Mutations to MT-ATP6 and other genes affecting
oxidative phosphorylation in the mitochondria have been associated with a variety of
neurodegenerative and
cardiovascular disorders, including mitochondrial complex V deficiency,
Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (
MELAS),
Leigh syndrome, and
NARP syndrome. Most of the body's cells contain thousands of mitochondria, each with one or more copies of
mitochondrial DNA. The severity of some
mitochondrial disorders is associated with the percentage of mitochondria in each cell that has a particular genetic change. People with
Leigh syndrome due to a MT-ATP6 gene mutation tend to have a very high percentage of mitochondria with the mutation (from more than 90 percent to 95 percent). The less-severe features of
NARP result from a lower percentage of mitochondria with the mutation, typically 70 percent to 90 percent. Because these two conditions result from the same genetic changes and can occur in different members of a single family, researchers believe that they may represent a spectrum of overlapping features instead of two distinct syndromes.
Ataxia,
microcephaly, developmental delay and intellectual disability have been observed in patients with a frameshift mutation in MT-ATP6. This causes a C insertion at position 8612 that results in a truncated protein only 36 amino acids long, and two T > C
single-nucleotide polymorphisms at positions 8610 and 8614 that result in a homopolymeric
cytosine stretch. Another common feature of mitochondrial complex V deficiency is
hypertrophic cardiomyopathy. This condition is characterized by thickening (
hypertrophy) of the
cardiac muscle that can lead to
heart failure. Individuals with mitochondrial complex V deficiency may also have a characteristic pattern of facial features, including a high forehead, curved eyebrows, outside corners of the eyes that point downward (downslanting
palpebral fissures), a prominent bridge of the nose, low-set ears, thin lips, and a small chin (
micrognathia). MT-ATP6 gene mutations associated with Leigh syndrome change one DNA building block (
nucleotide) in the MT-ATP6 gene. The most common genetic change replaces the nucleotide
thymine with
guanine at position 8993 (written as T8993G). The mutations that cause
Leigh syndrome impair the function or stability of the
ATP synthase complex, inhibiting
ATP production and impairing
oxidative phosphorylation. Although the exact mechanism is unclear, researchers believe that impaired oxidative phosphorylation can lead to
cell death because of decreased energy available in the cell. Certain tissues that require large amounts of energy, such as the brain, muscles, and heart, seem especially sensitive to decreases in cellular energy. Cell death in the brain likely causes the characteristic changes in the brain seen in Leigh syndrome, which contribute to the signs and symptoms of the condition. Cell death in other sensitive tissues may also contribute to the features of Leigh syndrome. A
heteroplasmic T→C MT-ATP6 mutation at position 9185 results in the substitution of a highly conserved
leucine to
proline at
codon 220 and a
heteroplasmic T→C
missense mutation at position 9191 converted a highly conserved
leucine to a
proline at position 222 of the
polypeptide, leading to a Leigh-type
phenotype. The T9185C mutation resulted in a mild and reversible
phenotype, with 97% of the patient's muscle and blood samples reflecting the mutation. The T9191C mutation presented a much more severe phenotype that resulted in the death of the patient at 2 years of age.
NARP syndrome Some of the mutations of the ATP6 gene that cause Leigh syndrome are also responsible for a similar, but less severe, condition called
neuropathy, ataxia, and retinitis pigmentosa (NARP). A small number of mutations in the MT-ATP6 gene have been identified in people with NARP. Each of these mutations changes one
nucleotide in the MT-ATP6 gene. As in Leigh syndrome, the most common genetic change associated with NARP replaces the
nucleotide thymine with
guanine at position 8993 (written as T8993G). The mutations that cause NARP alter the structure or function of
ATP synthase, reducing the ability of mitochondria to produce ATP. Although the precise effects of these mutations are unclear, researchers continue to investigate how changes in the MT-ATP6 gene interfere with ATP production and lead to muscle weakness, vision loss, and the other features of NARP.
Familial bilateral striatal necrosis A condition called familial bilateral striatal necrosis, which is similar to Leigh syndrome, can also result from changes in the MT-ATP6 gene. In the few reported cases with these mutations, affected children have had delayed development, problems with movement and coordination, weak muscle tone (
hypotonia), and an unusually small head size (
microcephaly). Researchers have not determined why MT-ATP6 mutations result in this combination of signs and symptoms in children with bilateral striatal necrosis. == Interactions ==