The gene specific to PMD is called proteolipid protein (PLP) and it is located on the X chromosome. About 75 % of myelin is made up of fats and cholesterol and the remaining 25 % is protein. PLP constitutes about half of the protein of myelin and is its most abundant constituent other than the fatty lipids. Various mutations within this gene have been identified. The types of mutations that are known to cause PMD fall into two general categories: point mutations and duplications. A mutation (any alteration of the DNA) that affects only a single base (one letter) is called a point mutation. Other types of mutations can occur as well, including insertions (additions of DNA into a gene), deletions (removal of part of a gene), and duplications where entire genes are present in one or more additional copies.
The point and other small mutations usually cause the substitution of one of the amino acids for another somewhere in the protein or prevent PLP from reaching its full length. This probably results in the protein being unable to fold into the correct shape or to interact with other myelin constituents. These mutant proteins are toxic to the octopus-like cells called oligodendrocytes (see Figure 2), whose job it is to make myelin, and prevent them from making normal myelin. These cells operate by actually myelinating several axons at once. They develop tentacle-like appendages that wrap around neighboring axons providing the insulation needed for proper nerve function. However, in just the past two years or so it has been discovered that most PMD cases are caused by duplications of the entire PLP gene accounting for 50-75% of the cases. This seems to be the case for PMD families around the world and we still do not understand why it occurs. We currently believe that the duplication results in too much otherwise normal proteolipid protein being made. This excessive PLP also appears to be toxic to oligodendrocytes.
We also know that in addition to the regions that code for protein, there are regions of genes that regulate their expression. In order for the right proteins to be made in the right organs and in the right amounts, there are many processes that have to be regulated very precisely. Mutations that change these regulatory sequences can have drastic affects on the gene, and might result in the protein being made in too high or too low an amount, or to be made in the wrong organ or at the wrong time of life.