The GAN gene provides instructions for making a protein called gigaxonin. Gigaxonin is involved in a cellular function that destroys and gets rid of excess or damaged proteins using a mechanism called the ubiquitin-proteasome system. The ubiquitin-proteasome system is a multi-step process that begins with the activation of a protein called ubiquitin. With the assistance of other proteins called ubiquitin-conjugating enzymes and ubiquitin ligases, the ubiquitin attaches to a targeted protein. When a chain of ubiquitin proteins is attached to the targeted protein, the protein is recognized and destroyed by a complex of enzymes called a proteasome.
Researchers believe that gigaxonin belongs to a group of ubiquitin ligases called the BTB/kelch superfamily. These ubiquitin ligases help ubiquitin target specific proteins for destruction. Gigaxonin targets proteins that must be broken down in order for the cytoskeleton, the framework that gives structure to cells, to develop properly.
Several mutations in the GAN gene have been identified in people with giant axonal neuropathy. Some mutations change or remove one of the protein building blocks (amino acids) used to make gigaxonin. This type of alteration affects the shape of the gigaxonin protein, preventing it from binding to other proteins properly to help organize the structure of neurons. Other mutations result in the absence of any functional gigaxonin.
Absence of functional gigaxonin leads to accumulation of proteins that should have been destroyed by the ubiquitin-proteasome system. This accumulation of proteins results in disorganization of the cytoskeleton.
In nerve cells (neurons), the absence of functional gigaxonin results in abnormally large, densely packed accumulations of neurofilaments, an important part of the cytoskeleton. Neurofilaments are particularly abundant in axons, the long nerve cell extensions that transmit signals to other cells.
The excess neurofilaments that build up in the axon as a result of a deficiency of functional gigaxonin result in distended or giant axons that do not transmit signals properly. Affected axons eventually deteriorate, causing problems with movement and sensation. The giant axons are commonly seen in the peripheral nerves, which carry signals between the brain and spinal cord (central nervous system) and other areas of the body. However, neurons in the central nervous system can be affected as well.
- giant axonal neuropathy (gigaxonin)