The Gly571arg mutation, associated with the autonomic and sensory disordercongenital insensitivity to pain with anhidrosis, causes the inactivation of the NTRK1/nerve growth factor receptor

Point mutations affecting the NTRK1/TRKA gene, encoding one of the receptor s for the nerve growth factor (NGF), have been detected in congenital insen sitivity to pain with anhidrosis (CIPA), a human hereditary sensory neuropa thy characterized by absence of reaction to noxious stimuli and anhidrosis. To define the detect of NTRK1 in CIPA patients, we have introduced one of the previously reported mutations (Gly571Arg) into both the NTRK1 and the T RK-T3 oncogene cDNAs. The expression of the mutated constructs into COS1 ce lls revealed that the introduced mutation, while not affecting its correct membrane localization, rendered the NTRK1 protein unable to undergo activat ion upon stimulation with NGF. Similarly, the mutation abolished the consti tutive activation of the TRK-T3 oncogene. Transfection into NIH3T3 and PC12 cells showed the loss of transforming and differentiating activity by the mutated constructs. Our results demonstrate clearly that the CIPA mutations cause the inactivation of the NTRK1 receptor, thus exerting a loss of func tion effect, and provide an experimental approach to distinguish functional mutations from genetic polymorphisms. J. Cell. Physiol. 182:127-133, 2000. (C) 2000 Wiley-Liss, Inc.