Alternative titles; symbols
HGNC Approved Gene Symbol: MT-ATP6
SNOMEDCT: 237984008, 58610003; ICD10CM: H47.22;
Complex V (ATP synthase) of the mitochondrion comprises 10-16 subunits encoded by nuclear DNA and 2 subunits (ATPase 6 and ATPase 8) encoded by mtDNA. Subunit 6 of mitochondrial ATP synthase (complex V) is encoded by nucleotides 8527-9207 of the mitochondrial genome.
In an isolated case of mental retardation and ataxia without retinitis pigmentosa, de Coo et al. (1996) found an 8993T-G transversion (516060.0001). There was perinatal asphyxia but the neonatal period was unremarkable. Investigations at the age of 5 years showed elevated lactic acid level in blood and cerebrospinal fluid. DNA from peripheral blood cells and muscle showed 74% and 79% mutated DNA, respectively. No mutated mtDNA could be observed in any of the maternal tissues. The authors commented that low levels of deleted mtDNA occur in oocytes and that point mutations may occur in oocyte mtDNA. Yoneda et al. (1992) suggested that the mitochondrion is the unit of segregation. De Coo et al. (1996) stated that if the mutation in this case arose before or during the mitochondrial expansion in the oocyte, the stochastic purification following the dilution of the mtDNA down to 1 copy per organelle may have led to the survival of 1 mitochondrion with only mutated mtDNA. In vitro experiments with various mtDNA point mutations in mtDNA-less cells indicated that 'in culture, the shift to either wild type or mutant may be dependent on the nuclear background.'
White et al. (1999) described 13 pedigrees with mtDNA mutations at nucleotide 8993: 10 pedigrees with 8993T-G (516060.0001) and 3 with 8993T-C (516060.0002). Prenatal diagnosis was technically possible; however, there were 3 major concerns: (1) that there is variation in mutant loads among tissues; (2) that the mutant load in a tissue may change over time; and (3) that the genotype/phenotype correlation is not clearly understood. White et al. (1999) determined specifically the extent of tissue- and age-related variation of the 2 mutations at nucleotide 8993 in the mtDNA. The tissue variation was investigated by analyzing 2 or more different tissues from a total of 18 individuals; no substantial tissue variation was found. The age-related variation of the mutation was investigated by comparing the amount of both mutations in blood taken at birth and at a later age; there was no substantial change in the proportion of either mutation over periods of 8 to 23 years in 4 individuals studied. In addition, White et al. (1999) noted that 2 features were remarkably common in families with nucleotide 8993 mutations, namely, unexplained infant death (8 cases in 13 pedigrees) and de novo mutations (5 of the 10 8993T-G pedigrees).
Prenatal diagnosis for mtDNA mutations has been hindered by an inability to predict accurately the clinical severity expected from a mutant load measured in fetal tissue. After reviewing 44 published and 12 unpublished pedigrees, White et al. (1999) considered the possibility of prenatal diagnosis for 2 common mtDNA mutations at nucleotide 8993. They related the severity of symptoms to the mutant load and predicted the clinical outcome of a given mutant load. They also used the available data to generate empirical recurrence risks for genetic counseling, which may be used in conjunction with prenatal diagnosis.
In 4 unrelated infants who presented with isolated hypertrophic cardiomyopathy and congestive heart failure (500006), who later developed severe feeding difficulties and failure to thrive, Ware et al. (2009) identified an 8528T-C transition, resulting in concurrent changes in the overlapping MTATP6 and MTATP8 genes, M1T (516060.0010) and W55R (516070.0003), respectively. Ware et al. (2009) stated that this was the first description of a mitochondrial mutation affecting both complex V genes.
D'Aurelio et al. (2010) investigated the bioenergetics of cybrids from 5 patients carrying different ATP6 mutations: 3 harboring the T8993G (516060.0001) mutation, 1 with the T8993C (516060.0002) mutation, and 1 with the T9176G (516060.0011) mutation. The bioenergetic defects varied dramatically, not only among different ATP6 mutants, but also among lines carrying the same T8993G mutation. Mutants with the most severe ATP synthesis impairment showed defective respiration and disassembly of respiratory chain complexes. This indicates that respiratory chain defects may modulate the bioenergetic impairment in NARP/MILS cells. Sequencing of the entire mtDNA from the different mutant cell lines identified variations in structural genes, resulting in amino acid changes that destabilized the respiratory chain. D'Aurelio et al. (2010) concluded that the mtDNA background plays an important role in modulating the biochemical defects and clinical outcome in NARP/MILS.
Burrage et al. (2014) detected a novel variant in the MTATP6 gene (m.8969G-A, S148N; 516060.0012) in a patient with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA3; 500011). Next-generation sequencing confirmed the presence of this variant at 96% and 88% heteroplasmy in the proband's blood and muscle specimens, respectively, and did not detect the variant in his mother's blood sample. Functional studies using a patient-derived skin fibroblast line showed a profound reduction in oligomycin-sensitive respiration compared to control, consistent with a defect in mitochondrial complex V function. Whole-exome sequencing of relevant nuclear genes detected no pathogenic variants.
The striking regional variation of human mtDNA has traditionally been attributed to genetic drift, although drift alone does not easily explain that while only 2 mtDNA lineages, M and N, left Africa to colonize Eurasia, lineages A, C, D, and G show a 5-fold enrichment from central Asia to Siberia. As an alternative to drift, natural selection might have enriched for certain mtDNA lineages as people migrated north into colder climates. To test this hypothesis, Mishmar et al. (2003) analyzed 104 complete mtDNA sequences from all global regions and lineages. African mtDNA variation did not significantly deviate from the standard neutral model, whereas European, Asian, and Siberian plus North American variations did. Analysis of amino acid substitutions for all 13 mtDNA protein-coding genes revealed that the ATP6 gene had the highest amino acid sequence variation of any mtDNA gene, even though ATP6 is one of the more conserved mtDNA proteins. ATP6 was highly variable in the mtDNAs from the arctic zone, cytochrome b (516020) was particularly variable in the temperate zone, and cytochrome oxidase I (516030) was notably more variable in the tropics. Moreover, multiple amino acid changes found in ATP6, cytochrome b, and cytochrome oxidase I appeared to be functionally significant. From these analyses, Mishmar et al. (2003) concluded that selection may have played a role in shaping human regional mtDNA variation and that one of the selective influences was climate.
Elson et al. (2004) presented results that, like those of other investigators, did not support a simple model in which climatic adaptation had been a major force during human mtDNA evolution. Although they granted that this does not necessarily mean that the conclusion of Mishmar et al. (2003) is wrong with regard to the role of climatic adaptation as a major force, there were a number of potential limitations to their study.
Holt et al. (1990) found a heteroplasmic T-to-G transversion at nucleotide pair 8993 in a maternal pedigree which resulted in the change of a hydrophobic leucine to a hydrophilic arginine at position 156 in subunit 6 of mitochondrial H(+)-ATPase. The clinical symptoms varied in proportion to the percentage of mutant mtDNAs but the most common clinical presentation included neurogenic muscle weakness, ataxia, and retinitis pigmentosa, leading to the designation of NARP syndrome (551500). The insertion of an arginine in the hydrophobic sequence of ATPase 6 probably interferes with the hydrogen ion channel formed by subunits 6 and 9 of the ATPase, thus causing failure of ATP synthesis. Harding et al. (1992) demonstrated that prenatal diagnosis was possible, although the approach was hampered by incomplete knowledge concerning the proportion of mutant mtDNA and its relationship to disease severity, how it may change during fetal and postnatal development, and its tissue distribution.
