title: Novel pathogenic mechanisms of congenital insensitivity to pain with anhidrosis genetic disorder unveiled by functional analysis of neurotrophic tyrosine receptor kinase type 1/nerve growth factor receptor mutations.
abstract: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare genetic disease characterized by absence of reaction to noxious stimuli and anhidrosis. The genetic bases of CIPA have remained long unknown. A few years ago, point mutations affecting both coding and noncoding regions of the neurotrophic tyrosine receptor kinase type 1 (NTRK1)/nerve growth factor receptor gene have been detected in CIPA patients, demonstrating the implication of the nerve growth factor/NTRK1 pathway in the pathogenesis of the disease. We have previously shown that two CIPA mutations, the G571R and the R774P, inactivate the NTRK1 receptor by interfering with the autophosphorylation process. We have extended our functional analysis to seven additional NTRK1 mutations associated with CIPA recently reported by others. Through a combination of biochemical and biological assays, we have identified polymorphisms and pathogenic mutations. In addition to the identification of residues important for NTRK1 activity, our analysis suggests the existence of two novel pathogenic mechanisms in CIPA: one based on the NTRK1 receptor processing and the other acting through the reduction of the receptor activity.
authors.affiliation: Department of Experimental Oncology, Istituto Nazionale Tumori, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Miranda
authors.forename: Michela
authors.initials: M
authors.lastname: Di Virgilio
authors.forename: Silvia
authors.initials: S
authors.lastname: Selleri
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zanotti
authors.forename: Sonia
authors.initials: S
authors.lastname: Pagliardini
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: Angela
authors.initials: A
authors.lastname: Greco
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D007007:Hypohidrosis / Q000235:genetics*; D007700:Kinetics; D009154:Mutation; D020125:Mutation, Missense; D020932:Nerve Growth Factor / Q000494:pharmacology*; D000699:Pain Insensitivity, Congenital / Q000235:genetics*; D020800:Receptor, Nerve Growth Factor / Q000235:genetics*; D020917:Receptor, trkA / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014162:Transfection
chemical_list: D020800:Receptor, Nerve Growth Factor; D011994:Recombinant Proteins; D020932:Nerve Growth Factor; D020917:Receptor, trkA