Molecular genetics of congenital insensitivity to pain with anhidrosis

先天性疼痛不敏感伴无汗症的分子遗传学

• 批准号: 09672314
• 负责人: INDO Yasuhiro
• 金额: $ 1.92万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672314/
• 关键词: Congenital insensitivity to pain with anhidrosis; Nerve growth factor; Nerve growth factor receptor; TRKA; Molecular genetics; 遺伝性感覚自律神経性ニューロパチー

Congenital insensitivity to pain with anhidrosis (CIPA ; MIM 256800) is an autosomalrecessive disorder characterized by absence of reaction to noxious stimuli, anhidrosis (absence of sweating) and mental retardation. Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. We hypothesized that genetic defect(s) of NGF signal transduction might cause CIPA.We have identified TRKA encoding a high-affinity receptor for NGF as a responsible gene for CIPA by detecting mutations in patients with this disorder. Then we have determined structure and organization of the TRKA.Based on this information, we have established a comprehensive method to detect a putative mutation(s) in the gene derive from patients with CIPA.So far we have identified 22 mutations in 30 CIPA patients from Japan and foreign countries. CIPA is a rare genetic disorder and shows no abnormality in blood chemistry or routine clinical examination. Thus patients wer … More e often observed and followed without having diagnosis. Only a specialist of neuropathology has usually established final diagnosis since the biopsy of peripheral nervous system is essential. This study makes the gene diagnosis of CIPA possible, using peripheral blood as a sample. These results will be useful for prenatal diagnosis and give us important information to develop treatment for CIPA.Our findings also strongly suggest 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. It is well known that sweat glands (eccrine glands) are most developed in humans. Mice lacking the gene for TrkA, a murine homologue of the TRKA, do not show apparent defect of thermoregulation probably because sweating is not a main way of thermoregulation in these animals. Thus, importance of the NGF-TRKA system for thermoregulation via sweating is elucidated and established by the analysis of human genetic disorder. Other neurotrophic factors also act on corresponding neurons. Our results also suggest that abnormal signal transduction of these factors implicates for a developmental defect or a genetic disorder of nervous system. Less

先天性无汗痛不敏感症(CIPA；MIM 256800)是一种常染色体隐性遗传病，其特征是对有害刺激无反应、多汗(无汗)和智力低下。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。我们假设神经生长因子信号转导途径的遗传缺陷(S)可能导致CIPA。通过检测这种疾病患者的突变，我们发现编码高亲和力神经生长因子受体的TrkA基因是CIPA的致病基因。在此基础上，我们建立了一种完整的检测CIPA患者基因突变的方法(S)，到目前为止，我们已经在来自日本和国外的30例CIPA患者中发现了22个突变。CIPA是一种罕见的遗传性疾病，在血液化学和常规临床检查中均无异常。因此，患者是…更多的是在没有诊断的情况下观察和随访。只有神经病理学专家通常才能确定最终诊断，因为周围神经系统的活检是必不可少的。本研究以外周血为样本，使CIPA的基因诊断成为可能。这些结果将有助于产前诊断，并为我们开发CIPA的治疗方法提供重要信息。我们的研究结果也有力地表明，NGF-TrkA系统在人类伤害性感受的发育和功能以及通过出汗建立体温调节方面具有至关重要的作用。众所周知，人类的汗腺(分泌腺)最为发达。缺乏TrkA基因的小鼠没有明显的体温调节缺陷，可能是因为出汗不是这些动物体温调节的主要方式。因此，通过对人类遗传疾病的分析，阐明并确立了NGF-TrkA系统通过出汗调节体温的重要性。其他神经营养因子也作用于相应的神经元。我们的结果还表明，这些因子的信号转导异常与神经系统发育缺陷或遗传性疾病有关。较少

项目成果

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Indo, Y.等人：“先天性对疼痛不敏感伴无汗症患者的 TRKA/NGF 受体基因突变”《自然遗传学》。

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Y.Indo et al.: "Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis." Nature Genetics. 13. 485-488 (1996)

Y.Indo 等人：“先天性疼痛不敏感伴无汗症患者的 TRKA/NGF 受体基因突变。”

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