Alternative titles; symbols
HGNC Approved Gene Symbol: MT-ND5
SNOMEDCT: 230426003, 39925003, 58610003; ICD10CM: E88.41, E88.42, H47.22;
Subunit 5 is 1 of the 7 mitochondrial DNA (mtDNA) encoded subunits (MTND1, MTND2, MTND3, MTND4L, MTND4, MTND5, MTND6) included among the approximately 41 polypeptides of respiratory complex I (NADH:ubiquinone oxidoreductase, EC 1.6.5.3)(Shoffner and Wallace, 1995; Arizmendi et al., 1992; Walker et al., 1992; Anderson et al., 1981; Attardi et al., 1986; Chomyn et al. (1985, 1986); Wallace et al., 1986; Oliver and Wallace, 1982; Wallace et al., 1994). Complex I accepts electron from NADH, transfers them to ubiquinone (Coenzyme Q10) and uses the energy released to pump protons across the mitochondrial inner membrane. Complex I is more fully described under 516000. MTND5 is probably a component of the hydrophobic protein fragment (Ragan, 1987).
MTND5 is encoded by the guanine-rich heavy (H) strand of the mtDNA and located between nucleotide pairs (nps) 12337 and 14148 (Anderson et al., 1981; Wallace et al., 1994). It is maternally inherited along with the mtDNA (Giles et al., 1980; Case and Wallace, 1981).
This gene encompasses 1811 nps of continuous coding sequence contained within a mRNA which begins with the AUA methionine start codon, ends with a UAA stop codon, and extends an additional 521 nps as 3-prime noncoding sequence before the polyadenosine tail begins. The 3-prime noncoding sequence of the MTND5 mRNA is the antisense sequence of the MTND6 sequence (Anderson et al., 1981). This mRNA is transcribed as a part of the polycistronic H-strand transcript, flanked by tRNALeu(CUN) and the 5-prime end and tRNA(Glu) on the 3-prime end. These tRNAs are cleaved from the transcript freeing transcript 5, the MTND5 mRNA. The mRNA is then polyadenylated (Anderson et al., 1981; Ojala et al., 1981; Attardi et al., 1982; Wallace et al., 1994).
The predicted polypeptide molecular mass is 66.6 kD (Anderson et al., 1981; Wallace et al., 1994). However, the apparent molecular mass on SDS-PAGE using Tris-glycine buffer is 43.5 kD (Wallace et al., 1986; Oliver et al., 1984), whereas using urea-phosphate buffer the molecular mass is 51 kD (Wallace et al., 1994).
Park et al. (2009) examined the contribution of mtDNA mutation and mitochondrial dysfunction in tumorigenesis using human cell lines carrying a frameshift in the MTND5 gene. With increasing mutant MTND5 mtDNA content, respiratory function (including oxygen consumption and ATP generation through oxidative phosphorylation) declined progressively, while lactate production and dependence on glucose increased. The reactive oxygen species (ROS) levels and apoptosis exhibited antagonistic pleiotropy associated with mitochondrial defects. The anchorage-dependence phenotype and tumor-forming capacity of cells carrying wildtype and mutant mtDNA were tested by growth assay in soft agar and subcutaneous implantation of the cells in nude mice. A cell line with a heteroplasmic MTND5 mutation showed significantly enhanced tumor growth, while cells with the same homoplasmic mutation inhibited tumor formation. Similar results were obtained from the analysis of a series of mouse cell lines carrying a MTND5 nonsense mutation. Park et al. (2009) hypothesized that the mtDNA mutations might play an important role in the early stage of cancer development, possibly through alteration of ROS generation and apoptosis.
