Alternative titles; symbols
HGNC Approved Gene Symbol: MT-TK
SNOMEDCT: 230426003, 237619009, 29570005, 718214007; ICD10CM: E88.42, G31.82;
The mitochondrial tRNA for lysine is encoded by nucleotides 8295-8364.
Chomyn et al. (1994) demonstrated the feasibility of using human blood platelets as donors of mitochondria for the repopulation of nucleotide DNA-less cells. The approach was applied to platelets from several normal persons and one individual affected by MERRF (545000). Compared with normal individuals, a much greater variability in restoration of respiratory capacity was observed among the transformants derived from the MERRF patient; this was found to be related to the presence and amount of the mitochondrial tRNA(lys) mutation associated with the MERRF syndrome. With certain caveats, the method should be a useful way to investigate defects in the respiratory chain in neurodegenerative disorders, such as Alzheimer or Parkinson disease, or in aging.
Kinetoplastid protozoa, including Leishmania, have evolved specialized systems for importing nucleus-encoded tRNAs into mitochondria. Mahata et al. (2006) found that the Leishmania RNA import complex could enter human cells by a caveolin-1 (601047)-dependent pathway, where it induced import of endogenous cytosolic tRNAs, including tRNA-lys, and restored mitochondrial function in a cybrid harboring a mutant mitochondrial MTTK gene. Mahata et al. (2006) suggested that the use of protein complexes to modulate mitochondrial function may help in the management of mitochondrial tRNA-associated neuromyopathies.
Recombination of mtDNA has been described in plants, fungi, protists, muscles, and fish (Rokas et al., 2003). In the human, however, mitochondrial DNA recombination was thought not to occur (Pakendorf and Stoneking, 2005). Kraytsberg et al. (2004) provided the first experimental evidence of mtDNA recombination in the skeletal muscle of an individual with biparental inheritance of the mitochondrial genome. Furthermore, in a set of skeletal-muscle samples from individuals with multiple heteroplasmy (who carried a mixture of wildtype and mutated alleles at more that 1 locus in the mitochondrial genomes), Zsurka et al. (2005) were able to show the frequent presence of recombinant mtDNA molecules. Zsurka et al. (2007) presented experimental data of 2 double heteroplasmic families that strongly suggested that recombinant mtDNA molecules can be inherited. Furthermore, 1 of the 2 families provided an example of how persisting heteroplasmy and recombination might explain certain reticulations of the human mitochondrial DNA phylogenetic tree.
One of the families studied by Zsurka et al. (2007), with the A8344G (590060.0001) and the A16182C mutation included a boy, aged 14 years, who had MERRF syndrome (545000) and his sister, aged 29 years, who had occasional seizures. Their parents (and the mother's sister) were free of symptoms. The second family with the A3243G (590050.0001) and G16428A mutations included a man, aged 29 years, with the diagnosis of systemic MELAS syndrome (540000); his maternal aunt, aged 44 years, and her daughter, aged 12 years, were also affected. In different tissue samples from the A8344G/A16182C double-heteroplasmic family, Zsurka et al. (2007) observed that (1) all 4 allelic combinations of the 2 heteroplasmic mutations were present in the family, although, as expected, the distribution showed significant differences between individuals; (2) two family members carried the double-mutant (and possibly recombinant) allelic combination; and (3) high amounts of the possibly recombinant genotype, along with all other possible allelic combinations, were present in the fibroblast sample from one individual. The A16182C mutation was situated in the noncoding D-loop region of the mtDNA. In the second family, Zsurka et al. (2007) identified the rare G16428A D-hoop mutation in heteroplasmic state in addition to the pathogenic A3243G MELAS mutation (590050.0001). A wide range of 3243G mutational load was observed in various tissues of family members. In contrast, the mutant 16428A allele was in most samples close to homoplasmy; only the patient's muscle harbored a high degree of the wildtype 16428G allele. In all investigated samples, Zsurka et al. (2007) found that both alleles of G16428A were present in combination with both alleles of A3243G, at comparable proportions (tetraplasmy). Thus this family demonstrated that (1) all 4 allelic combinations of the 2 heteroplasmic mutations were present in 2 family members, and (2) the proportions of the rarer 16428G allele were balanced between both alleles 3243A and 3243G. Zsurka et al. (2007) concluded that recombination of the human mtDNA is not restricted to somatic tissues; rather, recombinant mtDNA molecules can be transmitted through the germline. This feature could explain the presence of certain allelic combinations in maternal lineages that cannot be inferred from a plain sequential order of mutational events. Thus, their hypothesis--that recombination of coexisting heteroplasmic mutations creates reticulations--eliminates the need to seek specific molecular mechanisms to explain individual reticulations in the human mtDNA phylogenetic tree.
