Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families

The human TRKA gene encodes a high-affinity tyrosine kinase receptor for ne rve growth factor Congenital insensitivity to pain with anhidrosis (CIPA) i s an autosomal recessive genetic disorder-reported from various countries a nd characterized by anhidrosis (inability to sweat), the absence of reactio n to noxious stimuli, and mental retardation. We have found that TRKA is th e gene responsible for CIPA. We have studied TRKA in 46 CIPA chromosomes de rived from 23 unrelated Japanese CIPA families. including three that have b een previously reported. and identified 11 novel mutations. Four (L93P, G51 6R, R638 C, and D668Y) are missense mutations that result in amino acid sub stitutions at positions conserved in the TRK family, including TRKA, TRKB, and TRKC. Three (S131 fs. L579 fs, and D770 fs) are frameshift mutations. T hr ee (E164X, Y359X, and R596X) ale nonsense mutations. The other is an int ronic branch-site (IVS7-33T-->A) mutation, causing aberrant splicing in vit ro. We also report the characterization of eight intragenic polymorphic sit es, including a variable dinucleotide repeat and seven single nucleotide po lymorphisms, and describe the haplotypic associations of alleles at these s ites in 106 normal chromosomes and 46 CIPA chromosomes More than 50% of CIP A chromosomes share the frameshift mutation (R548 fs) that we described ear lier. This mutation apparently shows linkage disequilibrium with a rare hap lotype in normal chromosomes, strongly suggesting that it is a common found er mutation. These findings represent the first extensive analysis of CIPA mutations and associated intragenic polymorphisms; they should facilitate t he detection of CIPA mutations and aid in the diagnosis and genetic counsel ing of this painless but severe genetic disorder with devastating complicat ions.