The MT-ATP6 gene provides information for making a protein that is essential for normal mitochondrial function. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. These cellular structures produce energy through a process called oxidative phosphorylation, which uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell's main energy source.
The MT-ATP6 protein forms one part (subunit) of a large enzyme called ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation. Specifically, one segment of ATP synthase allows positively charged particles, called protons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule called adenosine diphosphate (ADP) to ATP.
Health Conditions Related to Genetic Changes
Mutations in the MT-ATP6 gene have been found in approximately 10 percent of people with Leigh syndrome. Leigh syndrome is a progressive brain disorder that usually appears in infancy or early childhood. Affected children may experience delayed development, muscle weakness, problems with movement, or difficulty breathing.
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 the nucleotide 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 and in other sensitive tissues likely cause the characteristic signs and symptoms of Leigh syndrome.More About This Health Condition
Mitochondrial complex V deficiency
MedlinePlus Genetics provides information about Mitochondrial complex V deficiencyMore About This Health Condition
Neuropathy, ataxia, and retinitis pigmentosa
Some of the mutations 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 the nucleotide 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.
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 an 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.More About This Health Condition
MedlinePlus Genetics provides information about Charcot-Marie-Tooth diseaseMore About This Health Condition
A condition called familial bilateral striatal necrosis, which is similar to Leigh syndrome (described above), can also result from changes in the MT-ATP6 gene. In the few reported cases with these mutations, affected children have 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.
Other Names for This Gene
- ATP synthase 6
- ATP synthase F0 subunit 6
- ATPase protein 6
- mitochondrially encoded ATP synthase 6
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Blanco-Grau A, Bonaventura-Ibars I, Coll-Canti J, Melia MJ, Martinez R, Martinez-Gallo M, Andreu AL, Pinos T, Garcia-Arumi E. Identification and biochemical characterization of the novel mutation m.8839G>C in the mitochondrial ATP6 gene associated with NARP syndrome. Genes Brain Behav. 2013 Nov;12(8):812-20. doi: 10.1111/gbb.12089. Epub 2013 Oct 25. Citation on PubMed
- De Meirleir L, Seneca S, Lissens W, Schoentjes E, Desprechins B. Bilateral striatal necrosis with a novel point mutation in the mitochondrial ATPase 6 gene. Pediatr Neurol. 1995 Oct;13(3):242-6. doi: 10.1016/0887-8994(95)00184-h. Citation on PubMed
- Ganetzky RD, Stendel C, McCormick EM, Zolkipli-Cunningham Z, Goldstein AC, Klopstock T, Falk MJ. MT-ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases. Hum Mutat. 2019 May;40(5):499-515. doi: 10.1002/humu.23723. Epub 2019 Mar 4. Citation on PubMed or Free article on PubMed Central
- Lenaz G, Baracca A, Carelli V, D'Aurelio M, Sgarbi G, Solaini G. Bioenergetics of mitochondrial diseases associated with mtDNA mutations. Biochim Biophys Acta. 2004 Jul 23;1658(1-2):89-94. doi: 10.1016/j.bbabio.2004.03.013. Citation on PubMed
- Mattiazzi M, Vijayvergiya C, Gajewski CD, DeVivo DC, Lenaz G, Wiedmann M, Manfredi G. The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. Hum Mol Genet. 2004 Apr 15;13(8):869-79. doi: 10.1093/hmg/ddh103. Epub 2004 Mar 3. Citation on PubMed
- Moslemi AR, Darin N, Tulinius M, Oldfors A, Holme E. Two new mutations in the MTATP6 gene associated with Leigh syndrome. Neuropediatrics. 2005 Oct;36(5):314-8. doi: 10.1055/s-2005-872845. Citation on PubMed
- Ng YS, Martikainen MH, Gorman GS, Blain A, Bugiardini E, Bunting A, Schaefer AM, Alston CL, Blakely EL, Sharma S, Hughes I, Lim A, de Goede C, McEntagart M, Spinty S, Horrocks I, Roberts M, Woodward CE, Chinnery PF, Horvath R, Nesbitt V, Fratter C, Poulton J, Hanna MG, Pitceathly RDS, Taylor RW, Turnbull DM, McFarland R. Pathogenic variants in MT-ATP6: A United Kingdom-based mitochondrial disease cohort study. Ann Neurol. 2019 Aug;86(2):310-315. doi: 10.1002/ana.25525. Epub 2019 Jul 1. Citation on PubMed
- Schon EA, Santra S, Pallotti F, Girvin ME. Pathogenesis of primary defects in mitochondrial ATP synthesis. Semin Cell Dev Biol. 2001 Dec;12(6):441-8. doi: 10.1006/scdb.2001.0281. Citation on PubMed
- Sgarbi G, Baracca A, Lenaz G, Valentino LM, Carelli V, Solaini G. Inefficient coupling between proton transport and ATP synthesis may be the pathogenic mechanism for NARP and Leigh syndrome resulting from the T8993G mutation in mtDNA. Biochem J. 2006 May 1;395(3):493-500. doi: 10.1042/BJ20051748. Citation on PubMed or Free article on PubMed Central
- Thorburn DR, Rahman J, Rahman S. Mitochondrial DNA-Associated Leigh Syndrome and NARP. 2003 Oct 30 [updated 2017 Sep 28]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1173/ Citation on PubMed
- Thyagarajan D, Shanske S, Vazquez-Memije M, De Vivo D, DiMauro S. A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis. Ann Neurol. 1995 Sep;38(3):468-72. doi: 10.1002/ana.410380321. Citation on PubMed
- Uziel G, Moroni I, Lamantea E, Fratta GM, Ciceri E, Carrara F, Zeviani M. Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical, and molecular study in six families. J Neurol Neurosurg Psychiatry. 1997 Jul;63(1):16-22. doi: 10.1136/jnnp.63.1.16. Citation on PubMed or Free article on PubMed Central
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