X-Linked Developmental Defects of Myelination: From Mouse Mutants to Human Genetic Diseases

Molecular cloning of the major myelin-specific genes and a systematic analysis of mouse mutants have led to the identification of molecular defects in human genetic diseases that affect myelination. In the central nervous system, Pelizaeus-Merzbacher disease (PMD) and X-linked spastic paraplegia (SPG-2) are clinically distinct with respect to the severity of motor dysfunction but involve the same gene for myelin proteolipid protein (PLP). Spontaneous mouse mutants of the PLP gene, such as jimpy and rumpshaker, provide faithful models of these human diseases and allow a detailed analysis of PLP dysfunction. Hypomyelination in jimpy and, presumably, in PMD is largely the result of abnormally increased oligodendrocyte death and a lack of terminal differentiation. In rumpshaker, a model for X-linked spastic paraplegia, myelinating oligodendrocytes appear normal in number but fail to assemble myelin correctly. Recently, PLP-transgenic mice have provided experimental evidence that increasing the normal PLP gene dosage (e.g., by a gene duplication) is by itself sufficient to cause PMD. The latter is strikingly similar to the peripheral neuropathy Charcot-Marie-Tooth disease frequently associated with a duplication of the myelin protein gene PMP-22.