Safra et al. (2017) developed an approach that allows the transcriptomewide mapping of N1-methyladenosine (m1A) at single-nucleotide resolution. Within the cytosol, m1A is present in a low number of mRNAs, typically at low stoichiometries, and almost invariably in tRNA T-loop-like structures, where it is introduced by the TRMT6/TRMT61A complex. Safra et al. (2017) identify a single m1A site in the mitochondrial ND5 mRNA, catalyzed by TRMT10C (615423), with methylation levels that are highly tissue-specific and tightly developmentally controlled. m1A leads to translational repression, probably through a mechanism involving ribosomal scanning or translation. Safra et al. (2017) concluded that their findings suggested that m1A on mRNA, probably because of its disruptive impact on basepairing, leads to translational repression, and is generally avoided by cells, while revealing 1 case in mitochondria where tight spatiotemporal control over m1A levels was adopted as a potential means of posttranscriptional regulation.
Heteroplasmic mutations in the MTND5 gene can result in several different mitochondrial disorders, including Leber hereditary optic neuropathy (LHON; 535000), MELAS syndrome (540000), Leigh syndrome (256000), and complex I deficiency (252010).
Nishigaki et al. (2004) found that the MTND5 gene was a hotspot for mtDNA deletions in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; 603041), an autosomal recessive multisystem disorder associated with depletion, multiple deletions, and site-specific point mutations of mtDNA. MNGIE is caused by loss-of-function mutations in the ECGF1 gene (TYMP; 131222), which result in increased levels of circulating thymidine and deoxyuridine. The authors postulated that alterations of pyrimidine nucleoside metabolism cause imbalances of mitochondrial nucleotide pools that, in turn, may cause somatic alterations of mtDNA.
Among 116 patients suspected to have an oxidative phosphorylation disease and in whom common mitochondrial mutations had been excluded, Blok et al. (2007) identified 14 pathogenic mutations in mitochondrial-encoded genes, 4 (27%) of which were in the MTND5 gene (see, e.g., 516005.0007; 516005.0008). The authors suggested that screening of this gene may be beneficial in routine diagnosis of these patients.
Piccoli et al. (2008) presented evidence that mutation in the MTND5 gene (516005.0010) may modify the onset and severity of Parkinson disease (see, e.g., PARK6; 605909) caused by nuclear mutations. See also 556500 for a discussion of Parkinson disease associated with mutations in mitochondrial genes.
Restriction site polymorphisms have been identified at the following nucleotide position for the indicated enzymes (where '+' = site gain, '-' = site loss relative to the reference sequence, Anderson et al., 1981): Alu I: -12560, +12763, +12990/12993/12996/13594, +13068, +13262, +13284, -14015; Ava II: -12629, -13367; BamHI: +13366, -14258; BstNI: -13704; Dde I: -12663, -12891, +12946, -13065, +13467; Hae II: +12949; Hae III: +13018, -13051, +13284, +13633, -13702, -13957; Hha I: +12940, +12950, -13208, +13940; HincII: +12026, -12406, -13259, -13634; HinfI: +12925, -13031, -13103, -13268, -13916; Hpa I: -12406; Mbo I: +12528, +12629, +12795/12798/12806/13374, +12849, +13004/13018/13182/13194, +13104, +13152, +13180, +13367, +13575; Msp I: +13100, +14139; Rsa I: +12345, +12345/12350/12528, +12810, +13096, -13325, +13542; Taq I: -13404, +13635, +14050/14366 (Wallace et al., 1994).
This allele changes the moderately conserved alanine at amino acid 458 to a threonine (A458T). This mutation does not in itself appear to cause LHON, but is present in about 30% of Caucasian patients as compared to 6% of random population controls. The mutation is generally associated with the primary LHON mutations MTND6*LHON14484A (516006.0001) and/or MTCYB*LHON15257A (516020.0001) and occasionally with the secondary LHON mutations MTND2*LHON5244A (516001.0002) and MTCYB*LHON15812A (516020.0002). (Brown et al., 1992; Johns and Berman, 1991; Johns et al., 1992; Johns and Neufield, 1991).
