Insertion of Mutant Proteolipid Protein Results in Missorting of Myelin Proteins

The PLP gene maps to the long arm of the human X chromosome at Xq21–q22 and encodes for the two major myelin proteins of the central nervous system (CNS), the proteolipid protein (PLP), and its spliced isoform DM20.1 PLP is the major structural component of CNS myelin, whereas DM20, which is produced earlier in CNS development, may be involved in oligodendrocyte differentiation and survival,2 as well as in the maintenance of myelin compaction.3 Additional alternative splicing products with a soma-restricted expression (sr-PLP and sr-DM20) has been found in mice. In addition to oligodendrocytes, these sr-PLP/DM20 proteins also are expressed by several classes of neurons.4 In humans, the clinical findings associated with PLP mutations are spread over a wide continuum, extending from the most severe form of Pelizaeus–Merzbacher disease to the relatively mild, late-onset spastic paraplegia, leading to the concept of PLP-related disorders.5–7 A demyelinating peripheral neuropathy is frequently observed in PLP1 null mutations8 and mutations which truncate PLP1 expression within the PLP1-specific domain without alteration of DM20 expression.9 In our investigation of patients with leukodystrophies of unknown cause, we identified a novel PLP mutation associated with aggregation and abnormal distribution of myelin proteins in the peripheral nervous system (PNS).