A point mutation in the proteolipid protein gene of the 'shaking pup' interrupts oligodendrocyte development.
The differentiation of the oligodendrocyte from its bipotential progenitor culminates in the production of the myelin-specific proteins and the elaboration of membrane processes that ensheath the axon. Mutations in proteolipid protein (PLP) and its alternatively spliced isoform DM-20, the major protein constituents of central nervous system myelin, are characterized by a significant reduction in the number of mature oligodendrocytes, resulting in severe hypomyelination, tremor and early death. The canine shaking pup carries such a mutation, a single base change that substitutes a proline for a histidine near the first transmembrane region of PLP and DM-20. This mutation hinders oligodendrocyte differentiation, as evidence by a splicing pattern at the PLP locus characteristic of immature oligodendrocytes. The spliced transcript expressed earliest in development, DM-20, continues to be overexpressed in shaking pup oligodendrocytes. The disruption of the normal maturation schedule in these X-linked dysmyelinating disorders suggests that PLP or DM-20 plays a fundamental role in oligodendrocyte development. We propose that, while the more abundant PLP is the primary structural component of myelin, DM-20 may be critical to oligodendrocyte maturation.
Nadon
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NL
Laboratory of Viral and Molecular Pathogenesis, NINDS, NIH, Bethesda, MD.
Duncan
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ID
Hudson
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LD
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002490:Central Nervous System / Q000002:abnormalities*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics*; D004195:Disease Models, Animal; D004285:Dogs; D005091:Exons; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009185:Myelin Proteins / Q000235:genetics*; D018991:Myelin Proteolipid Protein; D009186:Myelin Sheath / Q000473:pathology; D009419:Nerve Tissue Proteins; D009836:Oligodendroglia / Q000473:pathology*; D011510:Proteolipids / Q000235:genetics*
D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; C047516:Plp1 protein, mouse; D011510:Proteolipids