In a screening of bilateral optic atrophy patients who did not carry known primary LHON mutations, Howell et al. (1993) identified 1 patient with a transition mutation at nucleotide 13730 that resulted in the substitution of glutamic acid for glycine at position 465 of the ND5 protein. The patient was heteroplasmic for the mutation, which the authors believed was the primary event contributing to bilateral optic atrophy. Studies suggested that the mutation was of recent origin, probably within the germline of the patient's mother. The mutation was similar to the primary LHON mutation at nucleotide 14484 in the ND6 protein (516006.0001) in that it was weakly conserved and occurred within a hydrophobic region of the complex I region. Further, the patient with the 13730 mutation showed substantial recovery of vision, as do patients with the 14484 mutation. Howell et al. (1993) suggested that the screening of a broad range of optic atrophies would result in identification of additional primary or secondary LHON mutations.
Taylor et al. (2002) reported a 12706T-C transition in the MTND5 gene in a patient with Leigh syndrome (256000) and specific complex I deficiency (33% of control value in muscle mitochondria) (252010). The mutation was heteroplasmic (43% mutant load in skeletal muscle and 30% mutant load in skin fibroblasts) and changed an invariant amino acid (phe124 to leu) in a highly conserved transmembrane helix of the protein. The patient presented at age 6 years with optic atrophy. At age 20, he complained of leg weakness, and over the next several years he developed ataxia, facial weakness, impaired hearing, ophthalmoplegia, and weakness of the muscles of mastication, palate, and larynx. He died at age 24. Neuropathology revealed symmetrical foci of neuronal loss, gliosis and microcapillary proliferation in the putamen, periaqueductal gray matter, inferior olives, and cerebellar cortex. There was no family history, but the family declined further investigation.
In a patient with MELAS syndrome (540000) characterized by focal neurologic dysfunction, increased CSF lactate, and abnormalities on MRI, Liolitsa et al. (2003) identified a heteroplasmic 12770A-G transition in the MTND5 gene, resulting in a glu145-to-gly (E145G) mutation. Skeletal muscle biopsy was normal, with no ragged-red fibers or COX-negative fibers. There was a 48% mutant load in muscle.
In a patient with phenotypic overlap of MELAS syndrome (540000), Leber optic atrophy (535000), and Leigh syndrome (256000), Liolitsa et al. (2003) identified a heteroplasmic 13045A-C transversion in the MTND5 gene, resulting in a met237-to-leu (M237L) mutation. The patient had neurologic symptoms including migraine, ataxia, seizures, cognitive impairment, lesions on MRI, and ocular abnormalities. Muscle biopsy showed no ragged-red fibers or COX-negative fibers, and complex I activity was mildly reduced (252010). Mutant load was 82% in muscle.
In a patient with a progressive neurodegenerative disorder combining features of Leigh (256000) and MELAS (540000) syndromes, Crimi et al. (2003) identified a 13084A-T transversion in the MTND5 gene, resulting in a ser250-to-cys (S250C) substitution. Muscle biopsy revealed partial complex I deficiency (252010). The mutation was detected in a heteroplasmic state in the lymphocytes of the patient's mother (57%), who had migraine and optic atrophy, and younger sister (41%).
In a patient with MELAS syndrome (540000), Santorelli et al. (1997) identified a heteroplasmic 13513G-A transition in the MTND5 gene, resulting in an asp393-to-asn (D393N) substitution.
Kirby et al. (2003) identified the D393N mutation in 3 unrelated patients with Leigh syndrome (256000) and complex I deficiency (252010). The mutation was present in mutant loads of approximately 50% or less in all tissues tested, including multiple brain regions. The threshold mutant load for causing a complex I defect in cultured cells was approximately 30%. The findings suggested that the mutation causes a complex I defect when present at unusually low mutant loads and may act dominantly.
In 3 of 14 unrelated children with Leigh syndrome and complex I deficiency, Chol et al. (2003) identified the D393N mutation in the MTND5 gene. All 3 children had a peculiar MRI aspect distinct from typical Leigh syndrome: brain MRI consistently showed a specific involvement of the substantia nigra and medulla oblongata sparing the basal ganglia. The mutation, which affects an evolutionarily conserved amino acid, had previously been observed in adult patients with MELAS syndrome or an overlap of Leber hereditary optic neuropathy (LHON; 535000) and MELAS syndromes (Pulkes et al., 1999), emphasizing the clinical heterogeneity of mitochondrial DNA mutations.
