Borghini Silvia, Bocciardi Renata, Bonardi Giulia, Matera Ivana, Santamaria Giuseppe, Ravazzolo Roberto, Ceccherini Isabella
Laboratorio di Genetica Molecolare, Istituto G. Gaslini, 16148 Genova, Italy.
Eur J Hum Genet. 2002 Mar;10(3):183-7. doi: 10.1038/sj.ejhg.5200785.
Hirschsprung disease (HSCR) is a complex disorder characterised by aganglia of distal gastrointestinal tracts. The highest proportion of both familial and sporadic cases is due to mutations of the RET proto-oncogene. Five germline mutations in the glial cell-line-derived neurotrophic factor (GDNF) gene, one of the RET ligands, have been detected in HSCR patients. Pedigrees analysis and the observed association between these GDNF alterations and RET variants in the same patients raised the question of whether the GDNF gene plays any causative/predisposing role in HSCR pathogenesis. In the present work, we have studied the ability of GDNF proteins, each bearing one of the reported mutations, to activate RET by performing a functional test in cultured neuroblastoma cells. Consistently with the lack of genotype/phenotype correlation in human subjects, our results indicate absence of detectable alterations of mutant GDNF induced RET activation.
先天性巨结肠症（HSCR）是一种复杂的疾病，其特征为远端胃肠道无神经节。家族性和散发性病例中，最高比例是由RET原癌基因突变引起的。在HSCR患者中已检测到胶质细胞源性神经营养因子（GDNF）基因（RET配体之一）的五种种系突变。家系分析以及在同一患者中观察到的这些GDNF改变与RET变异之间的关联，引发了GDNF基因在HSCR发病机制中是否起任何致病/易感作用的问题。在本研究中，我们通过在培养的神经母细胞瘤细胞中进行功能测试，研究了携带每种已报道突变的GDNF蛋白激活RET的能力。与人类受试者中缺乏基因型/表型相关性一致，我们的结果表明突变型GDNF诱导的RET激活没有可检测到的改变。
