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

先天性多汗症疼痛不敏感(CIPA；MIM 256800)是一种常染色体隐性遗传病，其特征是反复发作不明原因的发热、多汗(无汗)、对有害刺激无反应、自残行为和智力迟缓。神经生长因子(NGF)诱导神经突起生长，促进胚胎感觉神经元和交感神经元存活。缺乏TrkA基因的小鼠具有CIPA的戏剧性表型特征，包括对疼痛刺激的反应丧失，尽管这些动物的汗水不明显。TrkA是NGF的一种受体酪氨酸激酶。因此，我们认为人类TrkA同源基因是CIPA基因的候选基因。对3例父母有血缘关系的无血缘关系的CIPA患者的TrkA基因和编码TrkA的基因进行了分析。我们在这三名患者中检测到酪氨酸激酶域的缺失、剪接和错义突变。我们的发现有力地表明，TrkA的缺陷导致了CIPA，并且NGF-TrkA系统在人类伤害性感受的发展和功能以及通过出汗建立体温调节方面起着至关重要的作用。这些结果也提示编码TRK和神经营养因子家族其他成员的基因可能是神经系统发育缺陷(S)的候选基因。

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.