Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): Mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor

Congenital insensitivity to pain with anhidrosis (CIPA), also referred to a s hereditary sensory and autonomic neuropathy type IV (HSAN-IV), is an auto somal recessive hereditary disorder characterized by recurrent episodic fev er, anhidrosis (inability to sweat), absence of reaction to noxious stimuli , self mutilating behavior, and mental retardation. The TRKA (NTRK1) gene l ocated on chromosome 1 (1q21-q22), consists of 17 exons and spans at least 23 kb. TRKA encodes the receptor tyrosine kinase (RTK) for nerve growth fac tor (NGF) and is the gene responsible for CIPA. Defects in NGF signal trans duction at the TRKA receptor lead to failure to support survival of sympath etic ganglion neurons and nociceptive sensory neurons derived from the neur al crest. Thirty,seven different TRKA mutations, identified in patients in various countries, including nine frameshift, seven nonsense, seven splice, and 14 missense mutations, are distributed in an extracellular domain invo lved in NGF binding, as well as in the intracellular signal-transduction do main. Extensive analysis of CIPA mutations and associated intragenic polymo rphisms should facilitate detection of CIPA mutations and aid in the diagno sis and genetic counseling of this painless but severe genetic disorder wit h devastating complications. In addition, naturally occur. ring TRKA missen se mutations with loss of function provide considerable insight into the st ructure-function relationship in the RTK family. Further, molecular patholo gy of CIPA would provide unique opportunities to explore critical roles of the autonomic sympathetic nervous system as well as peripheral sensory nerv ous system that transmit noxious stimuli in humans. Hum Mutat 18:462-471, 2 001. (C) 2001 Wiley-Liss, Inc.