Myelin is a multi-lamellar structure that surrounds axons in both the CNS and PNS facilitating nerve conduction. MPZ,a transmembrane glycoprotein of the immunoglobulin supergene family, is the major structural protein in PNS myelin, and is expressed exclusively in Schwann cells, the myelinating glia. Human mutations in MPZ give rise to peripheral demyelinating neuropathies, Charcot Marie Tooth disease type IB (CMT1B). Several lines of evidence demonstrate that MPZ acts as a homophilic adhesion moleculeand, through its cytoplasmic domain, participates in a signal transduction cascade. Both the extracellular and intracellular domains of MPZ are necessary for homophilic adhesion in vitro and for myelination in vivo, hi order to more fully explore the molecular mechanisms by which mutations in MPZ cause neuropathy, we evaluated the clinical phenotype of 77 patients with CMT1B and correlated this to their genotype. We found that these patients fell into two distinct groups: one with disease onset in infancy, extremely slow nerve conductions, and pathological evidence of dysmyelination;and a second with disease onset as adults, essentially normal nerve conductions, and pathological evidence of axonal loss. Importantly, loss of MPZ adhesion did not correlate with either disease severity or the age of disease onset. These data suggest, however, that there are at least two separate disease mechanisms in CMT1B: one that effects myelin development, causing early onset disease, and a second that alters myelin maintenance, causing late onset disease. To further investigate the mechanisms of neuropathy in CMT1B we have produced three mouse models of the disease by homologous recombination and have also analyzed the expression of these mutant forms of MPZ in vitro and in human pathological material. Preliminary analysis of a mouse line carrying a Q186X mutation, causing early onset disease, suggests that this truncated protein acts like a dominant negative inhibitor of MPZ adhesion, consistent with the lack of compaction in nerve biopsies from patients with this mutation. In vitro analysis of a second mutation, R69C, for which we also have a mouse model, demonstrates that this protein does not reach the cell surface, suggesting that it causes disease by a """"""""gain of function"""""""" mechanism. Evaluation of nerves from a patient with the R69C mutation further suggests that the mutation effects myelin development. Finally, analysis of the nerve pathology and in vitro expression of two mutations, HI OPand T95M, causing late onset neuropathy suggest that these mutant proteins are incorporated into myelin where they produces a """"""""dying back gliopathy"""""""" by altering the process of myelin maintenance, and we have produced a mouse line encoding the T95M mutation, hi this grant we will analyze further the consequences of these MPZ mutations in the peripheral nerves of our mouse models, in transfected cells, and in human pathological material.
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