GJB1

The GJB1 gene provides instructions for making a protein called gap junction beta 1 (also known as connexin 32). This protein is a member of the gap junction connexin family, which plays a role in cell communication by forming channels, or gap junctions, between cells. Gap junctions speed the transport of nutrients, charged particles (ions), and small molecules that carry communication signals.

The gap junction beta 1 protein is made in several tissues, including those of the liver, pancreas, kidney, and nervous system. In the nervous system, this protein is located in the cell membrane of specialized cells called Schwann cells. Schwann cells play an important role in protecting nerves by producing a fatty substance called myelin, which is also found in the cell membrane. The Schwann cell membrane wraps around a nerve in concentric layers, like a jelly roll, to form a protective myelin sheath. The myelin sheath promotes the rapid transmission of nerve impulses. Gap junction beta 1 forms channels through the myelin sheath, allowing efficient transport and communication between the outer myelin layers and the interior of the Schwann cell.

Charcot-Marie-Tooth disease - caused by mutations in the GJB1 gene

Researchers have identified more than 250 GJB1 mutations in people with type X Charcot-Marie-Tooth disease. A few of these mutations also cause hearing loss in individuals with this type of Charcot-Marie-Tooth disease. Most GJB1 mutations replace one of the protein building blocks (amino acids) in gap junction beta 1 with an incorrect amino acid. Some GJB1 mutations result in a protein of abnormal size.

It is unclear how GJB1 mutations lead to the loss of myelin (demyelination) and the slowed transmission of nerve impulses, which are characteristics of this disorder. The altered protein may be quickly degraded or held inside the cell such that it never reaches 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, such as myelin production. Malfunctioning gap junctions could also disrupt cell communication between Schwann cells and the underlying nerve and disturb the transmission of nerve impulses.