Molecular genetics of congenital insensitivity to pain with anhidrosis

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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