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PMID: 16775378 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Pathomechanisms of mutant proteins in Charcot-Marie-Tooth disease.

Neuromolecular medicine ·Vol. 8 ·No. 1-2 ·2006-00-00 ·Pages 217-42

Niemann A, Berger P, Suter U

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.

MeSH Terms
Cell Cycle Proteins/genetics,metabolism Charcot-Marie-Tooth Disease/genetics,pathology,physiopathology Connexins/genetics,metabolism Cytoskeletal Proteins/genetics,metabolism DNA-Binding Proteins/genetics,metabolism Demyelinating Diseases/genetics,pathology,physiopathology Dynamin II/genetics,metabolism Early Growth Response Protein 2/genetics,metabolism Endocytosis/physiology GTP Phosphohydrolases Heat-Shock Proteins/genetics,metabolism High Mobility Group Proteins/genetics,metabolism Humans Intracellular Signaling Peptides and Proteins/genetics,metabolism Kinesins/genetics,metabolism Lamin Type A/genetics,metabolism Membrane Proteins/genetics,metabolism Mitochondrial Proteins/genetics,metabolism Mutation Myelin P0 Protein/genetics,metabolism Myelin Proteins/genetics,metabolism Myelin Proteolipid Protein/genetics,metabolism Myelin Sheath/genetics,metabolism Nerve Tissue Proteins/genetics,metabolism Neurofilament Proteins/genetics,metabolism Nuclear Proteins/genetics,metabolism Protein Transport Protein Tyrosine Phosphatases/genetics,metabolism Protein Tyrosine Phosphatases, Non-Receptor Proteins/genetics,metabolism SOXE Transcription Factors Transcription Factors/genetics,metabolism rab GTP-Binding Proteins/genetics,metabolism rab7 GTP-Binding Proteins
Chemicals
Cell Cycle Proteins Connexins Cytoskeletal Proteins DNA-Binding Proteins EGR2 protein, human Early Growth Response Protein 2 GAN protein, human GDAP protein Heat-Shock Proteins High Mobility Group Proteins Intracellular Signaling Peptides and Proteins LITAF protein, human LMNA protein, human Lamin Type A Membrane Proteins Mitochondrial Proteins Myelin P0 Protein Myelin Proteins Myelin Proteolipid Protein N-myc downstream-regulated gene 1 protein Nerve Tissue Proteins Neurofilament Proteins Nuclear Proteins PMP22 protein, human Proteins SH3TC2 protein, human SOX10 protein, human SOXE Transcription Factors Transcription Factors connexin 32 periaxin rab7 GTP-Binding Proteins MTMR2 protein, human Protein Tyrosine Phosphatases Protein Tyrosine Phosphatases, Non-Receptor SBF2 protein, human GTP Phosphohydrolases MFN2 protein, human Kinesins rab GTP-Binding Proteins Dynamin II
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Niemann Axel
Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, ETH-Hönggerberg, CH-8093 Zürich, Switzerland.
Berger Philipp
Suter Ueli
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Article Info
Journal
Neuromolecular medicine
Abbr.
Neuromolecular Med
ISSN
1535-1084
DOI
10.1385/nmm:8:1-2:217
Published
2006-00-00
Pages
217-42
Language
English
Region
United States
NLM ID
101135365
Subset
IM
External Links
PubMed source DOI: 10.1385/nmm:8:1-2:217 View journal details
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