Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene

Abstract

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 mouse^1,2 and subsequently in patients with PelizaeusMerzbacher disease^3,4. 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 myelindeficient, 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.