In patients with the MERRF syndrome (545000), Shoffner et al. (1990) and Yoneda et al. (1990) identified an A-to-G transition at nucleotide 8344 that altered a conserved nucleotide in the tRNA(lys) gene (MTTK) and was heteroplasmic. The mutation was found in 3 independent pedigrees with the disease, while 75 controls did not have the mutation. Treatment with CoQ at 300 mg/day resulted in marked improvement of the phenotype. The same mutation was reported by Berkovic et al. (1991), Seibel et al. (1991), Shih et al. (1991), Tanno et al. (1991), and Zeviani et al. (1991). In all 3 patients with the MERRF syndrome, Noer et al. (1991) found the A-to-G substitution of nucleotide 8344 in the tRNA-lys gene. There was evidence that the mutations had arisen independently in these patients. Boulet et al. (1992) studied the distribution and expression of mutant mtDNAs carrying the A-to-G mutation at position 8344 in the skeletal muscle of 4 patients with myoclonus epilepsy and ragged-red fibers. The proportion of mutant genomes was greater than 80% of total mtDNAs in muscle samples of all patients and was associated with a decrease in the activity of cytochrome c oxidase. The great majority of myoblasts, cloned from the satellite-cell population in the same muscles, were homoplasmic for the mutation. Translation of all mtDNA-encoded genes was severely depressed in homoplasmic mutant myoblast clones but not in heteroplasmic or wildtype clones. Approximately 15% wildtype mtDNAs restored translation and COX activity to near-normal levels. The results showed that the A-to-G substitution is functionally a recessive mutation that can be rescued by intraorganellar complementation. Proteins of the complex I and VI subunits were more affected than complex V subunits, and there was a rough correlation with both protein size and number of lysine residues. Among 9 affected members of a MERRF family, Suomalainen et al. (1993) showed that the mutated nucleotide 8344 comprised from 9 to 72% of the total mtDNA in the leukocytes. They made use of a solid-phase minisequencing technique which, in addition to identifying the A8344G mutation permitted simultaneous determination in the same assay from one blood sample of the relative amount of mutated mtDNA.
Lertrit et al. (1992) studied 6 tissues from a patient with MERRF caused by the 8344 mutation. Heteroplasmy was observed in all: cerebellum, cerebrum, pancreas, liver, muscle, and heart. Thus, the mutated population of mitochondria must have existed before the formation of the 3 primary embryonic layers. The patient had no family history of a CNS disorder. Lertrit et al. (1992) found a lack of correlation between the degree of mtDNA heteroplasmy and clinical symptoms related to a particular organ and suggested that this indicated the presence of tissue-specific nuclear factors that modify the phenotypic expression of the 8344 mutation. Perhaps rather than a specific nuclear factor there are merely tissue differences in the requirements for the particular element of the respiratory chain involved.
Shoffner and Wallace (1992) estimated that the MTTK*MERRF8334 mutation accounts for 80 to 90% of MERRF cases.
Penisson-Besnier et al. (1992) described a family with MERRF and the point mutation at 8344. The mutation was found in all the maternal lineage with a relatively narrow range of variation in the percentage of mutant mitochondrial genomes with one exception represented by a set of dizygotic twins; one was clinically affected and showed a high proportion of mutant mitochondrial DNAs in blood cells, while the other was asymptomatic and showed very small amounts of mutant mtDNA in blood and skin. This suggests that the mitochondria are segregated at an early stage in oogenesis. In a study of 150 patients, most of them with diagnosed or suspected mitochondrial disease, Silvestri et al. (1993) found a high correlation between the A-to-G transition at position 8344 and the MERRF syndrome, but they also showed that this mutation can be associated with other phenotypes, including Leigh syndrome (256000), myoclonus or myopathy with truncal lipomas, and proximal myopathy. Furthermore, the absence of the 8344 mutation in 4 typical MERRF patients suggested that other mutations in the MTTK gene or elsewhere in the mitochondrial genome can produce the same phenotype. Hammans et al. (1993) studied 7 patients with the A8344-to-G mutation and their relatives. In 1 family, the mutation was deduced to be present in 4 generations. The index cases showed the core clinical features of MERRF, namely, myoclonus, ataxia, and seizures. Among other features, progressive external ophthalmoplegia, Leigh syndrome, and stroke-like episodes were observed, well recognized features in mitochondrial myopathies but novel manifestations of this genotype. Analyses for the proportion of mutant mtDNA, using an oligonucleotide hybridization technique, indicated that the proportion of mutant mtDNA in blood was significantly greater in symptomatic than in asymptomatic cases. Furthermore, the proportion of mutant mtDNA in blood correlated with age of onset of disease and clinical severity assessed by a simple scale. In a Chinese family living in Taiwan, Fang et al. (1994) described MERRF caused by the A8344-to-G mutation in 6 persons, including the grandmother, 2 sibs, and 3 grandchildren. Action myoclonus was seen in 5; short stature, muscle weakness, and mental retardation in 4; lactic acidosis, hearing impairment, and ataxia in 2; and seizures in 1. Muscle biopsy from 2 affected sibs showed ragged-red fibers and abundant subsarcolemmal mitochondria with paracrystalline inclusions.
