Novel pathogenic mechanisms of congenital insensitivity to pain with anhidrosis genetic disorder unveiled by functional analysis of neurotrophic tyrosine receptor kinase type 1/nerve growth factor receptor mutations
Novel pathogenic mechanisms of congenital insensitivity to pain with anhidrosis genetic disorder unveiled by functional analysis of neurotrophic tyrosine receptor kinase type 1/nerve growth factor receptor mutations
复制标题
DOI：
10.1074/jbc.m110016200
复制
发表时间：
2002-02-22
影响因子：
4.8
通讯作者：
Greco, A
中科院分区：
文献类型：
--
作者：
Miranda, C;Di Virgilio, M;Greco, A
先天性无汗性疼痛不敏感(CIPA)是一种罕见的遗传性疾病，其特征是对有害刺激和无汗症无反应。CIPA的遗传基础长期以来一直不为人知。几年前，在CIPA患者中发现了影响神经营养酪氨酸受体K1(NTRK1)/神经生长因子受体基因编码区和非编码区的点突变，证实了神经生长因子/NTRK1通路在该病发病机制中的意义。我们之前已经证明，两个CIPA突变，G571R和R774P，通过干扰自动磷酸化过程而使NTRK1受体失活。我们已经将我们的功能分析扩展到其他人最近报道的与CIPA相关的另外七个NTRK1突变。通过生物化学和生物分析相结合的方法，我们已经确定了基因的多态和致病突变。除了鉴定对NTRK1活性重要的残基外，我们的分析表明在CIPA中存在两种新的致病机制：一种是基于NTRK1受体的加工，另一种是通过降低受体的活性来发挥作用。
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare genetic disease characterized by absence of reaction to noxious stimuli and anhidrosis. The genetic bases of CIPA have remained long unknown. A few years ago, point mutations affecting both coding and noncoding regions of the neurotrophic tyrosine receptor kinase type 1 (NTRK1)/nerve growth factor receptor gene have been detected in CIPA patients, demonstrating the implication of the nerve growth factor/ NTRK1 pathway in the pathogenesis of the disease. We have previously shown that two CIPA mutations, the G571R and the R774P, inactivate the NTRK1 receptor by interfering with the autophosphorylation process. We have extended our functional analysis to seven additional NTRK1 mutations associated with CIPA recently reported by others. Through a combination of biochemical and biological assays, we have identified polymorphisms and pathogenic mutations. In addition to the identification of residues important for NTRK1 activity, our analysis suggests the existence of two novel pathogenic mechanisms in CIPA: one based on the NTRK1 receptor processing and the other acting through the reduction of the receptor activity.