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Research paper
PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease
  1. Manisha Juneja1,2,
  2. Abdelkrim Azmi3,
  3. Jonathan Baets2,3,4,
  4. Andreas Roos5,6,
  5. Matthew J Jennings5,
  6. Paola Saveri7,
  7. Chiara Pisciotta7,
  8. Nathalie Bernard-Marissal8,9,
  9. Bernard L Schneider9,
  10. Catherine Verfaillie10,
  11. Roman Chrast11,12,
  12. Pavel Seeman13,
  13. Angelika F Hahn14,
  14. Peter de Jonghe2,3,
  15. Stuart Maudsley3,
  16. Rita Horvath5,
  17. Davide Pareyson7,
  18. Vincent Timmerman1,2
  1. 1Peripheral Neuropathy Research Group, University of Antwerp, Antwerp, Belgium
  2. 2Institute Born Bunge, Antwerp, Belgium
  3. 3VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium
  4. 4Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerpen, Belgium
  5. 5Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
  6. 6Leibniz-Institut für Analytische Wissenschaften -ISAS- e.V., Dortmund, Germany
  7. 7Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, C. Besta Neurological Institute IRCCS Foundation, Milan, Italy
  8. 8Aix Marseille University, INSERM, MMG, U1251, Marseille, France
  9. 9Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
  10. 10Stem Cell Institute, KU Leuven, Leuven, Belgium
  11. 11Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
  12. 12Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
  13. 13DNA Laboratory, Department of Child Neurology, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic
  14. 14Department of Clinical Neurological Sciences Centre, University Hospital, Western University, London, Ontario, Canada
  1. Correspondence to Dr Vincent Timmerman, Peripheral Neuropathy Research Group University of Antwerp, Antwerpen 2610, Belgium; vincent.timmerman{at}


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.

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  • Contributors MJ designed and performed the experimental work and wrote the manuscript. AA and SM assisted in the proteomics analysis and wrote the corresponding sections. NBM, BLS and RC provided tissues of the Mfn2 transgenic mouse model and wrote the corresponding sections. CV generated the iPSC lines. JB, AR, MJJ, PS, CP, PS, AFH, PdJ, RH and DP provided patient samples and summarised the clinical tables. VT coordinated the design of this study, wrote and edited the manuscript.

  • Funding This work was supported in part by the Fund for Scientific Research (FWO-Flanders), the ‘Association Belge contre les Maladies Neuromusculaires’ (ABMM), the Medical Foundation Queen Elisabeth (GSKE) and the EU FP7/2007_2013 under grant agreement number 2012-305121 (NEUROMICS). JB is supported by a Senior Clinical Researcher mandate of the Research Fund—Flanders (FWO). AR received support by the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen. RH is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the Medical Research Council (UK) (MR/N025431/1) and the European Research Council (309548). NBM, BLS and RC received support from the Neuromuscular Research Association Basel (NeRAB). NBM and BLS are also supported by ERANET E-Rare FaSMALS (grant 31ER30_160673). PS is supported by the Ministry of Health of the Czech Republic (AZV 16-30206 and DRO 00064203).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval University of Antwerp.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it was published Online First. A typo in Supplementary Figure 4 has been corrected.