In families with mitochondrial complex V (ATP synthase) deficiency mitochondrial type 1 (MC5DM1; 500015) resulting in Leigh syndrome (see 256000), Tatuch et al. (1992) and Shoffner et al. (1992) identified a nucleotide 8993 mutation in the MTAPT6 gene. Tatuch et al. (1992) found the heteroplasmic mtDNA mutation in a female infant showing lactic acidemia, hypotonia, and neurodegenerative disease leading to death at the age of 7 months. Autopsy revealed lesions typical of Leigh disease, both in the basal ganglia and in the brainstem. A maternal uncle and aunt died 5 months and 1 year, respectively, after a similar clinical course, while another maternal uncle, 33 years of age, had retinitis pigmentosa, ataxia, and mental retardation. The index patient had more than 95% abnormal mtDNA in her skin fibroblasts, brain, kidney, and liver tissues, as measured by laser densitometry. The maternal aunt who died at 1 year likewise had more than 95% abnormal mtDNA in her lymphoblasts. The uncle with retinitis pigmentosa had 78% and 79% abnormal mtDNA in his skin fibroblasts and lymphoblasts, respectively, while an asymptomatic maternal aunt and her son had no trace of the mutation. The mother of the index case had 71% and 39% abnormal mtDNA in her skin fibroblasts and lymphoblasts, respectively. Shoffner et al. (1992) reported a family which was heteroplasmic for the ATPase 6 nucleotide 8993 mutation in which 2 daughters died at ages 2.5 years and 14 months. Pathologic analyses showed classic basal ganglial lesions, vascular proliferation, and glioses. Two brothers manifested psychomotor retardation, ataxia, hypotonia, and retinal degeneration. The mother had retinal degeneration and experienced migraine headaches. The mother's 2 sisters were normal. The 4 affected children had high levels of mutant mtDNA, in excess of 95% by Southern blot. The mother had a 78% level of mutant mtDNA while her 2 sisters had 100% normal mtDNA.
Ciafaloni et al. (1993) described 2 sisters with Leigh syndrome who had a T-to-G transversion at nucleotide 8993 in the MTATP6 gene. The asymptomatic mother had the same mutation. All 3 were heteroplasmic. The proportion of mutant genomes was lower in the mother's blood than in the blood of the more mildly affected sister, whereas all tissues from the other sister were almost homoplasmic for the mutation.
Santorelli et al. (1993) found the T-to-G point mutation at nucleotide 8993 in 12 patients with Leigh syndrome from 10 unrelated families.
Pastores et al. (1994) expanded the clinical phenotype of the nucleotide 8993 mtDNA mutations to include hypertrophic cardiomyopathy and confirmed its role in producing Leigh syndrome. The patient was a boy of Chinese descent who presented at the age of 6 months with a history of developmental delay and hypotonia and who had recurrent lactic acidosis. The mother's first pregnancy resulted in the birth of a stillborn female; an apparently healthy older brother had died suddenly at age 2 months. The 8993T-G mutation was heteroplasmic in the patient's skeletal muscle (90%) and fibroblasts (90%). The identical mutation was present in leukocytes (38%) isolated from the mother, but not from the father or maternal grandmother.
Degoul et al. (1995) found the 8993T-G in a family with Leigh syndrome. The proband, who died at 9 years of age, developed hypotonia in the first 6 months of life and developmental retardation was noted. At 3 years of age he showed ataxia, dysmetria, myopathic weakness, nystagmus and ptosis. The electroretinogram was altered. She became deaf and developed progressive spasticity. Blood lactate concentration was normal. In contrast, lactate concentration in the CSF was always elevated. Two brothers died with acute apnea during infectious episodes, before the end of their first year. An older sister was mentally retarded, with ataxia, dysarthria, dystonia, and pes cavus, and had retinal degeneration. The mother's brother was mentally retarded and severely handicapped. Except for the father, all members of the family showed the mutation in all tissues studied, with high percentages in the 2 symptomatic sisters and even in 1 asymptomatic boy.
Ferlin et al. (1997) reported a child with Leigh syndrome who died at age 14 months. Genetic analysis identified the 8993T-G mutation in 3 generations of the family and showed that the percentage of mutant mtDNA increased through each generation. The maternal grandmother of the proband, the mother, and the eldest aunt had 10%, 52%, and 50% mutant mtDNA in lymphocytes, respectively. The proband's mother and the proband had 84% and 90% mutant mtDNA in skin fibroblasts, respectively. The eldest aunt terminated a pregnancy when the 8993T-G mutation was identified in chorionic villi. In fetal tissues, the mutation load ranged from 91 to 96%. Ferlin et al. (1997) concluded that the findings in this family were consistent with a threshold effect, in which over 90% mutant mtDNA load results in clinical disease, and noted that prenatal diagnosis is feasible.
Blok et al. (1997) analyzed mtDNA in oocytes from an asymptomatic mother of 3 children exhibiting heteroplasmic expression of the 8993T-G mutation associated with Leigh syndrome. The mother had 50% mutant mtDNA in her blood. One of the 7 oocytes analyzed showed no evidence of the mutation, while the remaining 6 had a mutant load of more than 95%. Blok et al. (1997) suggested that this observation reflected preferential amplification of the mtDNA variant during oogenesis. During formation of the zygote, mtDNA is derived exclusively from the oocyte; thus, it is possible that a de novo mutation may arise during oogenesis. A first carrier of a de novo mutation may be a mother who exhibits mosaicism for the mutation restricted to oocytes. However, the usual finding is that mothers of patients with Leigh syndrome and the 8993T-G mutation have substantial levels of the mutant mtDNA (38 to 76%). Takahashi et al. (1998) reported the case of a 1-year-old boy with Leigh syndrome associated with the 8993T-G mutation whose mother did not have the mutant mtDNA in her blood or urine sediment cells. Thus, a de novo mutation had occurred at a high level in oocytes, thereby causing Leigh syndrome in the boy. Generalized hypotonia was noted at birth. He developed apnea attacks and altered consciousness after upper respiratory infections at the ages of 2 and 4 months. At the age of 7 months, he showed symptoms of brainstem dysfunction, such as irregular respiration and swallowing difficulty. At the age of 9 months, growth retardation and microcephaly were obvious. Laboratory examinations showed increased lactate and pyruvate levels in blood and cerebrospinal fluid.
In plants, cytoplasmic male sterility (CMS) is a mitochondrially inherited inability to produce viable pollen, and has been observed in more than 150 different plant species. Kempken et al. (1998) pointed out that in sorghum RNA editing is required to generate codons that encode leucine residues at positions equivalent to human 156 and 217. Loss of ATP6 RNA editing, as it occurs in sorghum, thus mimics mutations in human mitochondrial diseases. In all ATP6 protein sequences found in databases, including protists, plants (edited sequence), fungi, and animals, both amino acid positions are completely conserved.
White et al. (1999) performed prenatal diagnosis in 2 mothers at risk of having affected children. One was the sister of a severely affected individual, and had previously had an unaffected child and a stillborn child. The other mother had 2 unaffected children and 2 affected children. The 8993T-G transversion was not found in the chorionic villus sample from 1 fetus or in the amniocytes from the other fetus. Both pregnancies were continued, and the resulting children were healthy at 2 years and 5 years of age.