Enriquez et al. (1995) studied the pathogenic mechanism of the A8344G mutation by comparing mtDNA-less cells which were transformed with either the mutant MTTK gene or the wildtype MTTK. A decrease of 50-60% in the specific tRNA-lys aminoacylation capacity per cell was found in mutant cells. Furthermore, several lines of evidence revealed that the severe protein synthesis impairment in MERRF mutation-carrying cells was due to premature termination of translation at each or near each lysine codon, with the deficiency of aminoacylated tRNA-lys being the most likely cause of this phenomenon.
Borner et al. (2000) generated conflicting results, using an assay that combines tRNA oxidation and circularization. The authors determined the relative amounts and states of aminoacylation of mutant and wildtype tRNAs in tissue samples from patients with MELAS syndrome (540000) and MERRF syndrome. In most biopsies from MELAS patients carrying the 3243A-G substitution in the mitochondrial tRNALeu(UUR) gene (590050), the mutant tRNA was underrepresented among processed and/or aminoacylated tRNAs. In contrast, in biopsies from MERRF patients harboring the 8344A-G substitution, neither the relative abundance nor the aminoacylation of the mutated tRNA was affected. The authors concluded that whereas the 3243A-G mutation may contribute to the pathogenesis of MELAS by reducing the amount of aminoacylated tRNALeu, the 8344A-G mutation does not affect tRNALys function in MERRF patients in the same way.
A specific mutation in mitochondrial DNA was first demonstrated by Shoffner et al. (1990); this was a missense mutation in the MTTK gene. The A-to-G mutation at nucleotide 8344 accounted for 80 to 90% of MERRF cases (Shoffner and Wallace, 1992). Biochemically, the mutation produced multiple deficiencies in the enzyme complexes of the respiratory chain, consistent with a defect in translation of all mtDNA-encoded genes. Chomyn et al. (1991) showed that transfer of mtDNAs carrying the mutation to human cell lines lacking their own mitochondrial DNA resulted in a severe defect in mitochondrial translation in the recipient cells, independent of nuclear background, implying that the tRNA mutation itself is sufficient to cause the disease. See 545000 for a discussion of the MERRF syndrome (myoclonus epilepsy associated with ragged-red fibers).
In a study of 67 Australian cases labeled Leigh syndrome from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features, Rahman et al. (1996) identified 11 patients with mitochondrial DNA point mutations. Two mutations were in the MTATP6 gene (8993T-G, 516060.0001; 8993T-C, 516060.0002), and one was the common MERRF mutation in the MTTK gene (8344A-G).
Chomyn (1998) reviewed the new insights into human mitochondrial function and genetics by study of the 8344A-G mutation in the gene encoding mitochondrial lysyl-tRNA.
Holme et al. (1993) reported a woman with multiple symmetric lipomas (MSL; see 151800) in the neck and shoulder area associated with a heteroplasmic c.8344A-G mutation in the MTTK gene (590060.0001). Her son, who also carried the mutation, had MERRF syndrome; the mother had no signs of MERRF syndrome. The fraction of mutant mtDNA in the woman varied between 62% and 80% in cultured skin fibroblasts, lymphocytes, normal adipose tissue, and muscle, whereas the fraction of mutant mtDNA in the lipomas ranged from 90 to 94%. Ultrastructural examination of the lipomas revealed numerous mitochondria and electron-dense inclusions in some adipocytes. Holme et al. (1993) concluded that the mutation may either directly or indirectly perturb the maturation process of the adipocytes, increasing the risk of lipoma formation.
Gamez et al. (1998) identified a heteroplasmic c.8344A-G mutation in the MTTK gene in 6 members of a family with MSL. The 36-year-old female proband had a history of progressive muscle weakness associated with peripheral polyneuropathy, neurosensory hypoacusis, and symmetric confluent large lipomas over the neck and upper trunk. She developed dysarthria, dysphagia, and ptosis, suggestive of a stroke, and subsequently had lactic acidosis with multiorgan failure. Muscle biopsy of the proband showed both ragged-red and COX-negative fibers. The proportion of mutated mtDNA was higher in lipomas than in muscle and blood. Five maternal relatives had multiple symmetric lipomatosis but no neuromuscular involvement; only the proband's affected mother had hearing loss.
