Alternative titles; symbols
HGNC Approved Gene Symbol: MT-TF
SNOMEDCT: 230426003, 39925003, 428255004; ICD10CM: E88.41, E88.42, N10-N16, N15.9, N16;
The mitochondrial tRNA for phenylalanine is encoded by nucleotides 577-647.
Zaganelli et al. (2017) found that RPUSD4 (617488) coprecipitated with mitochondrial tRNA(phe) and mitochondrial tRNA(met) (MTTM; 590065) and bound specifically to the pseudouridine at universal tRNA sites 39 and 50. Depletion of RPUSD4 significantly reduced pseudouridine-39 in mitochondrial tRNA(phe), but not in mitochondrial tRNA(gly) (MTTG; 590035). The pseudouridines in mitochondrial tRNA(met) were unaffected by RPUSD4 depletion. RPUSD4 depletion had no effect on mitochondrial tRNA(phe) steady-state levels or aminoacylation. Zaganelli et al. (2017) concluded that RPUSD4 is responsible for formation of pseudouridine-39 in mitochondrial tRNA(phe).
In patients with MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) (540000), Hanna et al. (1998) and Mancuso et al. (2004) identified mutations in the MTTF gene (590070.0001 and 590070.0002, respectively).
By in vitro studies, Ling et al. (2007) found that different pathogenic mutations in the MTTF gene resulted in aminoacylation defects, primarily by affecting the secondary or tertiary structure of the protein. The exception was the G34A mutation (590070.0002), which was not involved in global structure but resulted in decreased aminoacylation because it affected the tRNA anticodon.
Shapira et al. (1975) provided the first description of a disorder that includes stroke-like episodes, lactic acidemia, and ragged-red fibers. Pavlakis et al. (1984) described further cases, introduced the acronym MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) (540000), and suggested that this represents a distinct mitochondrial disorder. Goto et al. (1990) identified a point mutation in the gene encoding mtRNA leucine (UUR) (MTTL1; 590050.0001) in some patients with MELAS. Hanna et al. (1998) analyzed the sequence of mitochondrial DNA in 5 patients with the MELAS phenotype. In one of the patients, a novel heteroplasmic mitochondrial DNA mutation was identified in the tRNA gene for phenylalanine in skeletal muscle. This mutation was not detected in the patient's blood or in her mother's blood. No pathogenic mutations were identified in the other patients. The mutation was a G-to-A transition at position 583 in the aminoacyl acceptor stem region of the MTTF gene. The proportion of the 583G-A mutation in the patient's muscle was 58%. Evolutionary comparisons showed that the 583G-A nucleotide is highly conserved. The patient was a 32-year-old woman who developed normally until the age of 12 years when she had an acute episode of headache, photophobia, vomiting, and left arm focal motor fitting from which she fully recovered. She experienced 2 further similar episodes and after the second developed a dense left hemiplegia which subsequently resolved. There followed progressive cognitive decline, cerebellar ataxia, and complex partial seizures. At the age of 29 years, a salt and pepper type retinopathy, cerebellar ataxia, mild spasticity in all 4 limbs, and intermittent dystonic posturing of her upper limbs as she walked were found. There was no limb weakness. Brain CT showed extensive low density areas involving both gray and white matter, most marked posteriorly. These were consistent with areas of infarction. Plasma lactate was raised. Muscle biopsy at age 12 years showed 3% ragged-red fibers.
In a patient with MERRF syndrome (545000), Mancuso et al. (2004) identified a heteroplasmic 611G-A transition in the MTTF gene, resulting in a gly34-to-ala (G34A) substitution. The mutation was abundant in muscle (91%), particularly in COX-negative fibers, but undetectable in the patient's blood, urinary sediment, skin fibroblasts, and buccal smear.
Ling et al. (2007) demonstrated that the G34A mutation affects the anticodon of the protein and therefore results in decreased aminoacylation activity in vitro by 100-fold, but does not affect global folding or recognition by elongation factor. Modification of the tRNA binding region of nuclear-encoded human mitochondrial PheRS (611592) was able to partially restore aminoacylation efficiency for the G34A mutation in vitro.
