GDAP1

The GDAP1 gene provides instructions for making a protein called ganglioside-induced differentiation-associated protein 1. This protein is made in several different types of cells throughout the body, particularly cells of the nervous system. Within cells, the GDAP1 protein is found in the outer envelope (membrane) of mitochondria, the structures that produce energy to power cell activities. Mitochondria are dynamic structures that change shape through processes called fission (splitting into smaller pieces) and fusion (combining pieces). Changes in shape are thought to be critical for mitochondria to work properly. Although its function is not well understood, the GDAP1 protein appears to play a role in controlling the shape of mitochondria by promoting fission.

Charcot-Marie-Tooth disease - caused by mutations in the GDAP1 gene

Researchers have identified more than 20 mutations in the GDAP1 gene that can cause one of two forms of Charcot-Marie-Tooth disease, type 2K or type 4A. About half of these mutations create a premature stop signal in the instructions for making the GDAP1 protein. As a result, an abnormally small protein is made that is unlikely to be inserted into the outer membrane of mitochondria. Other mutations change one of the building blocks (amino acids) used to make the GDAP1 protein, which may alter the shape of the protein. Although the altered protein is inserted into the outer mitochondrial membrane, it does not function properly.

It is unclear how GDAP1 mutations lead to the characteristic features of Charcot-Marie-Tooth disease. These mutations probably impair the mitochondria's ability to change shape, which could disrupt the energy supply to cells. Cells in the nervous system might be particularly sensitive to energy disruptions and function less efficiently.