UNCOUPLING OF HYPOMYELINATION AND GLIAL-CELL DEATH BY A MUTATION IN THE PROTEOLIPID PROTEIN GENE

PROTEOLIPID protein (PLP; M(r) 30,000) is a highly conserved major polytopic membrane protein in myelin but its cellular function remains obscure. Neurological mutant mice can often provide model systems for human genetic disorders. Mutations of the X-chromosome-linked PLP gene are lethal, identified first in the jimpy mouse1,2 and subsequently in patients with Pelizaeus-Merzbacher disease3,4. The unexplained phenotype of these mutations includes degeneration and premature cell death of oligodendrocytes with associated hypomyelination5. Here we show that a new mouse mutant rumpshaker6 is defined by the amino-acid substitution Ile-to-Thr at residue 186 in a membrane-embedded domain of PLP. Surprisingly, rumpshaker mice, although myelin-deficient, have normal longevity and a full complement of morphologically normal oligodendrocytes7. Hypomyelination can thus be genetically separated from the PLP-dependent oligodendrocyte degeneration. We suggest that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum8 of Pelizaeus-Merzbacher disease.