Sudo et al. (2004) identified the D393N mutation in 6 of 84 (7%) Japanese patients with Leigh syndrome. The proportions of mutant mtDNA in muscles were relatively low (42 to 70%). The onset in patients with this mutation was delayed compared to those with the more common mutations at nucleotide 8993 in the MTATP6 gene (see 516060.0001 and 516060.0002), and ptosis and cardiac conduction abnormalities were frequently seen (83%). Sudo et al. (2004) suggested that the 13513G-A mutation is a frequent cause of Leigh syndrome and that patients with this mutation may have a characteristic clinical course.
In a clinical presentation case, Dickerson et al. (2005) discussed a patient with the MELAS syndrome due to the 13513G-A mutation who had onset of her illness in her early sixties, making her the oldest patient with this syndrome known to carry that specific mutation. The onset of the clinical manifestations consisted of seizures and altered mental status at the age of 61 years. Difficulty hearing began about 6 months later. The patient died about 2 years after onset. Dickerson et al. (2005) stated that among the 6 reported patients with the MELAS syndrome and the 13513G-A mutation, all had the clinical features of the disorder, including hearing loss, by their mid-forties, and most were in their second decade at onset.
Blok et al. (2007) reported 2 unrelated patients with oxidative phosphorylation defects associated with low levels of 13513G-A heteroplasmy. An 11-year-old girl presented with exercise intolerance and mild developmental delay. Brain MRI showed a subinsular cerebral infarct consistent with MELAS. She also had mild external ophthalmoplegia and strabismus. Skeletal muscle biopsy as an adult showed decreased complex I activity (58% of control). The mutation was present in blood (4 to 6%), fibroblasts (1 to 5%) and muscle (13 to 15%). A 5-month-old boy with a MELAS/Leigh phenotype showed failure to thrive, psychomotor retardation, retinitis pigmentosa, microcytic anemia, and characteristic brain lesions on MRI. He died at age 19 months after a viral infection. Skeletal muscle complex I activity was 8% of control; the mutation was present at 11 to 17% in blood, hair, and skeletal muscle. Blok et al. (2007) noted that low loads of MTND5 mutations can still result in a severe clinical phenotype because ND5 synthesis is probably the rate-limiting step for the activity of complex I.
Shanske et al. (2008) reported 12 patients with the 13513G-A mutation. The 3 adult patients had typical features of MELAS, whereas the other 9 infants and children had typical features of Leigh syndrome. Biochemical studies showed that complex I deficiency was inconsistent and generally mild, but mutation load in muscle and blood was relatively high.
In a 25-year-old man with MELAS syndrome (540000), Naini et al. (2005) identified a heteroplasmic 13042G-A transition in the MTND5 gene, resulting in an ala236-to-thr (A236T) substitution. The patient had normal psychomotor development until age 17 years, when he had a tonic-clonic seizure. At age 20 years, he had a severe stroke necessitating prolonged rehabilitation. In the following years, he experienced more stroke-like episodes, partial seizures, memory loss, migraine-like headaches, myoclonus, exercise intolerance, and osteoporosis with vertebral fracture. Naini et al. (2005) noted the similarities to MERRF syndrome (545000), although there were no ragged-red fibers on muscle biopsy. Muscle biopsy showed decreased activity of complex I. The mutation was heteroplasmic in both muscle (90%) and blood (50%). The patient's mother reportedly had multiple strokes and seizures since her thirties, as well as migraine headaches and mild hearing loss. She did not have myoclonus.
Blok et al. (2007) reported a boy with a Leigh-like syndrome (see 256000) who was heteroplasmic for the 13042G-A mutation, which was identified in blood (77%), muscle (84%), and fibroblasts (86%). He presented at age 3 years with ataxia, internuclear ophthalmoplegia, increased serum and CSF lactate, and hyperintensities in the pons and midbrain. Skeletal muscle histology was normal. The patient's unaffected mother and grandmother also carried the mutation at much lower levels (2 to 25% in various tissues).
