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2002 Fiscal Year Final Research Report Summary

Molecular pathology of congenital insensitivity to pain with anhidrosis due to genetic defects of the receptor tyrosine kinase for nerve growth factor

Research Project

Project/Area Number 13672378
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Human genetics
Research InstitutionKumamoto University

Principal Investigator

INDO Yasuhiro  Kumamoto University, Kumamoto University Hospital, Lecturer, 医学部附属病院, 講師 (40244131)

Project Period (FY) 2001 – 2002
Keywordscongenital insensitivity to pain with anhidrosis / hereditary sensory and autonomic neuropathy type IV / nerve growth factor / nerve growth factor receptor / receptor tyrosine kinase / TRKA / NTRK1
Research Abstract

1. We have analyzed the TRKA gene derived from 23 Japanese and 8 foreign patients with congenital insensitivity to pain with anhidrosis (CIPA) and detected responsible mutations in all these patients. We also report the characterization of intragenic polymorphic sites and describe the haplotypic associations of alleles at these sites in Japanese CIPA families. More than 50% of CIPA chromosomes share the frameshift mutation (R548fs) that we described earlier. This mutation apparently shows linkage disequilibrium with a rare haplotype in normal chromosomes, strongly suggesting that it is a common founder mutation.
2. Uniparental disomy (UPD) is defined as the presence of a chromosome pair that derives from only one patient in a diploid individual. We have observed a male CIPA patient with non-Mendelian inheritance. He had a homozygous mutation at the TRKA locus on chromosome 1. Haplotype analysis of the TRKA locus and allelotype analyses of whole chromosome 1 revealed that the chromosome … More pair was exclusively derived from his father. Non-maternity was excluded by analyses of autosomes other than chromosome 1. Thus, we have identified a complete paternal isodisomy for chromosome 1 as the cause of reduction to homozygosity of the TRKA gene mutation, leading to CIPA.
3. We have demonstrated that an intronic branch-site (IVS7-33T>A) mutation in the TRKA gene causes aberrant splicing in vitro by the exon-trap analysis. We also reported 11 putative missense mutations in 32 CIPA families from various ethnic groups. Here we have introduced the corresponding mutations into the TRKA cDNA and examined NGF-stimulated autophosphorylation. Two mutants (L93P and L213P) in the extracellular domain were aberrantly processed and showed diminished autophosphorylation in neuronal cells. Five mutants (G516R, G571R, R643W, R648C and G708S) in the tyrosine kinase domain were processed as wild-type TRKA but showed significantly diminished autophosphorylation in both neuronal and non-neuronal cells. In contrast, R85S and H598Y; G607V detected previously as double and triple mutations, are probably polymorphisms in a particular ethnic background. The other putative mutant D668Y might be a rare polymorphism or might impair the function of TRKA without compromising autophosphorylation. Mutated residues in the tyrosine kinase domain are conserved in various receptor tyrosine kinases (RTKs) and probably contribute to critical function of these proteins. Thus, naturally occurring TRKA missense mutations with loss-of-function provide considerable insight into the structure-function relationship in the RTK family. Less

  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] S.Mardy: "Congenital insensitivity to pain with anhidrosis : novel mutations in the TRKA(NTRK1) gene enoding a high-affinity receptor for nerve growth factor"American Journal of Human Genetics. 64. 1570-1579 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Miura: "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"Human Genetics. 106. 116-124 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] E.Toscano: "Multisystem involvement in congenital insensitivity to pain with anhidrosis (CIPA), a nerve growth factor receptor (Trk A)-related disorder"Neuropediatrics. 31. 39-41 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Miura: "Complete paternal uniparental isodisomy for chromosome 1 revealed by mutation analyses of the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with congenital insensitivity to pain with anhidrosis"Human Genetics. 107. 205-209 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.Mardy: "Congenital insensitivity to pain with anhidrosis (CIPA) : effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor"Human Molecular Genetics. 10. 179-188 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 犬童康弘: "先天性無痛無汗症"生体の科学. 50. 379-380 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 犬童康弘: "先天性無痛無汗症の分子遺伝学的研究 (日本先天代謝異常学会奨励賞受賞論文)"日本先天代謝異常学会雑誌. 17. 38-43 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 犬童康弘: "先天性無痛無汗症の分子病態から見た交感神経と感覚神経の分化・生存とアポトーシス"自律神経. 39. 53-60 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 犬童康弘: "先天性無痛無汗症とアポトーシス"小児内科. 34. 1777-1781 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 犬童康弘: "遺伝子について先天性無痛無汗症 -難病の理解と生活支援のために-(二瓶、粟屋、三宅、小田 編)"日本小児医事出版社. 21-23 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 犬童康弘: "先天性無痛無汗症 小児科(第2版) (白木、前川 監修) (伊藤、大関、岡田、近藤、杉本、田澤、田村、埜中、原田、福嶋 編)"医学書院. 1534-1535 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S. Mardy: "Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA(NTRK1) gene encoding a high-affinity receptor for nerve growth factor"American Journal of Human Genetics. 64. 1570-1579 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Y. Miura: "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"Human Genetics. 106. 116-124 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] E. Toscano: "Multisystem involvement in congenital insensitivity to pain with anhidrosis (CIPA), a nerve growth factor receptor (Trk A)-related disorder"Neuropediatrics. 31. 39-41 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Y. Miura: "Complete paternal uniparental isodisomy for chromosome 1 revealed by mutation analyses of the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with congenital insensitivity to pain with anhidrosis"Human Genetics. 107. 205-209 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S. Mardy: "Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor"Human Molecular Genetics. 10. 179-188 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Y. Indo: "Differentiation, survival and apoptosis of sympathetic and sensory neurons: a lesson from molecular pathology of congenital insensitivity to pain with anhidrosis (CIPA)"The Autonomic Nervous System. 39. 53-60 (2002)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2004-04-14  

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