Myelin mutants: model systems for the study of normal and abnormal myelination.

Spontaneous mutations that perturb myelination occur in a range of species including man, and together with engineered mutations have been used to study disease, normal myelination and axon/glial inter-relationships. Only a minority of the currently defined mutations have an apparently simple pathogenesis due to lack of a functional protein. Mutations in the myelin basic protein gene lead to a lack of protein, resulting in changes in the structure of myelin, which can be rescued by transgenic complementation. The pathogenesis of autosomal dominant and X-linked mutations affecting either oligodendrocytes or Schwann cells is more complex. Point mutations may act in a dominant negative manner and gene dosage is clearly linked to phenotypic change. Mutations in regulatory genes, such as those encoding transcription factors, can also disturb myelination by selected cell types. Other less-well studied and unexpected consequences of myelin mutations, such as seizures in mutations affecting genes expressed in Schwann cells and axonal changes associated with dysmyelination, are also considered. With the major developments in gene mapping and cloning it is now relevant to study mutations in a variety of species with the real prospect of defining their molecular basis. Examples are given of unusual, but potentially useful, uncharacterized mutations in dog and bovine.