MT-ND4

Several variants (also called mutations) in the MT-ND4 gene are known to cause Leber hereditary optic neuropathy. This condition is an inherited form of vision loss. Each of these variants changes a single protein building block (amino acid) in the NADH dehydrogenase 4 protein. 

One MT-ND4 gene variant is the most common cause of Leber hereditary optic neuropathy; it is responsible for about 70 percent of all cases worldwide. This variant, which can be written as G11778A or Arg340His, replaces the amino acid arginine with the amino acid histidine at protein position 340. This variant tends to cause severe vision loss, with little chance of recovery.

Researchers are investigating how variants in the MT-ND4 gene lead to Leber hereditary optic neuropathy. These genetic changes appear to prevent complex I from interacting normally with ubiquinone, which may affect the generation of ATP.  MT-ND4 gene variants may also increase the production within mitochondria of potentially harmful molecules called reactive oxygen species. It remains unclear, however, why the effects of these variants are often limited to the nerve that relays visual information from the eye to the brain (the optic nerve).  Additional genetic and environmental factors probably contribute to the vision loss and other medical problems associated with Leber hereditary optic neuropathy.

A variant in the MT-ND4 gene also has been identified in a small number of people with Leigh syndrome, a progressive brain disorder that typically appears in infancy or early childhood. Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder.

The MT-ND4 variant that can cause Leigh syndrome, written as C11777A or Arg340Ser, replaces the amino acid arginine with the amino acid serine at protein position 340. This genetic change appears to disrupt the normal function of complex I in mitochondria. It is not known, however, how this MT-ND4 gene variant is related to the specific features of Leigh syndrome.

MedlinePlus Genetics provides information about Mitochondrial complex I deficiency