PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease
Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
G1000848
Medical Research Council - United Kingdom
MR/N025431/2
Medical Research Council - United Kingdom
MR/N025431/1
Medical Research Council - United Kingdom
109915/Z/15/Z
Wellcome Trust - United Kingdom
MR/N010035/1
Medical Research Council - United Kingdom
Odkazy
PubMed
29449460
DOI
10.1136/jnnp-2017-317562
PII: jnnp-2017-317562
Knihovny.cz E-zdroje
- MeSH
- axony patologie MeSH
- Charcotova-Marieova-Toothova nemoc genetika patologie MeSH
- dospělí MeSH
- fenotyp MeSH
- genotyp * MeSH
- guanidinacetát-N-methyltransferasa genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mutace * MeSH
- profiliny genetika MeSH
- proteomika MeSH
- rodokmen MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- GAMT protein, human MeSH Prohlížeč
- guanidinacetát-N-methyltransferasa MeSH
- PFN2 protein, human MeSH Prohlížeč
- profiliny MeSH
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.
Aix Marseille University INSERM MMG U1251 Marseille France
Brain Mind Institute Ecole Polytechnique Fédérale de Lausanne Lausanne Switzerland
Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden
Department of Neuroscience Karolinska Institutet Stockholm Sweden
Institute Born Bunge Antwerp Belgium
Institute of Genetic Medicine Newcastle University Newcastle upon Tyne UK
Leibniz Institut für Analytische Wissenschaften ISAS e 5 Dortmund Germany
Neuromuscular Reference Centre Department of Neurology Antwerp University Hospital Antwerpen Belgium
Peripheral Neuropathy Research Group University of Antwerp Antwerp Belgium
Stem Cell Institute KU Leuven Leuven Belgium
VIB Center for Molecular Neurology University of Antwerp Antwerp Belgium