No abstract

The Trembler mouse (Tr) suffers from a dominantly inherited autosomal mutation (glycine to aspartic acid. G150D) affecting the PMP22 gene, which results in an abnormal myelination of the peripheral nervous system. The Tr mouse represents an animal model for the human hereditary neuropathy, Charcot-Marie-Tooth disease. We compared the expression of PMP22, P0, myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) in nerve biopsies from a 1-year-old heterozygous Tr mouse (Tr/+) with that of a control mouse of the same age. Quantitative and qualitative ultrastructural immunocytochemical analysis showed a significant decrease in PMP22, P0 and MBP and an abnormal location of the MAG in the sciatic nerve of the Tr/+ mouse. We also noted a marked reduction in number of myelinated fibers associated with the presence of two types of myelinated axons: a population of abnormally thin myelin sheaths with lower PMP22 labeling than that observed in myelinated fibers from the control mouse, and some others fibers with normal sheaths for axons of comparable diameter to those of normal mouse with no difference in the PMP22 immunolabeling. This pointed to an involvement of PMP22 in the structure of myelin sheaths.

Hereditary sensorimotor neuropathies form a heterogeneous group of genetically determined diseases, of which Charcot-Marie-Tooth (CMT) disease is the most common. In order to establish relations between genotype and the expression of peripheral myelin proteins, we carried out a quantitative study by ultrastructural immunocytochemistry of several myelin proteins (PMP22, P0, MBP) on sural nerve biopsy samples from 12 unrelated CMT patients. The diagnosis of CMT was based on the clinical, electrophysiological, and histological findings along with those of molecular biological studies. CMT X diagnoses were not included in this study. The expression of myelin proteins was well correlated with the molecular biological findings in these patients. The results also provided evidence for interference between different myelin proteins. Our findings are in line with the results from animal studies (trembler and knock-out mice), which may provide insights into the pathogenesis of these human conditions.