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J. Biol. Chem., Vol. 277, Issue 8, 6455-6462, February 22, 2002
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From the 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.
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*
,,,,¶, and¶
Department of Experimental Oncology,
Istituto Nazionale Tumori, Via G. Venezian 1, Milan 20133, Italy and
the § Department of Organic Chemistry, University of Padova,
Via Marzolo 1, Padova 35131, Italy
*
This work was supported by Telethon Foundation Grant E.1159
and by the Italian Association for Cancer Research.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Istituto
Nazionale Tumori, Dept. of Experimental Oncology, Via Venezian 1, 20133 Milan, Italy. Tel.: 39 02 23 90 3222; Fax: 39 02 23 90 2764; E-mail: greco@istitutotumori.mi.it.
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