Novel pathogenic mechanisms of CIPA genetic disorder unveiled by functional analysis of NTRK1/NGF receptor mutations

doi:10.1074/jbc.M110016200

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Papers In Press, published online ahead of print November 21, 2001
J. Biol. Chem, 10.1074/jbc.M110016200
Submitted on October 17, 2001
Revised on November 19, 2001
Accepted on November 21, 2001

Novel pathogenic mechanisms of CIPA genetic disorder unveiled by functional analysis of NTRK1/NGF receptor mutations

Claudia Miranda, Michela Di Virgilio, Silvia Selleri, Giuseppe Zanotti, Sonia Pagliardini, Marco A. Pierotti, and Angela Greco

Experimental Oncology, Operative Unit #3, Istituto Nazionale Tumori, Milan 20133

Corresponding Author: greco{at}istitutotumori.mi.it

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 non-coding regions of the NTRK1/NGF receptor gene have been detected in CIPA patients, demonstrating the implication of the NGF/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 additional seven 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.

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