In a man with Leber optic atrophy (535000) with onset at age 20 years, Mayorov et al. (2005) identified a heteroplasmic 12848C-T transition in a highly conserved region of the MTND5 gene, resulting in an ala171-to-val (A171V) substitution. Lymphoblasts derived from the proband contained 54% mutant mtDNA, whereas lymphoblasts from his unaffected mother contained 37% mutant mtDNA.
In a patient with early-onset Parkinson disease (PARK6; 605909) due to a homozygous mutation in the PINK1 gene (608309.0002), Piccoli et al. (2008) identified a homoplasmic 12397A-G mutation in the MTND5 gene and a homoplasmic mutation in the MTND6 gene (516006.0008). The 12397A-G mutation results in a thr21-to-ala (T21A) substitution in a hydrophilic segment that is likely exposed to the intermembrane mitochondrial space. The patient had onset at age 22 years. His mother, who was heterozygous for the PINK1 mutation, was also homoplasmic for both mitochondrial mutations and showed disease onset at age 53. The father, who was heterozygous for the PINK1 mutation only, was unaffected at age 79. Biochemical studies of the proband's fibroblasts showed mitochondrial dysfunction, with decreased amounts of cytochrome c oxidase, impaired complex I activity, and increased hydrogen peroxide generation. Piccoli et al. (2008) concluded that the presence of the mitochondrial mutations in combination with the PINK1 mutation may have accelerated the onset of the disease.
Liu et al. (2011) investigated the molecular pathogenesis of LHON (535000) in 6 Han Chinese families in which 9 (6 males/3 females) of 86 matrilineal relatives exhibited variable severity and age of onset of optic neuropathy. The average age of onset was 20 years and the penetrance of visual impairment averaged 10.8%. Molecular analysis of mtDNA in these families identified the homoplasmic ND5 12338T-C mutation and a distinct set of variants belonging to the Asian haplogroup F2. The mutation resulted in the replacement of the first amino acid, translation-initiating methionine with a threonine (M1T). This methionine in ND5 is an extraordinarily conserved residue from bacteria to human mitochondria. The 12338T-C mutation was present in the maternal lineage of the 6 pedigrees and not in 178 Chinese controls.
Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., Young, I. G. Sequence and organization of the human mitochondrial genome. Nature 290: 457-465, 1981. [PubMed: 7219534] [Full Text: https://doi.org/10.1038/290457a0]
Arizmendi, J. M., Skehel, J. M., Runswick, M. J., Fearnley, I. M., Walker, J. E. Complementary DNA sequences of two 14.5 kDa subunits of NADH:ubiquinone oxidoreductase from bovine heart mitochondria. Complementation of the primary structure of the complex. FEBS Lett. 313: 80-84, 1992. [PubMed: 1426273] [Full Text: https://doi.org/10.1016/0014-5793(92)81189-s]
Attardi, G., Chomyn, A., Doolittle, R. F., Mariottini, P., Ragan, C. I. Seven unidentified reading frames of human mitochondrial DNA encode subunits of the respiratory chain NADH dehydrogenase. Cold Spring Harbor Symp. Quant. Biol. 51: 103-114, 1986. [PubMed: 3472707] [Full Text: https://doi.org/10.1101/sqb.1986.051.01.013]
Attardi, G., Chomyn, A., Montoya, J., Ojala, D. Identification and mapping of human mitochondrial genes. Cytogenet. Cell Genet. 32: 85-98, 1982. [PubMed: 7140372] [Full Text: https://doi.org/10.1159/000131689]
Blok, M. J., Spruijt, L., de Coo, I. F. M., Schoonderwoerd, K., Hendrickx, A., Smeets, H. J. Mutations in the ND5 subunit of complex I of the mitochondrial DNA are a frequent cause of oxidative phosphorylation disease. J. Med. Genet. 44: e74, 2007. Note: Electronic Article. [PubMed: 17400793] [Full Text: https://doi.org/10.1136/jmg.2006.045716]
