PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F18%3A10378534" target="_blank" >RIV/00216208:11130/18:10378534 - isvavai.cz</a>

Alternative codes found

RIV/00064203:_____/18:10378534

Result on the web

<a href="https://doi.org/10.1136/jnnp-2017-317562" target="_blank" >https://doi.org/10.1136/jnnp-2017-317562</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1136/jnnp-2017-317562" target="_blank" >10.1136/jnnp-2017-317562</a>

Result language

angličtina

Original language name

PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease

Original language description

Background Charcot-Marie-Tooth type 2 (CMT2) neuropathy is characterised by a vast clinical and genetic heterogeneity complicating its diagnosis and therapeutic intervention. Identification of molecular signatures that are common to multiple CMT2 subtypes can aid in developing therapeutic strategies and measuring disease outcomes. Methods A proteomics-based approach was performed on lymphoblasts from CMT2 patients genetically diagnosed with different gene mutations to identify differentially regulated proteins. The candidate proteins were validated through real-time quantitative PCR and western blotting on lymphoblast samples of patients and controls, motor neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) and sciatic nerves of CMT2 mouse models. Results Proteomic profiling of patient lymphoblasts resulted in the identification of profilin 2 (PFN2) and guanidinoacetate methyltransferase (GAMT) as commonly downregulated proteins in different genotypes compared with healthy controls. This decrease was also observed at the transcriptional level on screening 43 CMT2 patients and 22 controls, respectively. A progressive decrease in PFN2 expression with age was observed in patients, while in healthy controls its expression increased with age. Reduced PFN2 expression was also observed in motor neurons differentiated from CMT2 patient-derived iPSCs and sciatic nerves of CMT2 mice when compared with controls. However, no change in GAMT levels was observed in motor neurons and CMT2 mouse-derived sciatic nerves. Conclusions We unveil PFN2 and GAMT as molecular determinants of CMT2 with possible indications of the role of PFN2 in the pathogenesis and disease progression. This is the first study describing biomarkers that can boost the development of therapeutic strategies targeting a wider spectrum of CMT2 patients.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

<a href="/en/project/NV16-30206A" target="_blank" >NV16-30206A: Whole genome sequencing and RNA sequencing - a tool for elucidation of the causes of rare types of hereditary neuropathies.</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Neurology, Neurosurgery and Psychiatry

ISSN

0022-3050

e-ISSN

—

Volume of the periodical

89

Issue of the periodical within the volume

8

Country of publishing house

GB - UNITED KINGDOM

Number of pages

9

Pages from-to

870-878

UT code for WoS article

000442475000020

EID of the result in the Scopus database

2-s2.0-85048046162