Mutations in demyelinating peripheral neuropathies support molecular model of myelin P0-glycoprotein extracellular domain.

Homophilic interactions of the major integral membrane protein of peripheral nerve myelin, P0-glycoprotein, are thought to mediate membrane adhesion and compaction. Molecular modeling of its extracellular domain (P0-ED), based on its resemblance to an immunoglobulin variable domain and on X-ray diffraction measurements of inter-membrane spacings of myelin, has suggested which amino acid sidechains may be involved in the homophilic adhesion. Recently identified point-mutations in the human P0 gene result in amino acid substitutions in P0 protein and correlate with demyelinating motor and sensory neuropathies. The molecular model explains how these changes result in disrupted P0-P0 interactions; indicates how compensatory changes in amino acids, as occur in P0-ED of other species, preserve normal homophilic interactions; and predicts what other residue substitutions might underlie additional cases of demyelinating neuropathies.