Alternative titles; symbols
HGNC Approved Gene Symbol: MT-ND6
SNOMEDCT: 39925003, 58610003, 89439007; ICD10CM: E88.41, H47.22;
Subunit 6 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 electrons from NADH, transfers them to ubiquinone (Coenzyme Q10), and uses the energy released to pump protons across the mitochondria inner membrane. Complex I is more fully described under 516000. MTND6 has been proposed to be a component of the iron-protein fragment (Chomyn et al., 1986).
The predicted polypeptide has a molecular weight of 18.6 kD (Anderson et al., 1981). However, its apparent MW on SDS-polyacrylamide gels (PAGE) using Tris-glycine buffer is 16.7 kD (Oliver et al., 1984; Oliver and Wallace, 1982; Wallace et al., 1986), and the apparent MW on urea-phosphate gels is also close to the predicted molecular weight (Chomyn et al., 1986).
MTND6 is encoded by the cytosine-rich light (L) strand of the mtDNA and located between nucleotide pairs (nps) 14149 and 14673 (Anderson et al., 1981; Wallace et al., 1994). It is maternally inherited along with the mtDNA (Giles et al., 1980; Case and Wallace, 1981).
The MTND6 polypeptide encompasses 524 nps of continuous coding sequence. The gene contains no introns, begins with the AUG methionine start codon and ends with a UCG codon which has been proposed as the stop signal. The mRNA has a 3-prime noncoding sequence which includes 1811 nps corresponding to the anti-sense of the MTND5 coding sequence and may also extend through the tRNALeu(CUN), tRNASer(AGY), tRNAHis, and MTND4 genes, ending at tRNAArg. It is transcribed as a part of the large polycistronic L-strand transcript and is flanked on the 5-prime end by the tRNAGlu. Processing occurs at tRNAGlu and tRNAArg to give the stable L-strand transcript 3 (Anderson et al., 1981; Ojala et al., 1981; Attardi et al., 1982; Montoya et al., 1981; Wallace et al., 1994). Further processing at tRNALeu(CUN) could give a mRNA equivalent in length to the H-strand transcript 5 for MTND5.
Temperley et al. (2010) demonstrated that human mitoribosomes do invoke -1 frameshift at the AGA and AGG codons predicted to terminate the 2 ORFs in MTCO1 (516030) and MTND6, respectively. As a consequence, both ORFs terminate in the standard UAG codon, necessitating the use of only a single mitochondrial release factor.
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: -14304, +14322, +14509; BamHI: -14258; Dde I: +14385, +14394, -14608; Hae III: +14279; HincII: -14199, +14648/15765; HinfI: +14268, -14368; Mbo I: -14259, +14279; Msp I: +14567;; Rsa I: +14347; Taq I: +14050/14366, +14168 (Wallace et al., 1994).
Several allelic variants have been reported for MTND6, most associated with Leber hereditary optic neuropathy (LHON): MTND6*LHON14484C (516006.0001), MTND6*LDYT14459A (516006.0002), and MTND6*LDYT14596A (516006.0003). Ravn et al. (2001) identified a mutation, MTND6*MELAS14453A (516006.0005), associated with MELAS syndrome (540000).
Most mtDNA mutations that cause human disease are mild to moderately deleterious, yet many random mtDNA changes would be expected to be severe. To determine the fate of the more severe mtDNA mutations, Fan et al. (2008) introduced mtDNAs containing 2 mutations that affect oxidative phosphorylation, one mild and one severe, into the female mouse germ line. The severe mutation, 13885insC, created a frameshift mutation in the ND6 gene. When homoplasmic, this mutation inactivates oxidative phosphorylation complex I. The mild mutation was a missense mutation, T6589C, in the cytochrome c oxidase subunit 1 gene (COI; 516030) that converted the highly conserved valine at codon 421 to alanine (V421A). When homoplasmic, this mutation reduces the activity of oxidative phosphorylation complex IV by 50%. Fan et al. (2008) observed that the severe ND6 mutation was selectively eliminated during oogenesis within 4 generations, whereas the milder COI mutation was retained throughout multiple generations even though the offspring consistently developed mitochondrial myopathy and cardiomyopathy. Thus, Fan et al. (2008) concluded that severe mitochondrial DNA mutations appear to be selectively eliminated from the female germ line, thereby minimizing their impact on population fitness.
