THE MOLECULAR-GENETICS OF MYELINATION - AN UPDATE

Recent molecular genetic studies have provided new insights into the structure and function of 2 of the major integral membrane proteins of myelin-the proteolipid protein (PLP) and protein zero (P0)-and have uncovered a third such protein-PMP22/gas3. The rumpshaker mouse has been shown to carry a point mutation in the PLP gene that uncouples a deleterious effect on CNS myelin assembly, which these mice exhibit, from oligodendrocyte degeneration and cell death, which they do not. The developmental importance of the P0 protein in PNS myelination has been dramatically demonstrated by the analysis of loss-of-function mutations engineered through the expression of antisense RNA and through the insertional inactivation of the P0 gene by homologous recombination in embryonic stem cells and the generation of P0-deficient mice. The cloned promoter of the P0 gene has been shown to drive quantitative, Schwann cell-specific expression of heterologous genes in transgenic mice. The PMP22/gas3 gene, previously cloned from fibroblast cell lines, has been found to encode an axonally regulated Schwann cell protein that is assembled into PNS myelin. Importantly, this gene appears to be the target of mutations that result in the Trembler alleles in mice, and in Charcot-Marie-Tooth disease Type la, the most common inherited peripheral neuropathy in humans.