Congenital insensitivity to pain with anhidrosis (CIPA): Novel mutations of the TRK4 (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency

Congenital insensitivity to pain with anhidrosis is an autosomal recessive hereditary disorder characterized by recurrent episodic fever, anhidrosis ( inability to sweat), absence of reaction to noxious stimuli, self mutilatin g behavior, and mental retardation. The human TRKA gene (NTRK1), located on chromosome 1q21-q22 encodes the receptor tyrosine kinase for nerve growth factor. We reported that TRKA is the gene responsible for CIPA and we devel oped a comprehensive strategy to screen for TRKA mutations and polymorphism s, as based on the gene's structure and organization. Here we report eight novel mutations detected as either a homozygous or heterozygous state in ni ne CIPA families from five countries. Mendelian inheritance of the mutation s was confirmed in seven families for which samples from either parent were available. However, none mendelian inheritance seems likely for the family when only samples from the mother and siblings, (but not from the father) were available. A paternal uniparental disomy for chromosome 1 is likely to be the cause of reduction to homozygosity of the TRKA gene mutation in thi s family. Interestingly, a Hispanic patient from the USA has two autosomal genetic disorders, CIPA and pyruvate kinase deficiency, whose genetic loci are both mapped to a closely linked chromosomal region. A splice mutation a nd a missense mutation were detected in the TRKA and PKLR genes from the ho mozygous proband, respectively. Thus, concomitant occurrence of two disorde rs is ascribed to a combination of two separate mutant genes, not a contigu ous gene syndrome. This finding suggests a mechanism responsible for two au tosomal genetic disorders in one patient. All these data further support fi ndings that TRKA defects can cause CIPA in various ethnic groups. This will aid in diagnosis and genetic counseling of this painless but severe geneti c disorder. Hum Mutat 18:308-318, 2001. (C) 2001 Wiley-Liss, Inc.