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

先天性无汗性疼痛不敏感（CIPA; MIM 256800）是一种常染色体隐性疾病，其特征为反复发作的不明原因发热、无汗（无汗）、对有害刺激无反应、自残行为和智力低下。CIPA的遗传基础尚不清楚。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（NGF的一种受体酪氨酸激酶）的小鼠具有CIPA的显著表型特征，包括对疼痛刺激的反应丧失，尽管这些动物的无汗症状并不明显。因此，我们认为人类TRKA同源物是CIPA基因的候选物。对3例无血缘关系且父母系近亲的CIPA患者进行TRKA mRNA和基因组DNA编码分析。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缺陷导致CIPA， NGF-TRKA系统在人类伤害性接受的发育和功能以及通过出汗建立体温调节中起着至关重要的作用。这些结果也暗示编码其他TRK和神经营养蛋白家族成员的基因是神经系统发育缺陷的候选基因。

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.