Brown, M. D., Voljavec, A. S., Lott, M. T., MacDonald, I., Wallace, D. C. Leber's hereditary optic neuropathy; a model for mitochondrial neurodegenerative diseases. FASEB J. 6: 2791-2799, 1992. [PubMed: 1634041] [Full Text: https://doi.org/10.1096/fasebj.6.10.1634041]
Brown, M. D., Voljavec, A. S., Lott, M. T., Torroni, A., Yang, C.-C., Wallace, D. C. Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy. Genetics 130: 163-173, 1992. [PubMed: 1732158] [Full Text: https://doi.org/10.1093/genetics/130.1.163]
Case, J. T., Wallace, D. C. Maternal inheritance of mitochondrial DNA polymorphisms in cultured human fibroblasts. Somat. Cell Genet. 7: 103-108, 1981. [PubMed: 6261411] [Full Text: https://doi.org/10.1007/BF01544751]
Chol, M., Lebon, S., Benit, P., Chretien, D., de Lonlay, P., Goldenberg, A., Odent, S., Hertz-Pannier, L., Vincent-Delorme, C., Cormier-Daire, V., Rustin, P., Rotig, A., Munnich, A. The mitochondrial DNA G13513A MELAS mutation in the NADH dehydrogenase 5 gene is a frequent cause of Leigh-like syndrome with isolated complex I deficiency. J. Med. Genet. 40: 188-191, 2003. [PubMed: 12624137] [Full Text: https://doi.org/10.1136/jmg.40.3.188]
Chomyn, A., Cleeter, W. J., Ragan, C. I., Riley, M., Doolittle, R. F., Attardi, G. URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit. Science 234: 614-618, 1986. [PubMed: 3764430] [Full Text: https://doi.org/10.1126/science.3764430]
Chomyn, A., Mariottini, P., Cleeter, M. W. J., Ragan, C. I., Matsuno-Yagi, A., Hatefi, Y., Doolittle, R. G., Attardi, G. Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase. Nature 314: 592-597, 1985. [PubMed: 3921850] [Full Text: https://doi.org/10.1038/314592a0]
Crimi, M., Galbiati, S., Moroni, I., Bordoni, A., Perini, M. P., Lamantea, E., Sciacco, M., Zeviani, M., Biunno, I., Moggio, M., Scarlato, G., Comi, G. P. A missense mutation in the mitochondrial ND5 gene associated with a Leigh-MELAS overlap syndrome. Neurology 60: 1857-1861, 2003. [PubMed: 12796552] [Full Text: https://doi.org/10.1212/01.wnl.0000066048.72780.69]
Dickerson, B. C., Holtzman, D., Grant, P. E., Tian, D. Case 36-2005: a 61-year-old woman with seizure, disturbed gait, and altered mental status. New Eng. J. Med. 353: 2271-2280, 2005. [PubMed: 16306525] [Full Text: https://doi.org/10.1056/NEJMcpc059032]
Giles, R. E., Blanc, H., Cann, H. M., Wallace, D. C. Maternal inheritance of human mitochondrial DNA. Proc. Nat. Acad. Sci. 77: 6715-6719, 1980. [PubMed: 6256757] [Full Text: https://doi.org/10.1073/pnas.77.11.6715]
Howell, N., Halvorson, S., Burns, J., McCullough, D. A., Poulton, J. When does bilateral optic atrophy become Leber hereditary optic neuropathy? (Letter) Am. J. Hum. Genet. 53: 959-963, 1993. [PubMed: 8213825]
Johns, D. R., Berman, J. Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic atrophy. Biochem. Biophys. Res. Commun. 174: 1324-1330, 1991. [PubMed: 1900003] [Full Text: https://doi.org/10.1016/0006-291x(91)91567-v]
Johns, D. R., Neufeld, M. J., Park, R. D. An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem. Biophys. Res. Commun. 187: 1551-1557, 1992. [PubMed: 1417830] [Full Text: https://doi.org/10.1016/0006-291x(92)90479-5]
Johns, D. R., Neufield, M. J. Cytochrome b mutations in Leber hereditary optic neuropathy. Biochem. Biophys. Res. Commun. 181: 1358-1364, 1991. [PubMed: 1764087] [Full Text: https://doi.org/10.1016/0006-291x(91)92088-2]
Kirby, D. M., Boneh, A., Chow, C. W., Ohtake, A., Ryan, M. T., Thyagarajan, D., Thorburn, D. R. Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh's disease. Ann. Neurol. 54: 473-478, 2003. [PubMed: 14520659] [Full Text: https://doi.org/10.1002/ana.10687]