Horvath et al. (2007) reported a 66-year-old German man with the 8344A-G mutation who presented with an 8-year history of parkinsonism (556500). Symptoms included bradykinesia, resting tremor, and asymmetric rigidity. He also had proximal muscle weakness, hyporeflexia, decreased distal sensation, and bilateral hearing loss. Serum creatine kinase was elevated. He showed good response to levodopa. Skeletal muscle biopsy showed ragged-red fibers, fiber size variability, centrally placed nuclei, and atrophic and necrotic fibers. There was a mild decrease in some respiratory chain enzymes. The 8344A-G mutation was homoplasmic in muscle and 80% in leukocytes. A brother with progressive hearing loss since age 10 had 70% heteroplasmy in blood.
Biancheri et al. (2010) identified the 8344A-G mutation in a child with severe cavitating leukoencephalopathy. The infant had congenital cataracts, but developed normally until age 17 months when he showed psychomotor and neurologic regression. Symptoms included nystagmus, irritability, hypertonia, extensor plantar responses, and swallowing and feeding difficulties. Brain MRS showed increased lactate; muscle biopsy showed ragged-red fibers and decreased activity of mitochondrial complexes I+III and II+III (about 30% residual activity). Patient tissues showed high levels of mutant mtDNA that was not detected in the mother's tissues. Biancheri et al. (2010) noted the unusual early presentation in this patient and emphasized the characteristic cystic degenerative pattern of the brain imaging which is suggestive of a mitochondrial disorder.
Using mutant and control cybrids, Yen et al. (2016) found that the 8344A-G mutation in MTTK suppressed maturation of COQ5 (616359) and disrupted a COQ5-containing mitochondrial protein complex, concomitant with reduction in mitochondrial membrane potential, oxygen consumption, and ATP production.
In 1 of 5 MERRF (545000) patients who did not have the 8344A-G mutation, Silvestri et al. (1992) identified an 8356T-C transition in the MTTK gene. The patient was a 36-year-old woman with a history of myoclonic epilepsy, generalized seizures, ataxia, myopathy, and hearing loss that started at age 30 years. Laboratory studies showed a moderate increase in serum creatine kinase and lactic acidosis. Muscle biopsy showed abundant ragged-red fibers. Family history was suggestive of maternal inheritance: the patient's mother and 1 of her 2 sisters had similar symptoms and, in addition, features of hyperthyroidism; muscle biopsy showed ragged-red fibers in both. They died at ages 52 and 25, respectively. Another sister had hearing loss but refused examination. Two maternal uncles were moderately affected; 1 had seizures and the other had hearing loss. The mutation disrupted a highly conserved basepair in the T-psi-C tem. (Transfer RNA has a cloverleaf configuration with 4 major arms. Three of the arms consist of basepaired stems and unpaired loops. Whereas the anticodon arm is so named because it contains the anticodon triplet in the center of the loop and the D arm is named for its content of the base dihydrouridine, the T-psi-C arm is named for the presence of a triplet of nucleotides in which psi stands for pseudouridine, one of the unusual bases in tRNA.) The mutant mtDNA population was essentially homoplasmic in muscle but was heteroplasmic in blood (47%). The mutation was not found in 20 patients with other mitochondrial diseases or in 25 controls.
Zeviani et al. (1993) described a point mutation in mtDNA in several members of 3 generations of a Sardinian kindred with a maternally inherited syndrome characterized by features of both MERRF and MELAS (540000). A single, heteroplasmic T-to-C transition at nucleotide 8356 was identified. The mutation was in the region of the tRNA-lys gene corresponding to the T-psi-C stem. The relative amount of mutant mtDNA in muscle correlated with the severity of the clinical presentation. Clinical features included myoclonic epilepsy, neural deafness, ataxia, and stroke-like episodes.
Nakamura et al. (2010) reported a family in which 4 members carried both the 8356T-C mutation and a 3243A-G transition in the MTTL1 gene (590050.0001), which is usually associated with MELAS syndrome. The female proband and her cousin had MERRF, a deceased aunt had a MERRF/MELAS overlap syndrome, and the mother of the proband was asymptomatic. Genetic analysis showed that the double mutations were heteroplasmic in blood of the proband and her cousin but at low levels in her asymptomatic mother. In muscle tissue of the proband and her deceased aunt, the proportion of the 3243A-G mutation was higher than in blood, and the 8356T-C mutation was homoplasmic. Nakamura et al. (2010) hypothesized that the phenotype in affected individuals began with MERRF and evolved into MELAS later in life.
