Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
PLoS One. 2012;7(5):e36524. doi: 10.1371/journal.pone.0036524. Epub 2012 May 4.
Hirschsprung disease (HSCR, OMIM 142623) is a developmental disorder characterized by the absence of ganglion cells along variable lengths of the distal gastrointestinal tract, which results in tonic contraction of the aganglionic gut segment and functional intestinal obstruction. The RET proto-oncogene is the major gene for HSCR with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. Many other genes have been described to be associated with the pathology, as NRG1 gene (8p12), encoding neuregulin 1, which is implicated in the development of the enteric nervous system (ENS), and seems to contribute by both common and rare variants. Here we present the results of a comprehensive analysis of the NRG1 gene in the context of the disease in a series of 207 Spanish HSCR patients, by both mutational screening of its coding sequence and evaluation of 3 common tag SNPs as low penetrance susceptibility factors, finding some potentially damaging variants which we have functionally characterized. All of them were found to be associated with a significant reduction of the normal NRG1 protein levels. The fact that those mutations analyzed alter NRG1 protein would suggest that they would be related with HSCR disease not only in Chinese but also in a Caucasian population, which reinforces the implication of NRG1 gene in this pathology.
先天性巨结肠症（HSCR，OMIM 142623）是一种发育障碍，其特征是在远端胃肠道的可变长度上缺乏神经节细胞，导致无神经节肠段的强直性收缩和功能性肠梗阻。RET 原癌基因是 HSCR 的主要基因，其罕见和常见的、编码和非编码突变对该病理学的多因素性质有不同的贡献。许多其他基因已被描述与该病理学相关，例如 NRG1 基因（8p12），编码神经调节素 1，其参与肠神经系统（ENS）的发育，并且似乎通过常见和罕见变异体共同起作用。在这里，我们通过对其编码序列的突变筛选和对 3 个常见标记 SNP 的评估，作为低外显率易感性因素，在一系列 207 名西班牙 HSCR 患者中对 NRG1 基因进行了全面分析，发现了一些潜在的破坏性变体，我们对其进行了功能表征。所有这些变体都与正常 NRG1 蛋白水平的显著降低有关。这些分析的突变改变了 NRG1 蛋白，这表明它们不仅与中国人群，而且与白种人群的 HSCR 疾病有关，这进一步证实了 NRG1 基因在该病理学中的作用。
