Congenital insensitivity to pain with anhidrosis: Novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor

Congenital insensitivity to pain with anhidrosis (CIPA) is characterized by recurrent episodes of unexplained fever, anhidrosis (inability to sweat),a bsence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. Human TRKA encodes a. high-affinity tyrosine kinase receptor for nerve growth factor (NGF), a member of the neurotrophin family that ind uces neurite outgrowth and promotes survival of embryonic sensory and sympa thetic neurons. We have recently demonstrated that TRKA is responsible for CIPA by identifying three mutations in a region encoding the intracellular tyrosine, kinase domain of TRKA in one Ecuadorian and three Japanese famili es. We have developed a comprehensive strategy to screen for TRKA mutations , on the basis of the gene's structure and organization. Here we report 11 novel mutations, in seven affected families. These are six missense mutatio ns, two frameshift mutations, one nonsense mutation, and two splice-site mu tations. Mendelian inheritance of the mutations is confirmed in six familie s for which parent samples are available. Two mutations are linked, on the same chromosome, to Arg85Ser and to His598Tyr;Gly607Val, hence, they probab ly represent double and triple mutations. The mutations are distributed in an extracellular domain, involved in NGF binding, as well as the intracellu lar signal-transduction domain. These data suggest that TRKA,defects cause CIPA in various ethnic groups.