Role of R69C Myelin Protein Zero in Molecular Mechanisms of Charcot-Marie-Tooth Neuropathy IB Pathogenesis
von Gunten, Hope Elizabeth Rogers
Charcot~Marie-Tooth (CMT) Neuropathy 1B is a dominant negative neurogenetic disease caused by mutations in the gene coding for Myelin Protein Zero (MPZ), the most abundant integral myelin protein in the peripheral nervous system. Although mutation of MPZ is known to cause CMT 1B, the mechanism of the pathogenesis is still unknown. A homozygous mouse model of one MPZ mutation observed in a human CMT patient, R69C, was used to determine possible direct and indirect mechanisms of pathogenesis. Human CMT1B patients with this mutation display an early-onset neuropathy with symptoms including deceased nerve conduction velocities (NCVs) in afferent and efferent nerve fibers, partial loss of sensory capabilities, limb weakness, and a characteristic 'steppage gait'. Two possible molecular mechanisms of pathogenesis exist: a direct mechanism by which structural abnormalities prevent adhesion, or an indirect mechanism by which problems in the mediation of the signal transduction pathway disrupt the regulation of adhesion. These two mechanisms could also be operating concurrently, as they are not mutually exclusive. Western blotting of nerve extracts from wild-type and R69C mice showed that the mutant MPZ was retained in high molecular weight protein aggregates, preventing normal insertion into the membrane and thus providing a direct explanation for CMT pathogenesis. Western blotting of the wild-type mouse nerve extract also confirmed the presence of the components of the protein complex mediating signal transduction; however, western blotting of the mutant mouse nerve' extract will still be necessary to investigate the possibility of an indirect mechanism of pathogenesis.
iv, 28 p.
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