Santorelli et al. (1996) described a novel G-to-A mutation of nucleotide 8363 in the mtDNA gene for tRNA (lys) in 2 unrelated families with a syndrome consisting of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy. Muscle biopsies from the probands showed mitochondrial proliferation and partial defects of complexes I, III, and IV of the electron-transport chain. The 8363G-A mutation was very abundant (more than 95%) in muscle samples from the probands and was less copious in blood from 18 maternal relatives (mean 81.3% +/- 8.5%). Single-muscle-fiber analysis showed significantly higher levels of mutant genomes in cytochrome c oxidase-negative fibers than in cytochrome c oxidase-positive fibers. The proband in the first family was a Hispanic 16-year-old man who developed normally until age 8 years, when he presented with heart failure and cognitive regression. He died at the age of 17 years. The proband in the second family was a 44-year-old African American woman who was healthy until age 35 years when she first noted progressive hearing loss. At age 37 years, she developed slurred speech, gait difficulties with leg pain and heaviness, and shortness of breath after mild exercise. Physical examination showed 'horse collar' lipomas and increased fat tissue distributed in folds on the lateral aspects of the chest and abdomen. The thighs appeared thin, but the legs showed mild bilateral calf hypertrophy.
Verma et al. (1997) described a novel mitochondrial 8313G-A mutation in a boy with prominent gastrointestinal symptoms initially followed by progressive encephaloneuropathy. Development was normal until age 3 when he developed anorexia, episodic vomiting, intermittent abdominal pain with distention, and diarrhea. Intermittent pseudoobstructive GI symptoms and failure to thrive persisted despite attempts at jejunal tube feeding and, later, gastrostomy. At age 7, he developed generalized tonic-clonic seizures followed soon thereafter by frequent myoclonic jerks and progressive mental regression. EEG revealed multifocal spike and slow wave discharges. Between ages 8 and 10, parallel to progressive mental regression and persistent enteric symptoms, he developed cerebellar ataxia, peripheral neuropathy, neural deafness, and pigmentary retinal changes. Plasma lactate was elevated and a muscle biopsy revealed ragged-red fibers lacking cytochrome c oxidase activity and diminished levels of respiratory chain enzyme complexes. A unique SSCP was found in the segment of the mitochondrial chromosome that encompasses the MTTK gene, and direct sequencing of this segment revealed a G-to-A transition at the evolutionarily conserved nucleotide at position 8313. The 8313G-A transition was heteroplasmic in muscle and fibroblasts of the patient, but was absent in white blood cells and platelets from his maternal relatives.
Kameoka et al. (1998) screened 10 diabetic patients with clinical features suggesting mitochondrial DNA mutations and identified an adenine-to-guanine point mutation in the MTTK gene at position 8296. Thereafter, they screened 1,216 diabetic subjects, 44 patients with sensorineural deafness, and 300 nondiabetic control subjects for this mutation. They identified the mutation in 11 (0.90%) unrelated diabetic subjects, 1 (2.3%) patient with deafness, and no nondiabetic control subjects. Seven of the 12 subjects showed maternal inheritance. Deafness was seen in 7 of 12 probands (MIDD; 520000). Four family pedigrees showed maternal inheritance of diabetes over 2 or 3 generations. Thus, it appears that subjects carrying the 8296A-G mutation may develop diabetes and that the mutation may be responsible for approximately 1% of cases of diabetes.
Tiranti et al. (1999) described a patient who suffered from impaired ocular motility from age 10 years and at 16 years developed ptosis, proximal weakness, and progressive fatigability. At 35 years of age, she developed massive myoclonic jerks, and head and distal tremor. A muscle biopsy showed a high percentage of cytochrome c oxidase-negative fibers but no ragged-red fibers. A heteroplasmic mutation (8342G-A) was found in the mitochondrial transfer RNA(lys) gene. Approximately 80% of muscle mitochondrial DNA harbored the mutation, while the mutation was absent in lymphocyte DNA of the proband, as well as of her mother, daughter, and a maternal aunt.
In a boy with the MERRF syndrome (545000), Rossmanith et al. (2003) identified an 8361G-A transition in the MTTK gene, which disrupted a conserved base pairing interaction in the aminoacyl-acceptor stem of the encoded tRNA-lys. The patient was heteroplasmic for the mutation, with skeletal muscle having an 82% load. Age at onset was 6 years, and although he developed most of the classic clinical features of MERRF, he did not have lactic acidosis and he had near normal respiratory chain activity.
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