Abstract
We review the putative functions and malfunctions of proteins encoded by genes mutated in Charcot-Marie-Tooth disease (CMT; inherited motor and sensory neuropathies) in normal and affected peripheral nerves. Some proteins implicated in demyelinating CMT, peripheral myelin protein 22, protein zero (P0), and connexin32 (Cx32/GJB1) are crucial components of myelin. Periaxin is involved in connecting myelin to the surrounding basal lamina. Early growth response 2 (EGR2) and Sox10 are transcriptional regulators of myelin genes. Mutations in the small integral membrane protein of lysosome/late endosome, the myotubularin-related protein 2 (MTMR2), and MTMR13/set-binding factor 2 are involved in vesicle and membrane transport and the regulation of protein degradation. Pathomechanisms related to alterations of these processes are a widespread phenomenon in demyelinating neuropathies because mutations of myelin components may also affect protein biosynthesis, transport, and/or degradation. Related disease mechanisms are also involved in axonal neuropathies although there is considerably more functional heterogeneity. Some mutations, most notably in P0, GJB1, ganglioside-induced differentiation-associated protein 1 (GDAP1), neurofilament light chain (NF-L), and dynamin 2 (DNM2), can result in demyelinating or axonal neuropathies introducing additional complexity in the pathogenesis. Often, this relates to the intimate connection between Schwann cells and neurons/axons leading to axonal damage even if the mutation-caused defect is Schwann-cell-autonomous. This mechanism is likely for P0 and Cx32 mutations and provides the basis for the unifying hypothesis that also demyelinating neuropathies develop into functional axonopathies. In GDAP1 and DNM2 mutants, both Schwann cells and axons/neurons might be directly affected. NF-L mutants have a primary neuronal defect but also cause demyelination. The major challenge ahead lies in determining the individual contributions by neurons and Schwann cells to the pathology over time and to delineate the detailed molecular functions of the proteins associated with CMT in health and disease.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Charcot-Marie-Tooth Disease / genetics*
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Charcot-Marie-Tooth Disease / pathology
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Charcot-Marie-Tooth Disease / physiopathology*
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Connexins / genetics
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Connexins / metabolism
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Demyelinating Diseases / genetics*
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Demyelinating Diseases / pathology
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Demyelinating Diseases / physiopathology*
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Dynamin II / genetics
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Dynamin II / metabolism
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Early Growth Response Protein 2 / genetics
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Early Growth Response Protein 2 / metabolism
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Endocytosis / physiology
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GTP Phosphohydrolases
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Gap Junction beta-1 Protein
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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High Mobility Group Proteins / genetics
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High Mobility Group Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Kinesins / genetics
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Kinesins / metabolism
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Lamin Type A / genetics
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Lamin Type A / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Mutation*
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Myelin P0 Protein / genetics
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Myelin P0 Protein / metabolism
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Myelin Proteins / genetics
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Myelin Proteins / metabolism
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Myelin Proteolipid Protein / genetics
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Myelin Proteolipid Protein / metabolism
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Myelin Sheath / genetics
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Myelin Sheath / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurofilament Proteins / genetics
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Neurofilament Proteins / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Protein Transport
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism
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Protein Tyrosine Phosphatases, Non-Receptor
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Proteins / genetics
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Proteins / metabolism
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SOXE Transcription Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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rab GTP-Binding Proteins / genetics
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rab GTP-Binding Proteins / metabolism
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rab7 GTP-Binding Proteins
Substances
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Cell Cycle Proteins
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Connexins
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Cytoskeletal Proteins
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DNA-Binding Proteins
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EGR2 protein, human
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Early Growth Response Protein 2
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GAN protein, human
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GDAP protein
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Heat-Shock Proteins
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High Mobility Group Proteins
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Intracellular Signaling Peptides and Proteins
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LITAF protein, human
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LMNA protein, human
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Lamin Type A
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Membrane Proteins
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Mitochondrial Proteins
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Myelin P0 Protein
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Myelin Proteins
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Myelin Proteolipid Protein
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N-myc downstream-regulated gene 1 protein
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Nerve Tissue Proteins
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Neurofilament Proteins
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Nuclear Proteins
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PMP22 protein, human
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Proteins
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SH3TC2 protein, human
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SOX10 protein, human
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SOXE Transcription Factors
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Transcription Factors
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periaxin
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rab7 GTP-Binding Proteins
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MTMR2 protein, human
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Protein Tyrosine Phosphatases
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Protein Tyrosine Phosphatases, Non-Receptor
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SBF2 protein, human
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GTP Phosphohydrolases
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MFN2 protein, human
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Kinesins
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rab GTP-Binding Proteins
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Dynamin II