A novel point mutation affecting the tyrosine kinase domain of the TRKA gene in a family with congenital insensitivity to pain with anhidrosis

A nerve growth factor receptor encoded by the TRKA gene plays an important part in the formation of autonomic neurons and small sensory neurons in dor sal root ganglia and in signal transduction through its intracytoplasmic ty rosine kinase domain. Recently, three mutations in the tyrosine kinase doma in of TRKA have been reported in patients with congenital insensitivity to pain with anhidrosis, which is an autosomal recessive disorder characterize d by recurrent fever due to absence of sweating, no reaction to noxious sti muli, self-mutilating behavior, and mental retardation. We examined the TRK A gene in five generations of a large Japanese family with many consanguine ous marriages who live in a small remote island of the southern part of Jap an. We found a novel point mutation at nucleotide 1825 (A-->G transition) r esulting in Met-581-Val in the tyrosine kinase domain. Two of the three aff ected patients were homozygous for this mutation; however, the third affect ed patient was heterozygous. Further analysis revealed that the third patie nt was a compound heterozygote with the Met-581-Val mutation in one allele and with a single base C deletion mutation at nucleotide 1726 in exon 14 in the other allele, resulting in a frameshift and premature termination codo n.