In 3 patients from 2 unrelated families, Baracca et al. (2000) investigated the biochemical phenotype associated with the 8993T-G mutation in the MTATP6 gene. All 3 carried more than 80% mutant genome in platelets and were manifesting clinically various degrees of the NARP syndrome phenotype. Their results suggested that the 8993T-G mutation induces a structural defect in F1F0-ATPase that causes a severe impairment of ATP synthesis.
Kerrison et al. (2000) described the progression of retinopathy in NARP syndrome due to the T-to-G point mutation at the mtDNA nucleotide position 8993 in the MTATP6 gene. Prior to the onset of visual field constriction, ophthalmoscopy revealed salt-and-pepper retinopathy. After the visual fields had become constricted, fundus examination showed diffuse peripheral bone spicule formation, optic nerve pallor, and arteriolar attenuation consistent with retinitis pigmentosa. The authors stressed that mild mottling of the peripheral retinal pigment epithelium (salt-and-pepper retinopathy or retinitis pigmentosa sine pigmento) does not represent a specific entity but is an early stage of the retinitis pigmentosa, whether the patient has NARP or isolated retinitis pigmentosa.
Hayashi et al. (2000) reported the histopathologic findings in the eyes from a patient with Leigh syndrome associated with the 8993T-G point mutation in mtDNA. Ophthalmologic signs and symptoms of Leigh syndrome include nystagmus, ophthalmoplegia, strabismus, optic nerve atrophy, and loss of the foveal reflex. A child with hypotonia, developmental delay, persistent lactic acidosis, seizures, and ataxia died of aspiration pneumonia at age 15 months. Analysis of mtDNA was positive for the 8993T-G mutation. The proportion of mutant genomes was estimated at approximately 95%. Light microscopic examination of the left eye revealed thinning of the nerve fiber and ganglion cell layers in the nasal macula and mild atrophy of the temporal optic nerve. Electron microscopy of the right eye showed numerous distended mitochondria in all cells, particularly in the retinal pigment epithelium, nonpigmented ciliary epithelium, and corneal endothelium.
By transferring NARP mutant mtDNA (8993G-T in the MTATP6 gene) from fetal fibroblasts to lung carcinoma and osteosarcoma cells lacking endogenous mtDNA by cell-cytoplast fusion, Nijtmans et al. (2001) created mitochondrial transformant cells, or cybrids, able to grow in the absence of uridine. Immunoblot analysis revealed an abnormal amount of subcomplexes, F1-ATPase and V*, of mitochondrial ATP synthase. The cybrids had decreased subcomplex V assembly and decreased ATP synthesis capacity. However, the cells had no marked phenotype, suggesting that the effects of this mutation are subtle and have no effect on cell viability.
Geromel et al. (2001) investigated the oxidative stress resulting from the NARP mutation in MTATP6, using cultured skin fibroblasts from 2 NARP patients presenting with an isolated complex V deficiency. A huge induction of the superoxide dismutase (147450 and 147460) activity was observed in these fibroblasts harboring more than 90% of mutant mitochondrial DNA. The oxidative stress denoted by the high SOD activity was associated with increased cell death. In glucose-rich medium, apoptosis appeared as the main cell death process associated with complex V deficiency. Complex V-deficient fibroblasts were successfully rescued by perfluoro-tris-phenyl nitrone, an antioxidant spin-trap molecule. The authors hypothesized that the superoxide production associated with the ATPase deficiency triggered by the NARP mutation could be sufficient to override cell antioxidant defenses and to result in cell commitment to die.
Porto et al. (2001) reported an otherwise healthy 42-year-old woman with isolated late-onset cone-rod dystrophy characterized by difficulty driving at night beginning at age 40 years with deterioration of central and color vision due to the T8993G mitochondrial mutation. Two of her sons had NARP syndrome. A third son who was clinically diagnosed with Leigh syndrome died at age 4 years, prior to the recognition of the T8993G mutation in this family. The mother's mutation load was 50% T8993G mtDNA, while her sons with NARP had 75% T8993G mtDNA. The authors stated that Leigh disease is related to extreme heteroplasmy (more than 90%). They felt this family illustrated the remarkably variable expression of retinal and systemic manifestations related to the T8993G mutation, ranging from an isolated late-onset cone-rod dystrophy to a severe neurodegenerative process with a dramatic outcome. Porto et al. (2001) recommended genetic counseling for retinal dystrophy patients and emphasized careful evaluation of the family medical history.
The 8993T-G mutation in MTATP6 impairs mitochondrial ATP synthesis. To overcome the biochemical defect, Manfredi et al. (2002) expressed wildtype ATPase 6 protein allotopically. The protein was derived from nucleus-transfected constructs encoding an amino-terminal mitochondrial targeting signal appended to a recoded ATPase 6 gene (made compatible with the universal genetic code) that also contained a carboxy-terminal fluorescent epitope tag. After transfection of human cells, the precursor polypeptide was expressed, imported into and processed within mitochondria, and incorporated into complex V. Allotopic expression of stably transfected constructs in cytoplasmic hybrids (cybrids) homoplasmic with respect to the 8993T-G mutation showed a significantly improved recovery after growth in selective medium as well as a significant increase in ATP synthesis. This was said to be the first successful demonstration of allotopic expression of an mtDNA-encoded polypeptide in mammalian cells and could form the basis of a genetic approach to treatment of a number of human mitochondrial disorders.
Srivastava and Moraes (2001) showed that a mitochondrially targeted PstI restriction endonuclease degraded mtDNA harboring PstI sites, in some cases leading to a complete loss of mitochondrial genomes. When expressed in a heteroplasmic rodent cell line, containing 1 mtDNA haplotype with 2 sites for PstI and another haplotype having none, the mitochondrial PstI caused a significant shift in heteroplasmy, with an accumulation of the mtDNA haplotype lacking PstI sites. These experiments provided proof of the principle that restriction endonucleases may be feasible tools for genetic therapy of a subgroup of mitochondrial disorders. Patients harboring the T8993G mutation are potential candidates, since the mutation creates a novel PstI site which is not present in wildtype human mtDNA.
In 6 individuals from 3 unrelated Italian families who had the 8993T-G mutation, Carelli et al. (2002) showed a close relationship between extent of tissue heteroplasmy, expression of the biochemical defect in platelets, and clinical involvement. A defect of ATP synthesis was evident even at low levels of mutant heteroplasmy (10 to 34% of normal) in the absence of clinical symptoms. ATP synthesis was severely decreased (4 to 9% of control values) in patients with high levels of mutation (greater than 80%), who showed the more severe clinical phenotypes of NARP and Leigh syndromes. No biochemical threshold effect was found. Carelli et al. (2002) noted that the combined effect of decreased ATP synthesis and increased reactive oxygen species production underlie the pathophysiology of mitochondrial diseases.
Mattiazzi et al. (2004) showed that the 8993T-G mutation inhibits oxidative phosphorylation and results in enhanced free radical production. Antioxidants restored respiration and partially rescued ATP synthesis in cells harboring the T8993G mutation. The authors hypothesized that free radicals may play an important role in the pathogenesis of NARP/MILS and that antioxidants may be considered as a potentially useful tool in its treatment.
