Molecular analysis of the nerve growth factor receptor gene in patients with congenital insensitivity to pain with anhidrosis

先天性疼痛不敏感伴无汗症（Congenital insensitivity to pain with anhidrosis，CIPA ; MIM 256800）是一种常染色体隐性遗传疾病，以反复发作的不明原因发热、无汗（无汗）、对伤害性刺激无反应、自残行为和智力低下为特征。神经生长因子（NGF）诱导神经突生长，促进胚胎感觉和交感神经元的存活。缺乏TrkA基因（一种NGF受体酪氨酸激酶）的小鼠与CIPA具有显著的表型特征，包括对疼痛刺激的反应丧失，尽管这些动物的无汗症并不明显。因此，我们认为人类TRKA同源物作为CIPA基因的候选者。在三个不相关的CIPA患者有血缘关系的父母编码TRKA的mRNA和基因组DNA进行了分析。我们在这三名患者中检测到酪氨酸激酶结构域的缺失、剪接和错义突变。我们的研究结果强烈表明，TRKA的缺陷导致CIPA和NGF-TRKA系统在伤害性感受的发展和功能，以及建立体温调节通过出汗在人类中具有至关重要的作用。这些结果还暗示编码其他TRK和神经营养因子家族成员的基因是神经系统发育缺陷的候选者。

Congenital insensitivity to pain with anhidrosis (CIPA ; MIM 256800) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behavior and mental retardation.The genetic basis for CIPA is unknown. Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. Mice lacking the gene for TrkA,a receptor tyrosine kinase for NGF,share dramatic phenotypic features of CIPA,including loss of responses to painful stimuli, although anhidrosis is not apparent in these animials. We therefore considered the human TRKA homologue as a candidate for the CIPA gene. The mRNA and genomic DNA encoding TRKA were analyzed in three unrelated CIPA patients who had consanguineous parents. We detected a deletion-, splice-, and missense-mutation in the tyrosine kinase domain in these three patients. Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans. These results also implicate genes encoding other TRK and neurotrophin family members as candidates for developmental defect (s) of nervous system.