GJB1

Charcot-Marie-Tooth disease

Researchers have identified more than 400 GJB1 gene mutations in people with type X Charcot-Marie-Tooth disease, a disorder characterized by muscle weakness and sensory problems, especially in the hands and feet. A few of these mutations also cause hearing loss in individuals with this type of Charcot-Marie-Tooth disease.

Most GJB1 gene mutations change single protein building blocks (amino acids) in the connexin-32 protein. It is unclear how these mutations lead to the characteristic features of Charcot-Marie-Tooth disease, including a loss of myelin (demyelination) and the slowed transmission of nerve impulses in the peripheral nervous system. The altered protein may be broken down quickly or trapped inside the cell, preventing it from reaching the cell membrane to form gap junctions. In some cases, an altered protein reaches the cell membrane but does not form properly functioning gap junctions. The loss of functional gap junctions probably impairs the normal activities of Schwann cells, including myelin production. Malfunctioning gap junctions could also disrupt communication between Schwann cells and the underlying nerve cell, disturbing the transmission of nerve impulses.

In addition to the peripheral nervous system problems associated with this disorder, loss of myelin in the central nervous system has been reported in some people with Charcot-Marie-Tooth disease caused by GJB1 gene mutations. These central nervous system abnormalities do not generally cause any symptoms. Research suggests that another connexin protein whose function overlaps with that of connexin-32 helps compensate for the mutated connexin-32 protein in the oligodendrocytes of the central nervous system.