Jung et al. (2007) reported a family with the 8993T-G mutation in which adult-onset progressive myoclonic epilepsy was a prominent feature. The proband was a 46-year-old woman with myoclonus, epilepsy, ataxia, and peripheral neuropathy. She had onset of myoclonus at age 19, which progressively worsened over her life. She did not have retinitis pigmentosa. Her mother had possible epilepsy, and 1 of her daughters developed epilepsy and ataxia in her late teens. There was a history of 3 infantile deaths on the maternal side, resulting from seizures in 2. Genetic analysis identified heteroplasmy for the 8993T-G mutation in the proband (80% in fibroblasts) and her daughter (60% in lymphocytes).
Sgarbi et al. (2009) demonstrated that human fibroblasts containing the NARP-associated 8993T-G mutation could be protected from cell death when treated with alpha-ketoglutarate/aspartate to boost mitochondrial substrate-level phosphorylation (70% vs 5%; treated vs untreated survival after 72 hours). Homoplasmic 8993T-G cybrids showed similar results (75% vs 15%; treated vs untreated survival after 72 hours). In untreated fibroblasts and cybrids, the decrease in ATP content paralleled cell death, but ATP content returned to control levels after treatment. The findings indicated that ATP synthase-deficient cells can be rescued by increasing mitochondrial substrate-level phosphorylation, suggesting a potential therapeutic option for patients with such disorders.
In 4 sibs with mitochondrial complex V (ATP synthase) deficiency mitochondrial type 1 (MC5DM1; 500015) resulting in Leigh syndrome (see 256000), originally reported by van Erven et al. (1987), de Vries et al. (1993) found a T-to-C transition at nucleotide 8993 in the gene for ATPase 6. The mutation was predicted to cause a substitution of proline for leucine. The 4 sibs were severely affected and 1 of them died at the age of 17 years. The possibility of a mitochondrial basis was suggested by the fact that all children were affected; furthermore, beginning at the age of 56, the mother complained of weakness in her left leg, easy fatigability, and sensory disturbances in her feet. Neurologic examination demonstrated pyramidal signs in both legs, and ancillary investigations yielded results compatible with the diagnosis of Leigh syndrome. All patients, including the mother, were heteroplasmic for the mutation. The oldest of the 4 sibs died at age 17 after a progressive neurologic deterioration for 8 to 10 years. The other 3 sibs were living at ages 25, 23, and 20 years. Thus, the clinical picture did not agree strictly with that of infantile subacute necrotizing encephalopathy of Leigh. In the 3 living sibs there was no abnormality of pyruvate metabolism detected by study of serum and urine, but all 3 had marked elevation of CSF pyruvate and lactate concentration. Furthermore, pyruvate oxidation rates were normal in fibroblasts and leukocytes. A defect restricted to brain was suggested.
Chakrapani et al. (1998) described another family with the 8993T-C mutation causing Leigh syndrome. A brother and sister were found to be homoplasmic for the 8993T-C mutation; the asymptomatic mother was heteroplasmic. The features in the boy were those of NARP (551500). Beside delayed motor development, ataxia, and raised CSF lactate, developmental regression followed acute illnesses in early childhood, with slow reacquisition of skills and pronounced ataxia thereafter.
Fujii et al. (1998) reported a patient with Leigh syndrome with the 8993T-C mutation. They reviewed 9 other Leigh syndrome patients with the 8993T-C mutation and compared them with 18 reported cases with Leigh syndrome caused by the 8993T-G mutation (516060.0001). Leigh syndrome with the 8993T-C mutation was characterized by a significantly higher frequency of ataxia (P less than 0.01). None of the reviewed 8993T-C Leigh syndrome patients had retinitis pigmentosa, which is one of the characteristic findings in Leigh syndrome caused by the 8993T-G mutation. The milder symptoms of 8993T-C Leigh syndrome may be explained by the milder complex V dysfunction; however, the higher frequency of ataxia in association with 8993T-C requires more study.
Vilarinho et al. (2001) reported 4 new 8993T-C patients. One was a 17-year-old girl with remitting-relapsing neurodegenerative disease since age 16 months which worsened during fevers or infectious disease. She had elevated CSF lactate and brain MRI was compatible with Leigh syndrome. Proton magnetic resonance spectroscopy showed slight elevation of lactate in the basal ganglia. Her mother and maternal aunt showed a progressive cerebellar ataxia. The second case was of a 16 year-old boy who experienced episodes of loss of consciousness and awkward gait during febrile illness in childhood with a slow recovery. Blood and CSF lactate concentrations were elevated. Brain MRI showed basal ganglia involvement. The third case was of a 21 year-old girl who experienced her first episode of lethargy and hypotonia at age 5 months during a fever. Similar episodes reappeared in her first 10 years. At age 11 years, examination showed mental deficiency, severe dysarthria, and vertical gaze palsy. Blood lactate was elevated. Brain MRI showed hyperlucencies in the putamen and head caudate nucleus. Two older sisters had peripheral neuropathy with normal MRI and blood lactate. The fourth case was of a 16 year-old cousin of case 3 who had a subacute episode of leg weakness, ataxia and dysarthria during a fever at age 3 years. She improved but had permanent motor disability. Similar episodes recurred and always had a slow recovery. At age 9 she had elevated blood and CSF lactate and brain MRI was compatible with maternally inherited Leigh syndrome.
Debray et al. (2007) reported long-term follow-up on a patient who met the stringent criteria for Leigh syndrome established by Rahman et al. (1996). At age 4 years, the patient presented with respiratory distress, unexplained tachypnea, and a 2-day history of ptosis. On day 5 of hospitalization, he deteriorated with apnea and severe hypercapnia and required mechanical ventilation for 5 days. Ophthalmologic examination revealed nystagmus and supranuclear ophthalmoplegia. CT scan showed bilateral basal ganglia hypodensities. Blood lactate was 1.7 mmol/L (normal less than 2.2) and CSF lactate was 4.1 mmol/L (normal less than 1.8). He recovered without sequelae and functioned normally throughout childhood and early adolescence. Follow-up at age 18 revealed a slight cognitive decline in nonverbal tasks. The patient's leukocyte DNA revealed a greater than 95% 8993T-C mutant DNA; in contrast, the mutation was undetectable in his mother. Debray et al. (2007) reviewed 20 Leigh syndrome patients with the 8993T-C mutation. Only half (10/20) of the patients fulfilled the criteria of Rahman et al. (1996) for typical Leigh syndrome. Eighty-five percent (17/20) survived a median follow-up time of 16 years and 41% (7/20) did not have mental retardation. Debray et al. (2007) concluded that a favorable outcome can be observed in a significant percentage of Leigh syndrome patients with the 8993T-C mtDNA mutation.
Rantamaki et al. (2005) reported 4 sibs with adult-onset ataxia and polyneuropathy (500010) and a heteroplasmic 8993T-C mutation. One of the sibs had early-onset severe ataxia and moderate mental impairment and died at age 22 years. The remaining 3 sibs had adult-onset of variable gait abnormalities, axonal sensorimotor polyneuropathy, abnormal eye movements, and dysarthria. Genetic analysis of the 3 surviving sibs showed mutant mtDNA ranging from 64 to 89%. Rantamaki et al. (2005) emphasized the unique phenotypic presentation in this family.
