Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Swanson, A.G. Congenital insensitivity to pain with anhidrosis. Arch. Neurol. 8, 299–306 (1963).
Dyck, R.J. Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. In Peripheral Neuropathy (2nd Edn) (eds Dyck, RJ., Thomas, P.K., Lambert, E.H. & Bunge, R.) 1557–1599 (W. B. Saunders Company, Philadelphia, 1984).
McKusick, V.A. in Mendelian inheritance in man 11th edn. 2073. (The Johns Hopkins University Press, Baltimore, 1994).
Levi-Montalcini, R. The nerve growth factor: thirty-five years later. EMBO J. 6, 1145–1154 (1987).
Kaplan, D.R., Hempstead, B.L., Martin-Zanca, D., Chao, M.V. & Parada, L.F. The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science 252, 554–558 (1991).
Klein, R., Jing, S., Nanduri, V., O'Rourke, E. & Barbacid, M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 65, 189–197 (1991).
Smeyne, R.J. et al. Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature 368, 246–249 (1994).
Swanson, A.G., Buchan, G.C. & Alvord, E.G. Anatomic changes in congenital insensitivity to pain. Arch. Neurol. 12, 12–18 (1965).
Brown, J.W. & Podosin, R. A syndrome of the neural crest. Arch. Neurol. 15, 294–301 (1966).
Rafel, E., Alberca, R., Bautista, J., Navarrete, M. & Lazo, J. Congenital insensitivity to pain with anhidrosis. Muscle Nerve 3, 216–220 (1980).
Langer, J., Goebel, H.H. & Veit, S. Eccrine sweat glands are not innervated in hereditary sensory neuropathy type IV An electron-microscopic study. Acta Neuropathol. Berl. 54, 199–202 (1981).
Krawczak, M., Reiss, J. & Cooper, D.N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum. Genet. 90, 41–54 (1992).
Crowley, C. et al. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 76, 1001–1011 (1994).
Lee, K.-F. et al. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69, 737–749 (1992).
Vega, J.A. et al. Immunohistochemical localization of the high-affinity NGF receptor (gp140-trkA) in the adult human dorsal root and sympathetic ganglia and in the nerves and sensory corpuscles supplying digital skin. Anat. Rec. 240, 579–588 (1994).
Muragaki, Y. et al. Expression of trk receptors in the developing and adult human central and peripheral nervous system. J. Comp. Neurol. 356, 387–397 (1995).
Mountcastle, V.B. in Medical physiology 13th edn. 1319–1323 (The C. V. Mosby Company, St. Louis, 1974).
Gabella, G. in Structure of the autonomic nervous system. 153–154 (Chapman and Hall, London, 1976).
Wake, M.H. in Hyman's comparative vertebrate anatomy 3rd edn. 139–142 (The University of Chicago Press, Chicago, 1979).
Rosemberg, S., Marie, S.K.N. & Kliemann, S. Congenital insensitivity to pain with anhidrosis (hereditary sensory and autonomic neuropathy type IV). Pediatr. Neurol. 11, 50–56 (1994).
Martin-Zanca, D., Hughes, S.H. & Barbacid, M. A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature 319, 743–748 (1986).
Scribanu, N. & Grover-Johnson, N. Atypical nerve histology in a case of familial dysautonomia type II. Pediatr. Res. 12, 556 (1978).
Indo, Y., Kitano, A., Endo, F., Akaboshi, I. & Matsuda, I. Altered kinetic properties of the branched-chain α-keto acid dehydrogenase complex due to mutation of the β-subunit of the branched-chain α-keto acid decarboxylase (E1) component in lymphoblastoid cells derived from patients with maple syrup urine disease. J. Clin. Invest. 80, 63–70 (1987).
Martin-Zanca, D., Oskam, R., Mitra, G., Copeland, T. & Barbacid, M. Molecular and biochemical characterization of the human trk proto-oncogene. Molec. Cell. Biol. 9, 24–33 (1989).
Greco, A., Mariani, C., Miranda, C., Pagliardini, S. & Pierotti, M.A. Characterization of the NTRK1 genomic region involved in chromosomal rearrangements generating TRK oncogenes. Genomics 18, 397–400 (1993).
Chomczynski, R. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).
Sambrook, J., Fritsch, E.F. & Maniatis, T. in Molecular cloning: A laboratory manual 2nd edn. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor), 1989).
Marchuk, D., Drumm, M., Saulino, A. & Collins, F.S. Construction of T-vectors, a rapid and general system for direct cloning of unmodified PCR products. Nucl. Acids Res. 19, 1154 (1991).
Nakagawara, A. et al. Cloning and chromosomal localization of the human TRK-B tyrosine kinase receptor gene (NTRK2). Genomics 25, 538–546 (1995).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Indo, Y., Tsuruta, M., Hayashida, Y. et al. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet 13, 485–488 (1996). https://doi.org/10.1038/ng0896-485
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0896-485
This article is cited by
-
Autism spectrum disorder in a boy with congenital insensitivity to pain with anhidrosis: a case report
BMC Pediatrics (2022)
-
Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain
Nature Communications (2021)
-
The sympathetic nervous system in development and disease
Nature Reviews Neuroscience (2021)
-
NTRK1 gene-related congenital insensitivity to pain with anhidrosis: a nationwide multicenter retrospective study
neurogenetics (2021)
-
TRK Fusion Cancer: Patient Characteristics and Survival Analysis in the Real-World Setting
Targeted Oncology (2021)