Liolitsa, D., Rahman, S., Benton, S., Carr, L. J., Hanna, M. G. Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations? Ann. Neurol. 53: 128-132, 2003. [PubMed: 12509858] [Full Text: https://doi.org/10.1002/ana.10435]
Liu, X.-L., Zhou, X., Zhou, J., Zhao, F., Zhang, J., Li, C., Ji, Y., Zhang, Y., Wei, Q.-P., Sun, Y.-H., Yang, L., Lin, B., Yuan, Y., Li, Y., Qu, J., Guan, M.-X. Leber's hereditary optic neuropathy is associated with the T12338C mutation in mitochondrial ND5 gene in six Han Chinese families. Ophthalmology 118: 978-985, 2011. [PubMed: 21131053] [Full Text: https://doi.org/10.1016/j.ophtha.2010.09.003]
Mayorov, V., Biousse, V., Newman, N. J., Brown, M. D. The role of the ND5 gene in LHON: characterization of a new, heteroplasmic LHON mutation. Ann. Neurol. 58: 807-811, 2005. [PubMed: 16240359] [Full Text: https://doi.org/10.1002/ana.20669]
Montoya, J., Ojala, D., Attardi, G. Distinctive features of the 5'-terminal sequences of the human mitochondrial mRNAs. Nature 290: 465-470, 1981. [PubMed: 7219535] [Full Text: https://doi.org/10.1038/290465a0]
Naini, A. B., Lu, J., Kaufmann, P., Bernstein, R. A., Mancuso, M., Bonilla, E., Hirano, M., DiMauro, S. Novel mitochondrial DNA ND5 mutation in a patient with clinical features of MELAS and MERRF. Arch. Neurol. 62: 473-476, 2005. [PubMed: 15767514] [Full Text: https://doi.org/10.1001/archneur.62.3.473]
Nishigaki, Y., Marti, R., Hirano, M. ND5 is a hot-spot for multiple atypical mitochondrial DNA deletions in mitochondrial neurogastrointestinal encephalomyopathy. Hum. Molec. Genet. 13: 91-101, 2004. [PubMed: 14613972] [Full Text: https://doi.org/10.1093/hmg/ddh010]
Ojala, D., Montoya, J., Attardi, G. tRNA punctuation model of RNA processing in human mitochondria. Nature 290: 470-474, 1981. [PubMed: 7219536] [Full Text: https://doi.org/10.1038/290470a0]
Oliver, N. A., McCarthy, J., Wallace, D. C. Comparison of mitochondrially synthesized polypeptides of human, mouse, and monkey cell lines by a two-dimensional protease gel system. Somat. Cell Molec. Genet. 10: 639-643, 1984. [PubMed: 6438810] [Full Text: https://doi.org/10.1007/BF01535230]
Oliver, N. A., Wallace, D. C. Assignment of two mitochondrially synthesized polypeptides to human mitochondrial DNA and their use in the study of intracellular mitochondrial interaction. Molec. Cell. Biol. 2: 30-41, 1982. [PubMed: 6955589] [Full Text: https://doi.org/10.1128/mcb.2.1.30-41.1982]
Park, J. S., Sharma, L. K., Li, H., Xiang, R., Holstein, D., Wu, J., Lechleiter, J., Naylor, S. L., Deng, J. J., Lu, J., Bai, Y. A heteroplasmic, not homoplasmic, mitochondrial DNA mutation promotes tumorigenesis via alteration in reactive oxygen species generation and apoptosis. Hum. Molec. Genet. 18: 1578-1589, 2009. [PubMed: 19208652] [Full Text: https://doi.org/10.1093/hmg/ddp069]
Piccoli, C., Ripoli, M., Quarato, G., Scrima, R., D'Aprile, A., Boffoli, D., Margaglione, M., Criscuolo, C., De Michele, G., Sardanelli, A., Papa, S., Capitanio, N. Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism. (Letter) J. Med. Genet. 45: 596-602, 2008. [PubMed: 18524835] [Full Text: https://doi.org/10.1136/jmg.2008.058628]
Pulkes, T., Eunson, L., Patterson, V., Siddiqui, A., Wood, N. W., Nelson, I. P., Morgan-Hughes, J. A., Hanna, M. G. The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS. Ann. Neurol. 46: 916-919, 1999. Note: Erratum: Ann. Neurol. 47: 841 only, 2000. [PubMed: 10589546] [Full Text: https://doi.org/10.1002/1531-8249(199912)46:6<916::aid-ana16>3.0.co;2-r]
Ragan, C. I. Structure of NADH-ubiquinone reductase (complex I). Curr. Top. Bioenerg. 15: 1-36, 1987.
