MFN2

The MFN2 gene provides instructions for making a protein called mitofusin 2. This protein helps determine the shape and structure (morphology) of mitochondria, the energy-producing centers within cells. Mitofusin 2 is made in many types of cells and tissues, including muscles, the spinal cord, and nerves that connect the brain and spinal cord to muscles (peripheral nerves). Within cells, mitofusin 2 is found in the outer envelope (membrane) that surrounds mitochondria.

Mitochondria are dynamic structures that undergo changes in morphology through processes called fission (splitting into smaller pieces) and fusion (combining pieces). These changes in morphology are necessary for mitochondria to function properly. Mitofusin 2 helps to regulate the morphology of mitochondria by controlling the fusion process.

Charcot-Marie-Tooth disease - caused by mutations in the MFN2 gene

Researchers have identified more than 30 MFN2 mutations that cause a form of Charcot-Marie-Tooth disease known as type 2A. Almost all these mutations replace one of the protein building blocks (amino acids) in mitofusin 2 with an incorrect amino acid. As a result, the mitofusin 2 protein is altered in a critical region and cannot function properly. A few mutations create a premature stop signal in the instructions for making mitofusin 2. As a result, no protein is produced, or an abnormally small protein is made.

Several MFN2 mutations sometimes cause a variant of type 2A Charcot-Marie-Tooth disease that affects vision. (This variant is also called hereditary motor and sensory neuropathy VI.) Vision loss is caused by optic atrophy, in which the nerves that carry information from the eyes to the brain (optic nerves) shrink. People with this variant usually experience severe symptoms of Charcot-Marie-Tooth disease that begin before the age of 10.

It remains unclear how MFN2 mutations lead to nerve problems that are characteristic of type 2A Charcot-Marie-Tooth disease. Without functional mitofusin 2, researchers suggest that mitochondria cannot fuse properly, perhaps disrupting a steady supply of energy to the cell. Nerve cells, which have long extensions (axons) to transmit nerve impulses, may be particularly sensitive to an interrupted energy supply.