PLP1-related inherited dysmyelinating disorders:: Pelizaeus-Merzbacher disease and spastic paraplegia type 2

Pelizaeus-Merzbacher disease (PMD) and its allelic disorder, spastic paraplegia type 2 (SPG2), are among the best-characterized dysmyelinating leukodystrophies of the central nervous system (CNS). Both PMD and SPG2 are caused by mutations in the proteolipid protein 1 (PLP1) gene, which encodes a major component of CNS myelin proteins. Distinct types of mutations, including point mutations and genomic duplications and deletions, have been identified as causes of PMD/SPG2 that act through different molecular mechanisms. Studies of various PLP1 mutants in humans and animal models have shed light on the genomic, molecular, and cellular pathogeneses of PMD/SPG2. Recent discoveries include complex mutational mechanisms and associated disease phenotypes, novel cellular pathways that lead to the degeneration of oligodendrocytes, and genomic architectural features that result in unique chromosomal rearrangements. Here, I review the previous and current knowledge of the molecular pathogenesis of PMD/SPG2 and delineate future directions for PMD/SPG2 studies.