title: Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.
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 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 animals. 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-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 the nervous system.
authors.affiliation: Department of Pediatrics, Kumamoto University School of Medicine, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Indo
authors.forename: M
authors.initials: M
authors.lastname: Tsuruta
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashida
authors.forename: M A
authors.initials: MA
authors.lastname: Karim
authors.forename: K
authors.initials: K
authors.lastname: Ohta
authors.forename: T
authors.initials: T
authors.lastname: Kawano
authors.forename: H
authors.initials: H
authors.lastname: Mitsubuchi
authors.forename: H
authors.initials: H
authors.lastname: Tonoki
authors.forename: Y
authors.initials: Y
authors.lastname: Awaya
authors.forename: I
authors.initials: I
authors.lastname: Matsuda
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D016368:Frameshift Mutation; D015870:Gene Expression; D005796:Genes; D005808:Genes, Recessive; D006801:Humans; D007007:Hypohidrosis / Q000235:genetics*; D008969:Molecular Sequence Data; D000699:Pain Insensitivity, Congenital / Q000235:genetics*; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D015183:Restriction Mapping; D016415:Sequence Alignment; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013577:Syndrome
chemical_list: D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA