What is PMP22?

Answer: Peripheral myelin protein of 22kDa, also called Growth arrest-specific protein 3, is a protein that is expressed in Schwann cells and plays an important role in myelination of peripheral nervous system projections.

pmp22 myelin charcot marie tooth

Myelin is a fatty substance that can wrap around axonal projections. In doing so, the myelin serves as electrical insulation. A myelinated axon can send electrical impulses much faster than a similarly-shaped unmyelinated axon. The signals travel faster down a myelinated axon because the myelin sheath blocks the leak potassium channels that can cause the signal to diminish over some distance. Instead, the electrical signal “jumps” from one small patch of unmyelinated membrane to the next, a process called saltatory conduction.

The cells that are responsible for myelination are a class of glia called oligodendrocytes in the central nervous system, and Schwann cells in the peripheral nervous system. Oligodendrocytes can myelinate multiple axonal projections at once, but Schwann cells only add myelin at a small segment of the axon at a time.

For the Schwann cells to properly deposit the myelin around the axon, the surface of the Schwann cell must interact with the surface of the axon. This type of signaling can be accomplished by transmembrane proteins that protrude into the extracellular space. When they interact with another, the proteins can trigger internal cytoskeletal structural changes that brings the two cells closer together.

PMP22 itself is a 160 amino acid-long protein with a molecular weight of 22 kDa. PMP22 itself is synthesized adjacent to the nucleus, and is quickly sequestered in the endoplasmic reticulum and Golgi apparatus. Here, it is subjected to a series of modifications, such as N-terminal glycosylation, the addition of a sugar molecule to one end of the PMP22 protein. After this chemical change, the PMP22 protein is transported away from the nucleus and towards the cell surface when it exists lodged in the cell membrane. Structurally, the PMP22 protein has four transmembrane domains, two extracellular loops, and one intracellular loop.

Mutations in the gene that encodes for PMP22 are known to be associated with Charcot-Marie-Tooth disease, a genetic disorder of the peripheral motor system. This disease is one example of a peripheral neuropathy. The disease is characterized by high arches and muscle weakness in the extremities. Patients may exhibit hyporeflexia, a slowed or weakened reflex. Symptoms generally appear in the 20s. In general, Charcot-Marie-Tooth disease does not have any effect on lifespan, and most patients remain ambulatory into their old age.

One of the most well characterized abnormal genes is trisomy PMP22. This mutation contributes to type 1A Charcot-Marie-Tooth (CMT), the most common form of the disease. The current best treatment for CMT disease is rigorous physical therapy and orthopedic devices.

The disease results from abnormal myelination since the altered PMP22 protein is not able to function in the proper manner. The myelin does not form around axons as it should, resulting in poor transduction of signals. The inability to send signals from the central nervous system out to the muscles results in weakness of the muscles.