RT Journal Article
SR Electronic
T1 PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease
JF Journal of Neurology, Neurosurgery & Psychiatry
JO J Neurol Neurosurg Psychiatry
FD BMJ Publishing Group Ltd
SP 870
OP 878
DO 10.1136/jnnp-2017-317562
VO 89
IS 8
A1 Juneja, Manisha
A1 Azmi, Abdelkrim
A1 Baets, Jonathan
A1 Roos, Andreas
A1 Jennings, Matthew J
A1 Saveri, Paola
A1 Pisciotta, Chiara
A1 Bernard-Marissal, Nathalie
A1 Schneider, Bernard L
A1 Verfaillie, Catherine
A1 Chrast, Roman
A1 Seeman, Pavel
A1 Hahn, Angelika F
A1 de Jonghe, Peter
A1 Maudsley, Stuart
A1 Horvath, Rita
A1 Pareyson, Davide
A1 Timmerman, Vincent
YR 2018
UL http://jnnp.bmj.com/content/89/8/870.abstract
AB 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.