Craig et al. (2007) identified a 3-generation family with slowly progressive adult-onset ataxia associated with the heteroplasmic 8993T-C mutation. A mother, daughter, and granddaughter were affected, with 86%, 82%, and 83% mutation heteroplasmy, respectively, in the blood. Other features included cerebellar dysarthria, axonal sensory neuropathy, and gaze-evoked horizontal nystagmus. The daughter and granddaughter reported intermittent exacerbations of ataxia, associated with migraine in 1 case. The daughter had optic atrophy without retinal degeneration. The 8993T-C mutation was not identified in 191 additional patients with episodic ataxia, 307 patients with ataxia, or 96 patients with suspected Charcot-Marie-Tooth disease (see, e.g., CMT1A; 118220) suggesting that it is not a common finding in these phenotypic conditions.
In 1 of 24 Finnish Leber hereditary optic atrophy (535000) families, Lamminen et al. (1995) found a single affected male with a typical acute stage with peripapillary microangiopathy; onset was at age 21. A T-to-C base substitution at nucleotide 9101 in the MTATP6 gene was found that resulted in the replacement of an isoleucine by a threonine at residue 192. Using restriction site changes resulting from the base substitution, the mutation was detected in all maternal members of the proband's family but not in other individuals tested and was not found in any of the other Finnish LHON families or in 100 unrelated control individuals of Finnish origin.
In 2 Jewish brothers with mitochondrially inherited bilateral striatal necrosis (500003), Thyagarajan et al. (1995) identified a 9176T-C transition in the MTATP6 gene. In the more severely affected patient, the mutation was homoplasmic in muscle, leukocytes, and fibroblasts; 98% of mtDNA was mutant in leukocytes from his affected brother. The mother and 2 other sibs were asymptomatic, with varying degrees of heteroplasmy for the mutation.
In an Italian family, Dionisi-Vici et al. (1998) found that the 9176T-C mutation in the MTATP6 gene was associated with mitochondrial complex V (ATP synthase) deficiency mitochondrial type 1 (MC5DM1; 500015), resulting in early-onset fulminant Leigh syndrome (see 256000) and with sudden unexpected death in 2 sibs, respectively. PCR-SSCP analysis and direct sequencing showed that the mutation was homoplasmic in the mitochondrial DNA of the proband. The 9176T-C mutation changed the highly conserved leucine to proline in the MTATP6 gene and was maternally inherited, but maternal relatives were asymptomatic.
Among 80 patients with clinical and brain imaging characteristics of Leigh syndrome, Makino et al. (1998) found that 11 had the well-known 8993T-G mutation in the mitochondrial DNA (516060.0001). In addition, 3 patients had the 9176T-C mutation. In the 3 patients reported by Makino et al. (1998), 1 had the typical clinical characteristics of Leigh syndrome from early infancy, and 2 had later onset of neurologic deficits. All had a slowly progressive course and basal ganglia abnormalities by neuroimaging. As both nucleotide 8993 and nucleotide 9176 are located in the ATPase 6 coding region, altered ATPase function may be one of the enzyme abnormalities in Leigh syndrome and other similar conditions with bilateral striatal necrosis.
In a boy with bilateral striatal necrosis (500003), De Meirleir et al. (1995) identified an 8851T-C transition in the MTATP6 gene. The patient had less than 3% normal mtDNA in fibroblasts and his unaffected mother had 15% normal mtDNA. The mtDNA of the grandmother had no trace of the mutation.
Seneca et al. (1996) described a female newborn who presented with seizures and episodic lactic acidemia, symptoms consistent with mitochondrial dysfunction. They found a 2-bp deletion at positions 9204/5 or 9205/6 at the junction between the 2 genes MTATP6 and MTCO3 (516050) that removed the termination codon for RNA14, the ATPase 8- and 6-encoding bicistronic mRNA unit. The deletion removed the termination codon for MTATP6 and set MTCO3 immediately in-frame, generating a predicted ATPase6/COX3 fusion protein. Temperley et al. (2003) showed that accurate processing at this site still occurred, but there was a markedly decreased steady-state level of RNA14. The majority of mutated RNA14 terminated with short poly(A) extensions, and a second, partially truncated population was also present. Initial maturation of mutated RNA14 was unaffected, but deadenylation occurred rapidly. Inhibition of mitochondrial protein synthesis showed that the deadenylation was dependent on translation; deadenylation also enhanced mRNA decay. Temperley et al. (2003) referred to the deletion as mu-delta-9205.
In a patient with mitochondrial complex V (ATP synthase) deficiency mitochondrial type 1 (MC5DM1; 500015), resulting in Leigh syndrome (see 256000), Castagna et al. (2007) identified a heteroplasmic 9185T-C transition in the MTATP6 gene, resulting in a leu220-to-pro (L220P) substitution in the fifth transmembrane helix at the inner surface of the outer mitochondrial membrane. After a normal development, the boy presented at age 8.5 years with a 3-month history of frequent falls, ataxia, slowed speech, poor concentration, bilateral pes cavus, and absent ankle reflexes. Three months later, he developed saccadic paresis and nystagmus and rapidly deteriorated into a comatose state, followed by death. Brain MRI showed symmetric hyperintense signals in the basal ganglia with prominent cerebellar involvement, consistent with Leigh syndrome. The proband had a similarly affected brother, and both boys had greater than 90% mutant DNA levels. The mother and a maternal uncle had isolated peripheral neuropathy and ataxia with 86% and 85% heteroplasmy for the mutation, respectively. Family history revealed 4 additional maternal relatives with the mutation: 2 had Leigh syndrome, and 2 had isolated ataxia. Percentage of heteroplasmy correlated with the severity of the phenotype. Studies of the proband's mitochondria showed a 30% decrease in ATPase activity, although the overall process of ATP synthesis was not affected.
In a man with NARP syndrome (551500), Lopez-Gallardo et al. (2009) identified a 1-bp insertion (8618insT) in the MTATP6 gene, resulting in a frameshift and a truncated protein of 63 amino acids instead of the 227 residues of the mature wildtype protein. The mutation was heteroplasmic, present in 26% and 85% of blood and muscle, respectively. Western blot analysis showed decreased levels of MTATP6 protein but no truncated protein. The patient had delayed development, psychomotor retardation, and irritability in childhood, and later developed other neurologic signs, including hearing loss, blindness due to optic atrophy and retinitis pigmentosa, ataxia, and clonic spasms.
In 4 unrelated infants who presented with hypertrophic cardiomyopathy and congestive heart failure (500006), Ware et al. (2009) identified a heteroplasmic 8528T-C transition, resulting in concurrent substitutions in the overlapping MTATP6 and MTATP8 genes: a met1-to-thr (M1W) substitution in MTATP6, predicted to abrogate the start of translation, and a trp55-to-arg (W55R) substitution at a highly conserved residue in MTATP8 (516070.0003). The alteration appeared homoplasmic on sequence analysis; however, tissue analysis of 1 patient and her asymptomatic mother and maternal aunt revealed that the patient carried a high degree of heteroplasmic mutation (92 to 98%) in all 5 tissues examined, whereas her mother carried the heteroplasmic mutation at a much lower level (15 to 25%), and the mutation was not detected in her maternal aunt. Functional analysis in skin fibroblasts from this patient and her mother indicated a significant decrease in ATP synthesis in the patient.