Piccoli et al. (2008) presented evidence that mutations in the MTND6 gene (516006.0008) 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.
In an oncocytic tumor (553000) of the adnexal lacrimal glands of the conjunctiva, Bartoletti-Stella et al. (2011) analyzed the entire mtDNA sequence and identified a frameshift mutation in MTND6 (516006.0009).
Ishikawa et al. (2008) used cytoplasmic hybrid (cybrid) technology to replace the endogenous mtDNA in a mouse tumor cell line that was poorly metastatic with mtDNA from a cell line that was highly metastatic, and vice versa. Using assays of metastasis in mice, they found that the recipient tumor cells acquired the metastatic potential of the transferred mtDNA. The mtDNA conferring high metastatic potential contained G13997A and 13885insC mutations in the gene encoding NADH dehydrogenase subunit 6 (ND6). These mutations produced a deficiency in respiratory complex I activity and were associated with overproduction of reactive oxygen species. Pretreatment of the highly metastatic tumor cells with reactive oxygen species scavengers suppressed their metastatic potential in mice. Ishikawa et al. (2008) concluded that mtDNA mutations can contribute to tumor progression by enhancing the metastatic potential of tumor cells.
This allele changes the weakly conserved methionine at amino acid 64 to a valine (M64V). It is found in approximately 15% of Leber optic atrophy (LHON; 535000) patients, but has not been observed in any controls (less than 0.4%). It generally occurs in association with other LHON mutations. In one large Australian pedigree manifesting LHON and neurological disease, this allele occurred together with MTND1*LHON4160C (516000.0002). In most other pedigrees, the MTND6*LHON14484C allele is found together with MTND5*LHON13708A (516005.0001) in most LHON pedigrees, MTCYB*LHON15257A (516020.0001) or MTND1*LHON3394C (516000.0004) in a subset of these, and MTCYB*LHON15812A (516005.0001) and in one case MTND2*LHON5244A (516001.0002) in a subset of the MTCTB*LHON15257A pedigrees. The MTND6*LHON14484C + MTND1*LHON4160C pedigree is homoplasmic, with 76% of the maternal relatives affected, of which 54% are males. In the other MTND1*LHON 4160C pedigrees, the MTND6*LHON14484C pedigrees have all been homoplasmic except one, and between 27 and 80% of maternal relatives are affected, 68% of these being males. Patients with this mutation have an unusually high predilection for visual recovery (37%) (Brown et al., 1992; Johns et al. (1992, 1993); Mackey and Howell, 1992).
Brown et al. (1997) demonstrated that the 14484C mutation, unlike the other 2 primary LHON mutations (3460 and 11778), is not distributed on the phylogeny in proportion to the frequencies of the major Caucasian mtDNA haplogroups found in North America. The 14484 mutation was shown to occur on the haplogroup J background more frequently than expected, consistent with the observation that approximately 75% of worldwide 14484-positive LHON patients occur in association with haplogroup J. The 11778 mutation (516003.0001) also exhibited a moderate clustering on haplogroup J. Their finding suggested a pathogenic role for a subset of LHON secondary mutations and their interaction with primary mutations, and provides support for a polygenic model for LHON expression in some cases.
Carelli et al. (1998) described LHON in a patient of North African origin carrying the 14484 mutation of the ND6 gene.
