The molecular and cellular defects underlying Pelizaeus–Merzbacher disease

Abstract

Pelizaeus–Merzbacher disease (PMD) is a recessive X-linked dysmyelinating disorder of the central nervous system (CNS). The most frequent cause of PMD is a genomic duplication of chromosome Xq22 including the region encoding the dosage-sensitive proteolipid protein 1 (PLP1) gene. ThePLP1duplications are heterogeneous in size, unlike duplications causing many other genomic disorders, and arise by a distinct molecular mechanism. Other causes of PMD includePLP1deletions, triplications and point mutations. Mutations in thePLP1gene can also give rise to spastic paraplegia type 2 (SPG2), an allelic form of the disease. Thus, there is a spectrum of CNS disorder from mild SPG2 to severe connatal PMD.PLP1encodes a major protein in CNS myelin and is abundantly expressed in oligodendrocytes, the myelinating cells of the CNS. Significant advances in our understanding of PMD have been achieved by investigating mutantPLP1in PMD patients, animal models and in vitro studies. How the differentPLP1mutations and dosage effects give rise to PMD is being revealed. Interestingly, the underlying causes of pathogenesis are distinct for each of the different genetic abnormalities. This article reviews the genetics of PMD and summarises the current knowledge of causative molecular and cellular mechanisms.