In a 10-year-old girl with severe neurodegenerative disorder consistent mitochondrial complex V (ATP synthase) deficiency mitochondrial type 1 (MC5DM1; 500015), resulting in Leigh syndrome (see 256000), Carrozzo et al. (2001) identified a 9176T-G transversion in the MTATP6 gene. Her older sister had died of Leigh syndrome, and a maternal uncle had a spinocerebellar disorder. Biochemical studies revealed a reduced rate of ATP synthesis in patient skin fibroblast cultures.
Kucharczyk et al. (2009) created and analyzed the properties of a yeast strain bearing a mutation equivalent to the human 9176T-G mutation. Incorporation of mutant Atp6 within the ATP synthase was almost completely prevented in the mutant yeast. Based on previous characterization of human 9176T-G cells, it is likely that this mutation similarly affects the human ATP synthase instead of causing a block in the rotary mechanism of the enzyme as previously suggested. Mutant yeast exhibited important anomalies in mitochondrial morphology, indicating that the pathogenicity of 9176T-G may not be limited to a bioenergetic deficiency.
In a boy with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia-3 (MLASA3; 500011), Burrage et al. (2014) performed mitochondrial genome sequencing, which revealed a m.8969G-A transition in the MTATP6 gene resulting in a ser148-to-asn (S148N) substitution. The mutation, which occurred at a highly conserved residue, was not detected in any public databases. Patient-derived fibroblast cell lines analyzed for cellular respiration showed significant reductions compared to controls, consistent with a complex V defect. Next-generation sequencing confirmed the presence of this variant at 96% and 88% heteroplasmy in the proband's blood and muscle specimens, respectively, but did not detect the variant in his mother's blood sample, which suggested that S148N either occurred de novo or was transmitted through maternal gonadal mosaicism. Whole-exome sequencing did not identify mutations in PUS1 (608109), YARS2 (610957), or any known nuclear genes that could affect mitochondrial function and explain this phenotype. The patient also had stroke-like episodes, Wolff-Parkinson-White syndrome (194200), and sensorineural hearing loss. Burrage et al. (2014) stated that patients with MLASA phenotypes should be screened for mutations in the mitochondrial genome, especially if no mutations are detected in PUS1 or YARS2.
Baracca, A., Barogi, S., Carelli, V., Lenaz, G., Solaini, G. Catalytic activities of mitochondrial ATP synthase in patients with mitochondrial DNA T8993G mutation in the ATPase 6 gene encoding subunit a. J. Biol. Chem. 275: 4177-4182, 2000. [PubMed: 10660580] [Full Text: https://doi.org/10.1074/jbc.275.6.4177]
Blok, R. B., Gook, D. A., Thorburn, D. R., Dahl, H. H. M. Skewed segregation of the mtDNA nt 8993 (T-to-G) mutation in human oocytes. Am. J. Hum. Genet. 60: 1495-1501, 1997. [PubMed: 9199572] [Full Text: https://doi.org/10.1086/515453]
Burrage, L. C., Tang, S., Wang, J., Donti, T. R., Walkiewicz, M., Luchak, J. M., Chen, L.-C., Schmitt, E. S., Niu, Z., Erana, R., Hunter, J. V., Graham, B. H., Wong, L.-J., Scaglia, F. Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G-A) in the mitochondrial encoded ATP6 gene. Molec. Genet. Metab. 113: 207-212, 2014. [PubMed: 25037980] [Full Text: https://doi.org/10.1016/j.ymgme.2014.06.004]
Campos, Y., Martin, M. A., Rubio, J. C., Solana, L. G., Garcia-Benayas, C., Terradas, J. L., Arenas, J. Leigh syndrome associated with the T9176C mutation in the ATPase 6 gene of mitochondrial DNA. Neurology 49: 595-597, 1997. [PubMed: 9270604] [Full Text: https://doi.org/10.1212/wnl.49.2.595]
Carelli, V., Baracca, A., Barogi, S., Pallotti, F., Valentino, M. L., Montagna, P., Zeviani, M., Pini, A., Lenaz, G., Baruzzi, A., Solaini, G. Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation. Arch. Neurol. 59: 264-270, 2002. [PubMed: 11843698] [Full Text: https://doi.org/10.1001/archneur.59.2.264]
Carrozzo, R., Tessa, A., Vazquez-Memije, M. E., Piemonte, F., Patrono, C., Malandrini, A., Dionisi-Vici, C., Vilarinho, L., Villanova, M., Schagger, H., Federico, A., Bertini, E., Santorelli, F. M. The T9176G mtDNA mutation severely affects ATP production and results in Leigh syndrome. Neurology 56: 687-690, 2001. [PubMed: 11245730] [Full Text: https://doi.org/10.1212/wnl.56.5.687]
Castagna, A. E., Addis, J., McInnes, R. R., Clarke, J. T. R., Ashby, P., Blaser, S., Robinson, B. H. Late onset Leigh syndrome and ataxia due to a T to C mutation at bp 9,185 of mitochondrial DNA. Am. J. Med. Genet. 143A: 808-816, 2007. [PubMed: 17352390] [Full Text: https://doi.org/10.1002/ajmg.a.31637]
Chakrapani, A., Heptinstall, L., Walter, J. A family with Leigh syndrome caused by the rarer T8993C mutation. J. Inherit. Metab. Dis. 21: 685-686, 1998. [PubMed: 9762610] [Full Text: https://doi.org/10.1023/a:1005401121344]
Ciafaloni, E., Santorelli, F. M., Shanske, S., Deonna, T., Roulet, E., Janzer, C., Pescia, G., DiMauro, S. Maternally inherited Leigh syndrome. J. Pediat. 122: 419-422, 1993. [PubMed: 8095070] [Full Text: https://doi.org/10.1016/s0022-3476(05)83431-6]
Craig, K., Elliott, H. R., Keers, S. M., Lambert, C., Pyle, A., Graves, T. D., Woodward, C., Sweeney, M. G., Davis, M. B., Hanna, M. G., Chinnery, P. F. Episodic ataxia and hemiplegia caused by the 8993T-C mitochondrial DNA mutation. (Letter) J. Med. Genet. 44: 797-799, 2007. [PubMed: 18055910] [Full Text: https://doi.org/10.1136/jmg.2007.052902]
