidences of secondary neuronal intestinal displasia in a rat model of chronic intestinal obstruction. J Invest Surg. 17:31–39. 2004. View Article : Google Scholar : PubMed/NCBI
4.	Kobayashi H, Mahomed A and Ouri P: Intestinal neuronal dysplasia in twins. JPGN. 22:398–401. 1996.
5.	Costa M, Fava M, Seri M, et al: Evaluation of the HOX11L1 gene as a candidate for congenital disorders of intestinal innervation. J Med Genet. 37:E92000. View Article : Google Scholar : PubMed/NCBI
6.	Amiel J, Sproat-Emison E, Garcia-Barcelo M, et al: Hirschsprung Disease Consortium. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet. 45:1–14. 2008. View Article : Google Scholar : PubMed/NCBI
7.	Gath R, Goessling A, Keller K-M, et al: Analysis of the RET, GDNF, EDN3 and EDNRB genes in patient with intestinal neuronal dysplasia and Hirschprung disease. Gut. 48:671–675. 2001. View Article : Google Scholar : PubMed/NCBI
8.	Fernandez RM, Sanchez-Mejias A, Ruiz-Ferrer M, Lopez-Alonso M, Antiñolo G and Borrego S: Is the RET protooncogene involved in the pathogenesis of intestinal neuronal displasia type B? Mol Med Rep. 2:265–270. 2009.PubMed/NCBI
9.	Fava M, Borghini S, Cinti R, et al: HOX11L1: a promoter study to evaluate possible expression defects in intestinal motility disorders. Int J Mol Med. 10:101–106. 2002.PubMed/NCBI
10.	Borghini S, Duca MD, Pini Prato A, et al: Search for pathogenetic variants of the SPRY2 gene in intestinal innervation defects. Intern Med J. 39:335–337. 2009. View Article : Google Scholar : PubMed/NCBI
11.	Von Boyen GB, Krammer HJ, Suss A, Dembowski C, Ehrenreich H and Wedel T: Abnormalities of the enteric nervous system in heterozygous endothelin B receptor deficient (spotting lethal) rats resembling intestinal neuronal dysplasia. Gut. 51:414–419. 2002.PubMed/NCBI
12.	Sandgren K, Larsson LT and Ekblad E: Widespread changes in neurotransmitter expression and number of enteric neurons and interstitial cells od Cajal in lethal spotted mice. Dig Dis Sci. 47:1049–1064. 2002. View Article : Google Scholar : PubMed/NCBI
13.	Fernandez RM, Boru G, Peciña A, et al: Ancestral RET haplotype associated with Hirschsprung’s disease shows linkage disequilibrium breakpoint at -1249. J Med Genet. 42:322–327. 2005.
14.	Sánchez-Mejías A, Fernández RM, López-Alonso M, Antiñolo G and Borrego S: New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease. Genet Med. 12:39–43. 2010.PubMed/NCBI
15.	Auricchio A, Casari G, Staiano A and Ballabio A: Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. Hum Mol Genet. 5:351–354. 1996. View Article : Google Scholar : PubMed/NCBI
16.	Yamataka A, Hatano M, Kobayashi H, et al: Intestinal neuronal dysplasia-like pathology in Ncx/Hox11L.1 gene-deficient mice. J Pediatr Sur. 36:1293–1296. 2001. View Article : Google Scholar : PubMed/NCBI
17.	Yanai T, Kobayashi H, Yamataka A, et al: Acetylcholine-related bowel dysmotility in homozygous mutant NCX/HOX11L.1-deficiented in causing intestinal neuronal dysplasia. J Pediatr Sur. 39:927–930. 2004. View Article : Google Scholar : PubMed/NCBI
18.	Taketomi T, Yoshiga D, Taniguchi K, et al: Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia. Nat Neurosci. 8:855–857. 2005. View Article : Google Scholar : PubMed/NCBI
19.	Goldstein AM, Brewer KC, Doyle AM, Nandor N and Roberts DJ: BMP signaling is necessary for neural crest cell migration and genglion formation in the enteric nervous system. Mech Dev. 122:821–833. 2005. View Article : Google Scholar : PubMed/NCBI
20.	Chalazonitis A, D’Autréaux F, Guha U, et al: Bone morphogenetic protein-2 and -4 limit the number of enteric neurons but promote development of a TrkC-expressing neurotrophin-3-dependent subset. J Neurosci. 24:4266–4282. 2004. View Article : Google Scholar : PubMed/NCBI
21.	Kapur RP: Neuronal dysplasia: a controversial pathological correlate of intestinal pseudo-obstruction. Am J Med Genet. 122A:287–293. 2003. View Article : Google Scholar : PubMed/NCBI