Macmillan et al. (2000) analyzed 27 independently referred French-Canadian families with LHON and the 14484T-C mutation, all of which were homoplasmic for the 14484T-C mutation. They found 8 homoplasmic transition mutations (16069C-T, 16126T-C, 16213G-A, 73A-G, 185G-A, 228G-A, 263A-G, and 295C-T), compared with the Cambridge sequence of the Sanger group (Anderson et al., 1981), in the families with the 14484T-C mutation. Of the 27 families analyzed, 26 shared identical substitutions at all 8 sites that were different from the Cambridge sequence. Six of these mutations were found only in families with the 14484T-C mutation and not in either the family with 11778G-A or the family without LHON. The data were interpreted as demonstrating that French-Canadian families with LHON and the 14484T-C mutation probably share the same maternal lineage and suggested that they may all have been derived from a single founder woman.
The first report of LHON in French Canadians dated from 1970, when a large pedigree from southwestern Quebec was described by Brunette and Bernier (1970). A high rate (19.5%) of spontaneous recovery was observed in this large kindred: 4 patients regained a visual acuity of 20/50 or better in at least 1 eye and 6 regained bilateral normal vision.
Nishioka et al. (2003) identified the 14484T-C mutation in a 6-generation Indonesian LHON family. All of the maternal lineages had the 14484T-C mutation in homoplasmic form. Penetrance of the disease (33.3%) and male predominance (3:1) was similar to other worldwide LHON with the 14484T-C mutation. The incidence of offspring born to affected mothers was no different from that of unaffected mothers, and the age distribution of cases was no higher than that of asymptomatic carriers. Eight secondary mutations were sought but not detected. Patients of this family belonged to haplogroup M. These findings supported the idea that the mtDNA backgrounds involved in the expression of LHON mutations in southeast Asians are different from those of Europeans.
In platelet submitochondrial particles from 9 individuals with the 14484T-C mutation, Carelli et al. (1999) found no difference in overall complex I activity compared to controls. However, in the particles with the mutation, they detected significantly increased sensitivity to 2 inhibitors at the ubiquinol product site, myxothiazol and nonylbenzoquinol. The mutation affects the highly conserved helix C, the interaction site of ubiquinol products. Carelli et al. (1999) noted that the biochemical defect caused by the 14484T-C change resembles that reported for the ND4 11778 mutation (516003.0001).
Howell et al. (2003) determined the complete mtDNA sequences of 63 Dutch pedigrees with LHON, 56 of which carried 1 of the classic LHON mutations at nucleotide 3460 (516000.0001), 11778 (516003.0001), or 14484. The most striking incidence in which the mtDNA was either identical or related by descent was a haplogroup J mtDNA that carried the 14484 LHON mutation. In 7 of the pedigrees, 4 different but related mitochondrial genotypes were identified. The control region of the founder sequence for these Dutch pedigrees with LHON matched the control region sequence that Macmillan et al. (2000) identified in the founder mtDNA of French-Canadian pedigrees with LHON. In addition, Howell et al. (2003) obtained a perfect match between the Dutch 14484 founder sequence and the complete mtDNA sequences of 2 Canadian pedigrees with LHON. These results indicated that these Dutch and French-Canadian 14484 pedigrees with LHON shared a common ancestor, that the single origin of the 14484 mutation in this 'megalineage' occurred before the year 1600, and that there is a 14484/haplogroup J founder effect. Howell et al. (2003) estimated that this lineage (including the 14484 LHON mutation) arose 900 to 1,800 years ago.
Using genealogic reconstructions of maternal lineages, Laberge et al. (2005) identified a woman married in Quebec City in 1669 as the shared female ancestor for 11 of 13 French Canadian individuals with the T14484C mutation who were not previously known to be related. The individuals carried identical mitochondrial haplogroups.
