| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
1.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 congenital insensitivity to pain with anhidrosis(CIPA). We here further report eight novel mutations detected as either a homozygous or heterozygous state in nine CIPA families from five countries.
2.Mendelian inheritance of the mutations was confirmed in seven families for which samples from either parent were available. However, non-mendelian inheritance seems for likely for the family when only samples from the mother and siblings, (but not from the farther) 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 this family.
3.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 and a missense mutation were detected in the TRKA and PKLR genes from the homozygous proband, respectively. Thus, concomitant occurrence of two disorders is ascribed to a combination of two separate mutant genes, not a contiguous gene syndrome. This finding suggests a mechanism responsible for two autosomal genetic disorders in one patient.
4.We introduced the putative missense mutations into the TRKA cDNA, using in vitro mutagenesis, and examined NGF-stimulated autophosphorylation. Mutants in the extracellular domain were aberrantly processed and showed diminished autophosphorylation in neuronal cells. Mutants in the tyrosine kinase domain were processed as wild-type TRKA but significantly diminished autophosphorylation in cells.
5.All these data further support findings that TRKA defects can cause CIPA in various ethnic groups. This will aid in diagnosis and genetic counseling of this painless but severe genetic disorders.
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