Safra, M., Sas-Chen, A., Nir, R., Winkler, R., Nachshon, A., Bar-Yaacov, D., Erlacher, M., Rossmanith, W., Stern-Ginossar, N., Schwartz, S. The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature 551: 251-255, 2017. [PubMed: 29072297] [Full Text: https://doi.org/10.1038/nature24456]
Santorelli, F. M., Tanji, K., Kulikova, R., Shanske, S., Vilarinho, L., Hays, A. P., DiMauro, S. Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS. Biochem. Biophys. Res. Commun. 238: 326-328, 1997. [PubMed: 9299505] [Full Text: https://doi.org/10.1006/bbrc.1997.7167]
Shanske, S., Coku, J., Lu, J., Ganesh, J., Krishna, S., Tanji, K., Bonilla, E., Naini, A. B., Hirano, M., DiMauro, S. The G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome. Arch. Neurol. 65: 368-372, 2008. [PubMed: 18332249] [Full Text: https://doi.org/10.1001/archneurol.2007.67]
Shoffner, J. M., Wallace, D. C. Oxidative phosphorylation diseases.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. Vol. 1. New York: McGraw-Hill (pub.) 1995. Pp. 1535-1609.
Sudo, A., Honzawa, S., Nonaka, I., Goto, Y. Leigh syndrome caused by mitochondrial DNA G13513A mutation: frequency and clinical features in Japan. J. Hum. Genet. 49: 92-96, 2004. [PubMed: 14730434] [Full Text: https://doi.org/10.1007/s10038-003-0116-1]
Taylor, R. W., Morris, A. A. M., Hutchinson, M., Turnbull, D. M. Leigh disease associated with a novel mitochondrial DNA ND5 mutation. Europ. J. Hum. Genet. 10: 141-144, 2002. [PubMed: 11938446] [Full Text: https://doi.org/10.1038/sj.ejhg.5200773]
Walker, J. E., Arizmendi, J. M., Dupuis, A., Fearnley, I. M., Finel, M., Medd, S. M., Pilkington, S. J., Runswick, M. J., Skehel, J. M. Sequences of 20 subunits of NADH:ubiquinone oxidoreductase from bovine heart mitochondria. Application of a novel strategy for sequencing proteins using the polymerase chain reaction. J. Molec. Biol. 226: 1051, 1992. [PubMed: 1518044] [Full Text: https://doi.org/10.1016/0022-2836(92)91052-q]
Wallace, D. C., Lott, M. T., Torroni, A., Brown, M. D., Shoffner, J. M. Report of the Committee on human mitochondrial DNA.In: Cuticchia, A. J.; Pearson, P. L. (eds.) : Human Gene Mapping, 1993: A Compendium. Baltimore: Johns Hopkins Univ. Press (pub.) 1994. Pp. 813-845.
Wallace, D. C., Yang, J., Ye, J., Lott, M. T., Oliver, N. A., McCarthy, J. Computer prediction of peptide maps: Assignment of polypeptides to human and mouse mitochondrial DNA genes by analysis of two-dimensional-proteolytic digest gels. Am. J. Hum. Genet. 38: 461, 1986. [PubMed: 3518425]