Elliott et al. (2008) determined the frequency of 10 mitochondrial point mutations in 3,168 neonatal cord blood samples from sequential live births in North Cumbria in England, analyzing matched maternal blood samples to estimate the de novo mutation rate. Mitochondrial DNA mutations were detected in 15 offspring (0.54%, 95% confidence interval = 0.30-0.89%). Of these live births, 0.00107% (95% confidence interval = 0.00087-0.0127) harbored a mutation not detected in the mother's blood, providing an estimate of the de novo mutation rate. The mitochondrial 14484T-C mutation was only found on subbranches of mtDNA haplogroup J. Elliott et al. (2008) concluded that at least 1 in 200 healthy humans harbors a pathogenic mitochondrial DNA mutation that potentially causes disease in the offspring of female carriers. The exclusive detection of mitochondrial 1448T-C on haplogroup J implicates the background mitochondrial DNA haplotype in mutagenesis.
In affected members of a large Hispanic family with Leber optic atrophy and dystonia (500001), Jun et al. (1994) identified a heteroplasmic 14459G-A transition in the MTND6 gene. This mutation results in an ala72-to-val (A72V) substitution. Leber optic atrophy predominated in the early generations and dystonia together with bilateral striatal necrosis was found in later generations. Among members of the later generations, 48% of the maternal relatives manifested dystonia, 10% LHON, and 3% LHON and dystonia.
Shoffner et al. (1995) identified a heteroplasmic 14459G-A mutation in a mother and daughter with isolated LHON (535000) and in an unrelated girl with childhood-onset generalized dystonia. The daughter in the first family showed unilateral lesions in the basal ganglia on MRI, whereas the child in the second family had extensive bilateral lesions in the basal ganglia. Although the child with dystonia was severely affected, with dysarthria, quadriparesis, scoliosis, and pes cavus, intelligence was normal. The mother in the first family showed 50% heteroplasmy for the mutation in leukocytes, whereas her daughter showed homoplasmy in leukocytes and muscle. The girl in the second family showed 50% heteroplasmy for the mutation in skeletal muscle.
In 3 patients with Leigh syndrome (256000) from 2 unrelated families, Kirby et al. (2000) identified the 14459G-A mutation in the MTND6 gene. There was no evidence of Leber optic atrophy or dystonia.
Gropman et al. (2004) reported a family with a homoplasmic 14459G-A mtDNA mutation and a broad spectrum of clinical manifestations due to complex I deficiency (252010). The proband had anarthria, dystonia, spasticity, and mild encephalopathy, and an MRI revealed bilateral, symmetric basal ganglia lucencies associated with cerebral and systemic lactic acidosis. Among other family members with the mutation, some were asymptomatic and others were symptomatic with variable clinical and laboratory features, confirming the heterogeneous phenotype of homoplasmic 14459G-A mtDNA mutations, even within the same family.
Watanabe et al. (2006) identified the 14459G-A mutation in 2 Japanese sisters with childhood-onset dystonia, mental deterioration, adult-onset LHON, and basal ganglia lesions.
In a large Dutch kindred in which Leber optic atrophy was associated with hereditary spastic dystonia (see 500001 and 535000) in some members whereas only 1 type of abnormality was found in others, De Vries et al. (1996) found 2 previously unreported mtDNA mutations. One was a heteroplasmic A-to-G transition at nucleotide position 11696 in the ND4 gene (516003.0003) that resulted in the substitution of an isoleucine for valine at amino acid position 312. A second mutation, a homoplasmic T-to-A transition at nucleotide position 14596 in the ND6 gene, resulted in the substitution of a methionine for isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy showed severe complex I deficiency.
Chinnery et al. (2001) described 2 pedigrees with Leber optic atrophy (535000) that harbored the same novel point mutation in the MTND6 gene, i.e., a 14495A-G change resulting in a leu-to-ser substitution. The mutation was heteroplasmic in both families, and sequencing of the mitochondrial genome confirmed that the mutation arose on 2 independent occasions.
