Sánchez-Mejías Avencia, Fernández Raquel M, Antiñolo Guillermo, Borrego Salud
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; ; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Sevilla, Spain.
Exp Ther Med. 2010 Nov;1(6):999-1003. doi: 10.3892/etm.2010.140. Epub 2010 Aug 26.
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.
B型肠道神经元发育异常（INDB）的特征是肠道副交感神经黏膜下神经丛畸形。人们普遍认为INDB具有遗传基础，并且几个基因在被破坏时会在小鼠中产生类似INDB的表型，如内皮素受体B（EDNRB）。然而，在分析的几个系列中尚未发现与该疾病相关的突变。在本研究中，我们试图确定EDNRB/内皮素3（EDN3）信号通路是否在人类INDB的发病机制中起作用。采用变性高效液相色谱（dHPLC）技术对23例INDB患者的EDNRB和EDN3编码区进行筛查。此外，对这些基因与通过TaqMan技术策略性选择和基因分型的单核苷酸多态性进行关联研究。虽然在这两个基因中都检测到了几个新的变异，但这些变异似乎都没有在蛋白质功能或表达中发挥功能性作用。我们的结果表明，需要在更大的患者系列中对其他候选基因进行额外筛查，以阐明INDB的分子基础。此外，文献中报道的INDB候选基因筛查系统性缺乏阳性结果，以及我们的结果，使我们提出INDB可能是由于与肠神经系统发育相关基因的功能获得性突变而产生的。因此，建议在未来关于INDB遗传基础的研究中使用不同的分子方法，如筛查基因重复或增强子突变。
