MUTATIONS IN DEMYELINATING PERIPHERAL NEUROPATHIES SUPPORT MOLECULAR-MODEL OF MYELIN PO-GLYCOPROTEIN EXTRACELLULAR DOMAIN

Hemophilic interactions of the major integral membrane protein of peri pheral nerve myelin, P0-glycoprotein, are thought to mediate membrane adhesion and compaction. Molecular modeling of its extracellular domai n (P0-ED), based on its resemblance to an immunoglobulin variable doma in and on X-ray diffraction measurements of inter-membrane spacings of myelin, has suggested which amino acid sidechains may be involved in the hemophilic adhesion. Recently identified point-mutations in the hu man P0 gene result in amino acid substitutions in P0 protein and corre late with demyelinating motor and sensory neuropathies. The molecular model explains how these changes result in disrupted P0-P0 interaction s; indicates how compensatory changes in amino acids, as occur in P0-E D of other species, preserve normal hemophilic interactions; and predi cts what other residue substitutions might underlie additional cases o f demyelinating neuropathies. (C) 1994 Wiley-Liss, Inc.