In a sporadic case of MELAS syndrome (540000), Ravn et al. (2001) identified a heteroplasmic G-to-A transition at nucleotide 14453 of the ND6 gene, resulting in an ala74-to-val (A74V) substitution. The patient was a 7-year-old girl with normal development until the age of 2 years. Between 2 and 3 years of age, she had episodes of vomiting followed by ketotic acidosis. She developed myoclonic epilepsy, general weakness, and ataxia with intermitting dystonia. Magnetic resonance scans showed cerebellar hypoplasia and multiple infarctions in both hemispheres. A muscle biopsy revealed lipid storage myopathy with normal mitochondria on electron microscopy. The patient developed episodes of lethargy, lactic acidosis, and alternating uniparesis. Ophthalmologic examination revealed no sign of atrophy of the optic nerve but abolished visual evoked potentials (VEP). The mother was healthy, with no history of a mitochondrial disorder. Mitochondrial enzyme analysis in the patient showed a decreased activity of complex I in muscle. Sequencing of the entire mtDNA, except part of the D loop, revealed heteroplasmy for the 14453G-A mutation in 82% of the mtDNA of the patient's muscle and 78% in blood. The mutation was not detected in the blood of the mother nor in 50 healthy controls. In addition to the 14453G-A mutation, Ravn et al. (2001) identified 2 other homoplasmic mutations in the mtDNA of their patient, 5628T-C in the MTTA gene (590000) and 13535A-G in the MTND5 gene (516005), which might have contributed to the observed decrease in activity of complex I and the severe phenotype of the patient.
In 2 maternally related males with Leber optic atrophy (535000) characterized by visual recovery, Valentino et al. (2002) identified a homoplasmic 14482C-A transversion in the MTND6 gene, resulting in a met64-to-ile change in an area known to be a mutation hotspot. Sequencing of the area showed that the mutation was found on a haplogroup J mtDNA background, similar to the 14484T-C mutation (516006.0001), which results in a met64-to-val substitution. Methionine, isoleucine, and valine are all hydrophobic.
In a male infant with Leigh syndrome (256000), Ugalde et al. (2003) identified a heteroplasmic 14487T-C transition in the MTND6 gene, resulting in a met63-to-val (M63V) substitution. The patient presented at 4 months of age with tonic-clonic seizures, and was later found to have motor retardation, hypotonia, deafness, pyramidal and extrapyramidal tract signs, and episodic brainstem events with oculomotor palsies, strabismus, and recurrent apnea. Laboratory studies showed lactic acidemia and basal ganglia lesions. He died at age 7 months. The patient's mother had 24% mutant load in blood, and the patient had 65% mutant load in muscle and liver, and 86% mutant load in fibroblasts. Further studies showed that the mutation occurred in the most conserved transmembrane helix of the protein and caused an impaired assembly of complex I (252010). Ugalde et al. (2003) commented on the severe phenotypic expression of the M63V mutation.
In 2 unrelated males with progressive generalized dystonia and bilateral striatal necrosis beginning at ages 4 and 6 years, respectively, Solano et al. (2003) identified the M63V mutation. In 1 patient, there was a high proportion of mutant mtDNA in muscle (93%) and in blood (67%). His unaffected mother showed 26% heteroplasmy in blood. Biochemical analysis showed isolated complex I deficiency. Solano et al. (2003) noted that other reports (e.g., Funalot et al., 2002) had found association between mutation in MTND6 and dystonia and bilateral striatal necrosis.
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 14319T-C mutation in the MTND6 gene and a homoplasmic mutation in the MTND6 gene (516006.0010). The 14319T-C mutation results in an asn119-to-asp (N119D) substitution in the fifth of 6 predicted transmembrane helices. 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 was heterozygous for the PINK1 mutation only and 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.
In an oncocytic tumor (553000) of the adnexal lacrimal glands of the conjunctiva, Bartoletti-Stella et al. (2011) identified a 1-bp insertion (14249insC) in the MTND6 gene, predicted to cause a frameshift and hamper assembly of complex I. The mutation appeared to be heteroplasmic in the tumor, which was confirmed by immunohistochemical analysis showing that MTND6 expression was much fainter in the oncocytic neoplasm compared to nonneoplastic tissue. Ki67 staining revealed a low proliferation index of 1.8%, consistent with the benign nature of the case.
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