PMP22 gene

peripheral myelin protein 22

The PMP22 gene provides instructions for making a protein called peripheral myelin protein 22 (PMP22). This protein is found in the peripheral nervous system, which connects the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound.

The PMP22 protein is a component of myelin, a protective substance that covers nerves and promotes the efficient transmission of nerve impulses. The protein is produced primarily by specialized cells called Schwann cells that wrap around and insulate nerves. Within Schwann cells, PMP22 plays a crucial role in the development and maintenance of myelin. Studies suggest that the PMP22 protein is particularly important in protecting nerves from physical pressure, helping them restore their structure after compression. Compression can interrupt nerve signaling, leading to the sensation commonly referred to as a limb "falling asleep." The ability of nerves to recover from normal, day-to-day compression, for example when sitting for long periods, keeps the limbs from constantly losing sensation. The PMP22 gene also plays a role in Schwann cell growth and differentiation (the process by which cells mature to carry out specific functions).

Before it becomes part of myelin, newly produced PMP22 protein is processed and packaged in specialized cell structures called the endoplasmic reticulum and the Golgi apparatus. Completion of these processing and packaging steps is critical for proper myelin function.

Mutations in the PMP22 gene cause several forms of a neurological disorder called Charcot-Marie-Tooth disease.

An extra copy of the PMP22 gene in each cell is the most common genetic change that causes type 1A Charcot-Marie-Tooth disease. The extra gene leads to an overproduction of PMP22 protein, which prevents the protein from being processed correctly. A reduced amount of functional PMP22 protein impairs the formation of myelin. The unprocessed PMP22 may also disrupt other Schwann cell activities, which leads to instability and loss of myelin (demyelination). Demyelination reduces the ability of the peripheral nerves to activate muscles used for movement or relay information from sensory cells back to the brain. Typically beginning in adolescence, affected individuals experience weakness and wasting (atrophy) of the muscles of the lower legs and hands and decreased sensitivity to touch, heat, and cold.

Type 1A Charcot-Marie-Tooth disease is also caused by mutations that add, delete, or change the building blocks (amino acids) used to make PMP22 protein. The altered protein is probably processed at a slower rate, and some of the protein is processed abnormally. These disruptions of PMP22 processing impair the normal functions of the Schwann cell, leading to demyelination and producing the signs and symptoms of type 1A Charcot-Marie-Tooth disease.

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).

Some mutations in the PMP22 gene cause a severe form of Charcot-Marie-Tooth disease sometimes referred to as Dejerine-Sottas disease or type 3 Charcot-Marie-Tooth disease. This form of the disorder usually begins in infancy, causing muscle weakness and atrophy and delayed development of motor skills such as walking.

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. This disorder is characterized by recurrent episodes of numbness, tingling, or loss of muscle function, usually triggered by pressure on a nerve in the extremities. Deletion of one copy of the PMP22 gene reduces the amount of PMP22 protein produced by about half. This disorder is also caused by PMP22 gene mutations that change single amino acids in the PMP22 protein or that lead to production of an abnormally small protein. These abnormal proteins are rapidly broken down. The consequences of a shortage of PMP22 protein are not clearly understood. Shortage of PMP22 protein may affect the structure of the myelin covering, impairing the transmission of nerve impulses. In addition, the loss of this protein appears to make nerves less able to recover from compression, which also interrupts nerve signaling, causing the signs and symptoms of hereditary neuropathy with liability to pressure palsies.

Cytogenetic Location: 17p12, which is the short (p) arm of chromosome 17 at position 12

Molecular Location: base pairs 15,229,777 to 15,265,373 on chromosome 17 (Homo sapiens Annotation Release 109, GRCh38.p12) (NCBI)

Cytogenetic Location: 17p12, which is the short (p) arm of chromosome 17 at position 12
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