Nature Genetics
13, 485 - 488 (1996)
doi:10.1038/ng0896-485
Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosisYasuhiro Indo1, 4, Motoko Tsuruta1, Yumi Hayashida1, Mohammad Azharul Karim1, Kohji Ohta1, Tomoyasu Kawano1, Hiroshi Mitsubuchi1, Hidefumi Tonoki2, Yutaka Awaya3
& Ichiro Matsuda1
1Department of Pediatrics, Kumamoto University School of Medicine, Honjo 1-1-1, Kumamoto 860, Japan
2Department of Pediatrics, Hokkaido University School of Medicine, N15W7, Sapporo 060, Japa
3Department of Pediatrics, Seibo International Catholic Hospital/ HSAN-IV Association (Tomorrow), Tokyo 161, Japan
4Correspondence should be addressed to Y.I. 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 behaviour and mental retardation1−3. The genetic basis for CIPA is unknown. Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons4. Mice lacking the gene for TrkA, a receptor tyrosine kinase for NGF5,6, share dramatic phenotypic features of CIPA, including loss of responses to painful stimuli, although anhidrosis is not apparent in these animals7. We therefore considered the human TRKA homologue as a candidate for the CIPA gene. The mRNA and genomic DNA encoding TRKA were analysed in three unrelated CIPA patients who had consanguineous parents. We detected a deletion-, splice- and missense-muta-tion 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 the nervous system.
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