Congenital insensitivity to pain with anhidrosis:: Novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor
Congenital insensitivity to pain with anhidrosis:: Novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor
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DOI：
10.1086/302422
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发表时间：
1999-06-01
影响因子：
9.8
通讯作者：
Indo, Y
中科院分区：
文献类型：
--
作者：
Mardy, S;Miura, Y;Indo, Y
先天性疼痛不敏感伴无汗症（CIPA）的特征是反复发作的不明原因的发热、无汗症（不能出汗）、对有害刺激无反应、自残行为和智力迟钝。人TRKA编码a.神经生长因子（NGF）的高亲和力酪氨酸激酶受体，神经营养因子家族的一员，可诱导神经突生长并促进胚胎感觉和交感神经元的存活。我们最近证明，TRKA是负责CIPA通过确定在一个厄瓜多尔和三个日本家庭的TRKA的细胞内酪氨酸，激酶结构域编码的区域中的三个突变。我们已经开发了一种全面的策略来筛选TRKA突变，基于基因的结构和组织。在这里，我们报告了11个新的突变，在7个受影响的家庭。这是六个错义突变，两个移码突变，一个无义突变和两个剪接位点突变。孟德尔遗传的突变证实在6个家庭的父母样本。在同一染色体上，两个突变与Arg 85 Ser和His 598 Tyr; Gly 607 Val连锁，因此，它们可能代表双重和三重突变。这些突变分布在参与NGF结合的细胞外结构域以及细胞内信号转导结构域中。这些数据表明，TRKA，缺陷导致CIPA在不同的种族群体。
Congenital insensitivity to pain with anhidrosis (CIPA) is characterized by recurrent episodes of unexplained fever, anhidrosis (inability to sweat),absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. Human TRKA encodes a. high-affinity tyrosine kinase receptor for nerve growth factor (NGF), a member of the neurotrophin family that induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. We have recently demonstrated that TRKA is responsible for CIPA by identifying three mutations in a region encoding the intracellular tyrosine, kinase domain of TRKA in one Ecuadorian and three Japanese families. We have developed a comprehensive strategy to screen for TRKA mutations, on the basis of the gene's structure and organization. Here we report 11 novel mutations, in seven affected families. These are six missense mutations, two frameshift mutations, one nonsense mutation, and two splice-site mutations. Mendelian inheritance of the mutations is confirmed in six families for which parent samples are available. Two mutations are linked, on the same chromosome, to Arg85Ser and to His598Tyr;Gly607Val, hence, they probably represent double and triple mutations. The mutations are distributed in an extracellular domain, involved in NGF binding, as well as the intracellular signal-transduction domain. These data suggest that TRKA,defects cause CIPA in various ethnic groups.