Functional characterization of mutations in the GDNF gene of patients with Hirschsprung disease
Functional characterization of mutations in the GDNF gene of patients with Hirschsprung disease
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DOI：
10.1093/hmg/11.3.325
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发表时间：
2002-02-01
影响因子：
3.5
通讯作者：
Ibáñez, CF
中科院分区：
文献类型：
--
作者：
Eketjäll, S;Ibáñez, CF
先天性巨结肠症(HSCR)是一种先天性疾病，其特征是后肠缺乏肠神经丛。10%到40%的HSCR患者携带编码受体酪氨酸激酶RET的基因的显性功能丧失突变，RET是胶质细胞系源性神经营养因子(GDNF)的受体。虽然在HSCR患者的GDNF基因中也发现了几个突变，但它们对GDNF功能的影响尚不清楚。在这项研究中，我们表征了这些突变对GDNF结合和激活其受体的能力的影响。尽管所分析的四个突变似乎都没有影响GDNF激活RET的能力，但其中两个突变导致GDNF与受体复合体结合亚基GFRalpha1的结合亲和力显著降低。我们的结果表明，尽管到目前为止在HSCR患者中发现的GDNF突变本身都不可能导致HSCR，但其中两个突变(即D150N和I211M)可能与其他基因损伤一起导致这种疾病的发病。
Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of enteric nervous plexuses in hind gut. Ten to forty percent of HSCR patients carry a dominant loss-of-function mutation in the gene encoding the receptor tyrosine kinase RET, a receptor for glial cell line-derived neurotrophic factor (GDNF). Although several mutations have also been found in the GDNF gene of HSCR patients, their impact on GDNF function is unknown. In this study, we have characterized the effect of these mutations on the ability of GDNF to bind and activate its receptors. Although none of the four mutations analyzed appeared to affect the ability of GDNF to activate RET, two of them resulted in a significant reduction in the binding affinity of GDNF for the binding subunit of the receptor complex, GFRalpha1. Our results indicate that, although none of the GDNF mutations identified so far in HSCR patients are per se likely to result in HSCR, two of these mutations (i.e. D150N and I211M) may, in conjunction with other genetic lesions, contribute to the pathogenesis of this disease.