D'Aurelio, M., Vives-Bauza, C., Davidson, M. M., Manfredi, G. Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells. Hum. Molec. Genet. 19: 374-386, 2010. [PubMed: 19875463] [Full Text: https://doi.org/10.1093/hmg/ddp503]
De Coo, I. F. M., Smeets, H. J. M., Gabreels, F. J. M., Arts, N., van Oost, B. A. Isolated case of mental retardation and ataxia due to a de novo mitochondrial T8993G mutation. (Letter) Am. J. Hum. Genet. 58: 636-638, 1996. [PubMed: 8644724]
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. Pediat. Neurol. 13: 242-246, 1995. [PubMed: 8554662] [Full Text: https://doi.org/10.1016/0887-8994(95)00184-h]
de Vries, D. D., van Engelen, B. G. M., Gabreels, F. J. M., Ruitenbeek, W., van Oost, B. A. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome. Ann. Neurol. 34: 410-412, 1993. [PubMed: 8395787] [Full Text: https://doi.org/10.1002/ana.410340319]
Debray, F.-G., Lambert, M., Lortie, A., Vanasse, M., Mitchell, G. A. Long-term outcome of Leigh syndrome caused by the NARP-T8993C mtDNA mutation. Am. J. Med. Genet. 143A: 2046-2051, 2007. [PubMed: 17663470] [Full Text: https://doi.org/10.1002/ajmg.a.31880]
Degoul, F., Diry, M., Rodriguez, D., Robain, O., Francois, D., Ponsot, G., Marsac, C., Desguerre, I. Clinical, biochemical, and molecular analysis of a maternally inherited case of Leigh syndrome (MILS) associated with the mtDNA T8993G point mutation. J. Inherit. Metab. Dis. 18: 682-688, 1995. [PubMed: 8750605] [Full Text: https://doi.org/10.1007/BF02436757]
Dionisi-Vici, C., Seneca, S., Zeviani, M., Fariello, G., Rimoldi, M., Bertini, E., De Meirleir, L. Fulminant Leigh syndrome and sudden unexpected death in a family with the T9176C mutation of the mitochondrial ATPase 6 gene. J. Inherit. Metab. Dis. 21: 2-8, 1998. [PubMed: 9501263] [Full Text: https://doi.org/10.1023/a:1005397227996]
Elson, J. L., Turnbull, D. M., Howell, N. Comparative genomics and the evolution of human mitochondrial DNA: assessing the effects of selection. Am. J. Hum. Genet. 74: 229-238, 2004. [PubMed: 14712420] [Full Text: https://doi.org/10.1086/381505]
Ferlin, T., Landrieu, P., Rambaud, C., Fernandez, H., Dumoulin, R., Rustin, P., Mousson, B. Segregation of the G8993 mutant mitochondrial DNA through generations and embryonic tissues in a family at risk of Leigh syndrome. J. Pediat. 131: 447-449, 1997. [PubMed: 9329425] [Full Text: https://doi.org/10.1016/s0022-3476(97)80074-1]
Fujii, T., Hattori, H., Higuchi, Y., Tsuji, M., Mitsuyoshi, I. Phenotypic differences between T-C and T-G mutations at nt 8993 of mitochondrial DNA in Leigh syndrome. Pediat. Neurol. 18: 275-277, 1998. [PubMed: 9568930] [Full Text: https://doi.org/10.1016/s0887-8994(97)00187-2]
Geromel, V., Kadhom, N., Cebalos-Picot, I., Quari, O., Polidori, A., Munnich, A., Rotig, A., Rustin, P. Superoxide-induced massive apoptosis in cultured skin fibroblasts harboring the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the ATPase-6 gene of the mitochondrial DNA. Hum. Molec. Genet. 10: 1221-1228, 2001. [PubMed: 11371515] [Full Text: https://doi.org/10.1093/hmg/10.11.1221]
Harding, A. E., Holt, I. J., Sweeney, M. G., Brockington, M., Davis, M. B. Prenatal diagnosis of mitochondrial DNA(8993 T-to-G) disease. Am. J. Hum. Genet. 50: 629-633, 1992. [PubMed: 1539598]
Hayashi, N., Geraghty, M. T., Green, W. R. Ocular histopathologic study of a patient with the T 8993-G point mutation in Leigh's syndrome. Ophthalmology 107: 1397-1402, 2000. [PubMed: 10889120] [Full Text: https://doi.org/10.1016/s0161-6420(00)00110-x]
Holt, I. J., Harding, A. E., Petty, R. K. H., Morgan-Hughes, J. A. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am. J. Hum. Genet. 46: 428-433, 1990. [PubMed: 2137962]
Jung, J., Mauguiere, F., Clerc-Renaud, P., Ollagnon, E., Mousson de Camaret, B., Ryvlin, P. NARP mitochondriopathy: an unusual cause of progressive myoclonic epilepsy. Neurology 68: 1429-1430, 2007. [PubMed: 17452590] [Full Text: https://doi.org/10.1212/01.wnl.0000264019.53959.10]
Kempken, F., Howad, W., Pring, D. R. Mutations at specific atp6 codons which cause human mitochondrial diseases also lead to male sterility in a plant. FEBS Lett. 441: 159-160, 1998. [PubMed: 9883875] [Full Text: https://doi.org/10.1016/s0014-5793(98)01538-5]
Kerrison, J. B., Biousse, V., Newman, N. J. Retinopathy of NARP syndrome. Arch. Ophthal. 118: 298-299, 2000. [PubMed: 10676807] [Full Text: https://doi.org/10.1001/archopht.118.2.298]
Kucharczyk, R., Salin, B., di Rago, J.-P. Introducing the human Leigh syndrome mutation T9176G into Saccharomyces cerevisiae mitochondrial DNA leads to severe defects in the incorporation of Atp6p into the ATP synthase and in the mitochondrial morphology. Hum. Molec. Genet. 18: 2889-2898, 2009. [PubMed: 19454486] [Full Text: https://doi.org/10.1093/hmg/ddp226]
Lamminen, T., Majander, A., Juvonen, V., Wikstrom, M., Aula, P., Nikoskelainen, E., Savontaus, M.-L. A mitochondrial mutation at nt 9101 in the ATP synthase 6 gene associated with deficient oxidative phosphorylation in a family with Leber hereditary optic neuroretinopathy. (Letter) Am. J. Hum. Genet. 56: 1238-1240, 1995. [PubMed: 7726182]
Lopez-Gallardo, E., Solano, A., Herrero-Martin, M. D., Martinez-Romero, I., Castano-Perez, M. D., Andreu, A. L., Herrera, A., Lopez-Perez, M. J., Ruiz-Pesini, E., Montoya, J. NARP syndrome in a patient harbouring an insertion in the MT-ATP6 gene that results in a truncated protein. J. Med. Genet. 45: 64-67, 2009.
