PMP22

The PMP22 gene provides instructions for making a protein called peripheral myelin protein 22. This protein is a major component of myelin, a protective substance that covers nerves and promotes the efficient transmission of nerve impulses. Peripheral myelin protein 22 is produced primarily by specialized cells called Schwann cells, where the protein plays a crucial role in the development and maintenance of myelin. The PMP22 gene may also play a role in regulating cell division and maturation, cell shape, and cell death.

Before it becomes part of myelin, newly produced peripheral myelin protein 22 goes through several processing and packaging steps in specialized structures known as the endoplasmic reticulum and the Golgi apparatus. Completion of these processing and packaging steps is critical for proper myelin function.

Charcot-Marie-Tooth disease - caused by mutations in the PMP22 gene

An extra copy of the PMP22 gene in each cell is the most common mutation that causes a form of Charcot-Marie-Tooth disease known as type 1A. The extra gene leads to an overproduction of peripheral myelin protein 22, which clogs the Golgi apparatus in Schwann cells and prevents completion of the necessary processing steps. Myelin assembly is impaired due to the reduced availability of properly processed protein. The buildup of unprocessed peripheral myelin protein 22 probably also disrupts other Schwann cell activities, which leads to myelin instability and loss. The loss of myelin (demyelination) causes the signs and symptoms of type 1A Charcot-Marie-Tooth disease.

Type 1A Charcot-Marie-Tooth disease is also caused by mutations that affect the building blocks (amino acids) used to make peripheral myelin protein 22. These mutations alter the protein by adding or deleting amino acids, or by using incorrect amino acids to make the protein. The altered protein is probably processed at a slower rate, causing a buildup of unprocessed protein that could harm normal functions of the Schwann cell. The protein that finally emerges from the Golgi apparatus may have been processed improperly, which leads to unstable myelin. This instability can cause demyelination, producing the signs and symptoms of type 1A Charcot-Marie-Tooth disease. In general, mutations that alter amino acids cause more severe symptoms than mutations that generate an extra copy of the PMP22 gene. (Severe, early-onset cases of type 1A are sometimes called Dejerine-Sottas syndrome.)

Hearing loss is experienced by some people with a form of type 1 Charcot-Marie-Tooth disease called type 1E. Type 1E is associated with particular amino acid substitutions and deletions in the PMP22 gene. The most frequently reported mutation causing hearing loss replaces the amino acid alanine with the amino acid proline at protein position 67 (also written as Ala67Pro).

hereditary neuropathy with liability to pressure palsies - caused by mutations in the PMP22 gene

Loss of one copy of the PMP22 gene from each cell is the most common genetic cause of hereditary neuropathy with liability to pressure palsies. Deletion of one copy of the PMP22 gene (also called reduced gene dosage) probably decreases the amount of peripheral myelin protein 22 available for myelin production. This disorder is also caused by PMP22 mutations that produce an abnormally small protein, which rapidly decays. Other mutations change one of the protein building blocks (amino acids) used to make peripheral myelin protein 22, producing an unstable protein. Myelin is lost because of the reduced availability of stable protein, causing the signs and symptoms of hereditary neuropathy with liability to pressure palsies.