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PMP22 overexpression causes dysmyelination in mice
A Robaglia-Schlupp1, J Pizant, J-C Norreel
1INSERM U491, Medical Genetics and Development, Faculté de Médecine de la Timone, 27 Boulevard J. Moulin, 13385 Marseille cedex 5, France.
Brain : a Journal of Neurology
|September 24, 2002
Summary
Charcot-Marie-Tooth type 1A (CMT1A) is a common inherited neuropathy. PMP22 gene overexpression in a mouse model causes defective myelination, suggesting dysmyelination, not just demyelination, is key.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy, affecting 1 in 2500 individuals.
- CMT type 1A (CMT1A), an autosomal dominant form, is linked to a duplication on chromosome 17 involving the peripheral myelin protein 22 (PMP22) gene.
Purpose of the Study:
- To investigate the effects of PMP22 gene overexpression on myelination in a novel murine model.
- To explore the underlying mechanisms of CMT1A pathogenesis, focusing on the role of PMP22.
Main Methods:
- Construction of a transgenic mouse model (C22 line) with human YAC containing PMP22 and its regulatory elements, leading to PMP22 overexpression.
- Utilized electron microscopy, morphometry, electrophysiology, nerve conduction studies, and marker expression analysis (e.g., Krox20).
Main Results:
- PMP22 overexpression resulted in defective myelination of axons, particularly affecting larger diameter axons.
- Observed minimal demyelination/remyelination, suggesting a primary defect in myelin formation (dysmyelination).
- Evidence indicated PMP22 overexpression may also influence fibroblast collagen synthesis prior to myelination.
Conclusions:
- PMP22 overexpression in Schwann cells directly impairs the myelination process, leading to dysmyelination in CMT1A.
- The findings challenge the classical view of CMT1A as solely a demyelinating disease, highlighting dysmyelination as a critical factor.
- Non-Schwann cell components, like fibroblasts, might also be affected by PMP22 alterations in CMT1A.