Makino, M., Horai, S., Goto, Y., Nonaka, I. Confirmation that a T-to-C mutation at 9176 in mitochondrial DNA is an additional candidate mutation for Leigh's syndrome. Neuromusc. Dis. 8: 149-151, 1998. [PubMed: 9631394] [Full Text: https://doi.org/10.1016/s0960-8966(98)00017-0]
Manfredi, G., Fu, J., Ojaimi, J., Sadlock, J. E., Kwong, J. Q., Guy, J., Schon, E. A. Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nature Genet. 30: 394-399, 2002. [PubMed: 11925565] [Full Text: https://doi.org/10.1038/ng851]
Mattiazzi, M., Vijayvergiya, C., Gajewski, C. D., DeVivo, D. C., 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. Molec. Genet. 13: 869-879, 2004. [PubMed: 14998933] [Full Text: https://doi.org/10.1093/hmg/ddh103]
Mishmar, D., Ruiz-Pesini, E., Golik, P., Macaulay, V., Clark, A. G., Hosseini, S., Brandon, M., Easley, K., Chen, E., Brown, M. D., Sukernik, R. I., Olckers, A., Wallace, D. C. Natural selection shaped regional mtDNA variation in humans. Proc. Nat. Acad. Sci. 100: 171-176, 2003. [PubMed: 12509511] [Full Text: https://doi.org/10.1073/pnas.0136972100]
Nijtmans, L. G. J., Henderson, N. S., Attardi, G., Holt, I. J. Impaired ATP synthase assembly associated with a mutation in the human ATP synthase subunit 6 gene. J. Biol. Chem. 276: 6755-6762, 2001. [PubMed: 11076946] [Full Text: https://doi.org/10.1074/jbc.M008114200]
Pastores, G. M., Santorelli, F. M., Shanske, S., Gelb, B. D., Fyfe, B., Wolfe, D., Willner, J. P. Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G). Am. J. Med. Genet. 50: 265-271, 1994. [PubMed: 8042671] [Full Text: https://doi.org/10.1002/ajmg.1320500310]
Porto, F. B. O., Mack, G., Sterboul, M.-J., Lewin, P., Flament, J., Sahel, J., Dollfus, H. Isolated late-onset cone-rod dystrophy revealing a familial neurogenic muscle weakness, ataxia, and retinitis pigmentosa syndrome with the T8993G mitochondrial mutation. Am. J. Ophthal. 132: 935-937, 2001. [PubMed: 11730668] [Full Text: https://doi.org/10.1016/s0002-9394(01)01187-4]
Rahman, S., Blok, R. B., Dahl, H.-H. M., Danks, D. M., Kirby, D. M., Chow, C. W., Christodoulou, J., Thorburn, D. R. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann. Neurol. 39: 343-351, 1996. [PubMed: 8602753] [Full Text: https://doi.org/10.1002/ana.410390311]
Rantamaki, M. T., Soini, H. K., Finnila, S. M., Majamaa, K., Udd, B. Adult-onset ataxia and polyneuropathy caused by mitochondrial 8993T-C mutation. Ann. Neurol. 58: 337-340, 2005. [PubMed: 16049925] [Full Text: https://doi.org/10.1002/ana.20555]
Santorelli, F. M., Shanske, S., Macaya, A., DeVivo, D. C., DiMauro, S. The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome. Ann. Neurol. 34: 827-834, 1993. [PubMed: 8250532] [Full Text: https://doi.org/10.1002/ana.410340612]
Seneca, S., Abramowicz, M., Lissens, W., Muller, M., Vamos, E., De Meirleir, L. A mitochondrial DNA microdeletion in a newborn girl with transient lactic acidosis. J. Inherit. Metab. Dis. 19: 115-118, 1996. [PubMed: 8739943] [Full Text: https://doi.org/10.1007/BF01799407]
Sgarbi, G., Casalena, G. A., Baracca, A., Lenaz, G., DiMauro, S., Solaini, G. Human NARP mitochondrial mutation metabolism corrected with alpha-ketoglutarate/aspartate: a potential new therapy. Arch. Neurol. 66: 951-957, 2009. [PubMed: 19667215] [Full Text: https://doi.org/10.1001/archneurol.2009.134]
Shoffner, J. M., Fernhoff, P. M., Krawiecki, N. S., Caplan, D. B., Holt, P. J., Koontz, D. A., Takei, Y., Newman, N. J., Ortiz, R. G., Polak, M., Ballinger, S. W., Lott, M. T., Wallace, D. C. Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation. Neurology 42: 2168-2174, 1992. [PubMed: 1436530] [Full Text: https://doi.org/10.1212/wnl.42.11.2168]
Srivastava, S., Moraes, C. T. Manipulating mitochondrial DNA heteroplasmy by a mitochondrially targeted restriction endonuclease. Hum. Molec. Genet. 10: 3093-3099, 2001. [PubMed: 11751691] [Full Text: https://doi.org/10.1093/hmg/10.26.3093]
Takahashi, S., Makita, Y., Oki, J., Miyamoto, A., Yanagawa, J., Naito, E., Goto, Y., Okuno, A. De novo mtDNA nt 8993 (T-G) mutation resulting in Leigh syndrome. (Letter) Am. J. Hum. Genet. 62: 717-719, 1998. [PubMed: 9556461] [Full Text: https://doi.org/10.1086/301751]
Tatuch, Y., Christodoulou, J., Feigenbaum, A., Clarke, J. T. R., Wherret, J., Smith, C., Rudd, N., Petrova-Benedict, R., Robinson, B. H. Heteroplasmic mtDNA mutation (T-to-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am. J. Hum. Genet. 50: 852-858, 1992. [PubMed: 1550128]
Temperley, R. J., Seneca, S. H., Tonska, K., Bartnik, E., Bindoff, L. A., Lightowlers, R. N., Chrzanowska-Lightowlers, Z. M. A. Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria. Hum. Molec. Genet. 12: 2341-2348, 2003. [PubMed: 12915481] [Full Text: https://doi.org/10.1093/hmg/ddg238]
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. 38: 468-472, 1995. [PubMed: 7668837] [Full Text: https://doi.org/10.1002/ana.410380321]
Trounce, I., Neill, S., Wallace, D. C. Cytoplasmic transfer of the mtDNA nt 8993 T-to-G (ATP6) point mutation associated with Leigh syndrome into mtDNA-less cells demonstrates cosegregation with a decrease in state III respiration and ADP/O ratio. Proc. Nat. Acad. Sci. 91: 8334-8338, 1994. [PubMed: 8078883] [Full Text: https://doi.org/10.1073/pnas.91.18.8334]
van Erven, P. M. M., Gabreels, F. J. M., Ruitenbeek, W., Renier, W. O., Lamers, K. J. B., Slooff, J. L. Familial Leigh's syndrome: association with a defect in oxidative metabolism probably restricted to brain. J. Neurol. 234: 215-219, 1987. [PubMed: 3612192] [Full Text: https://doi.org/10.1007/BF00618253]
Vilarinho, L., Barbot, C., Carrozzo, R., Calado, E., Tessa, A., Dionisi-Vici, C., Guimaraes, A., Santorelli. F. M. Clinical and molecular findings in 4 new patients harbouring the mtDNA 8993T-C mutation. J. Inherit. Metab. Dis. 24: 883-884, 2001. [PubMed: 11916326] [Full Text: https://doi.org/10.1023/a:1013908728445]
Ware, S. M., El-Hassan, N., Kahler, S. G., Zhang, Q., Ma, Y.-W., Miller, E., Wong, B., Spicer, R. L., Craigen, W. J., Kozel, B. A., Grange, D. K., Wong, L.-J. Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes. J. Med. Genet. 46: 308-314, 2009. [PubMed: 19188198] [Full Text: https://doi.org/10.1136/jmg.2008.063149]
White, S. L., Collins, V. R., Wolfe, R., Cleary, M. A., Shanske, S., DiMauro, S., Dahl, H.-H. M., Thorburn, D. R. Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am. J. Hum. Genet. 65: 474-482, 1999. [PubMed: 10417290] [Full Text: https://doi.org/10.1086/302488]
White, S. L., Shanske, S., Biros, I., Warwick, L., Dahl, H. M., Thorburn, D. R., Di Mauro, S. Two cases of prenatal analysis for the pathogenic T to G substitution at nucleotide 8993 in mitochondrial DNA. Prenatal Diag. 19: 1165-1168, 1999. [PubMed: 10590437]
White, S. L., Shanske, S., McGill, J. J., Mountain, H., Geraghty, M. T., DiMauro, S., Dahl, H.-H. M., Thorburn, D. R. Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue- or age-related variation. J. Inherit. Metab. Dis. 22: 899-914, 1999. [PubMed: 10604142] [Full Text: https://doi.org/10.1023/a:1005639407166]
Yoneda, M., Chomyn, A., Martinuzzi, A., Hurko, O., Attardi, A. Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy. Proc. Nat. Acad. Sci. 89: 11164-11168, 1992. [PubMed: 1454794] [Full Text: https://doi.org/10.1073/pnas.89.23.11164]