In a 66-year-old woman with a 4-year history of walking difficulties due to exercise intolerance and paresthesias in the feet, Deschauer et al. (2006) identified a heteroplasmic 622G-A transition in the MTTF gene. The mutation occurs in a highly conserved nucleotide within the variable loop of the protein. The patient also had mild sensorineural hearing impairment with a loss of up to 60 dB at higher frequencies. Resting serum lactate levels were normal but increased significantly after gentle exercise. Skeletal muscle biopsy detected atrophic muscle fibers, and histochemical analysis showed over 35% COX-negative fibers. Enzyme assay showed decreased activity of several respiratory chain complexes. The 622G-A transition was detected in skeletal muscle (88%), hair (70%), urinary epithelia (66%), buccal epithelia (63%), and blood (36%). The patient's mother reportedly had walking difficulties later in life, and tissues from the patient's asymptomatic daughter showed low levels of the mutation (10 to 20%).
In a patient with severe epilepsy, Zsurka et al. (2010) identified a homoplasmic 616T-C transition in the MTTF gene in a highly conserved position in the anticodon stem. She had her first epileptic seizure at age 10 months, with a left-sided complex partial seizure followed by a transient paresis of the left arm. At age 2 years she had status epilepticus with bilateral myoclonus. She continued to have drug-resistant seizures, with myoclonus, complex partial seizures, and episodes of status epilepticus and epilepsia partialis continua. She also had chronic renal insufficiency and delayed psychomotor development. She died of heart failure after status epilepticus at the age of 17 years. There was no evidence of cerebellar ataxia, polyneuropathy, myopathy, or visual or hearing loss. A maternal cousin also had epileptic seizures starting in early childhood and died of kidney failure. Skeletal muscle biopsy of the proband did not show ragged red fibers, but did show a combined respiratory chain defect with reduced complex IV activity. Family members who were heteroplasmic for the mutation had no clinical symptoms.
In a patient with severe epilepsy, Zsurka et al. (2010) identified a homoplasmic 616T-G transversion in the MTTF gene in a highly conserved position in the anticodon stem. The male proband presented at age 15 years with generalized tonic-clonic seizures rapidly followed by continuous partial seizures affecting the left hemiface and myoclonus. He had status epilepticus at age 17 years and died of infection in intensive care unit after 4 months in status epilepticus. The patient's mother and maternal aunt both presented with status epilepticus at age 15 years. Skeletal muscle biopsy of the proband did not show ragged red fibers, but did show a combined respiratory chain defect with reduced complex IV activity.
In a 57-year-old woman with a progressive neurodegenerative disorder, Young et al. (2010) identified a heteroplasmic 586G-A transition in the MTTF gene. The phenotype was characterized by frontotemporal dementia, auditory hallucinations, sensorineural deafness, and akinesia-rigidity. The mutation level was highest in patient muscle (85%), with lower levels in urinary epithelia (29%) and blood (3%). Muscle biopsy showed ragged red fibers and decreased COX-positive fibers. Extraction of DNA from her deceased mother's paraffin-embedded tissue showed that the mother was heteroplasmic for the mutation (13% in breast tissue). Young et al. (2010) emphasized that the mutation appeared to cause an extrapyramidal symptom in this patient.
In 2 sibs with infantile onset of progressive renal failure due to tubulointerstitial nephropathy, Tzen et al. (2001) identified a homoplasmic 608A-G transition in a conserved nucleotide in the MTTF gene that affects the anticodon stem and loop of the tRNA, potentially altering the tertiary structure. The mutation was not found in 97 controls. Leukocyte mtDNA of the unaffected mother carried the same mutation. The disorder was multisystemic, but both patients were brought to medical attention for failure to thrive and chronic renal insufficiency. Additional features included delayed development, brain atrophy, ataxia, anemia, muscle weakness and atrophy, and lesions suggestive of stroke in deep brain regions. Renal ultrasound showed increased echogenicity, and biopsy showed tubulointerstitial nephropathy with sclerotic tufts and thickening of Bowman's capsule with evidence of fibrosis. Electron microscopy showed irregular mitochondria with crystalline inclusions and abnormal morphology, such as swollen intracristal spaces.
Deschauer, M., Swalwell, H., Strauss, M., Zierz, S., Taylor, R. W. Novel mitochondrial transfer RNA-phe gene mutation associated with late-onset neuromuscular disease. Arch. Neurol. 63: 902-905, 2006. [PubMed: 16769874] [Full Text: https://doi.org/10.1001/archneur.63.6.902]
Goto, Y., Nonaka, I., Horai, S. A mutation in the tRNA-leu (UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348: 651-653, 1990. [PubMed: 2102678] [Full Text: https://doi.org/10.1038/348651a0]
Hanna, M. G., Nelson, I. P., Morgan-Hughes, J. A., Wood, N. W. MELAS: a new disease associated mitochondrial DNA mutation and evidence for further genetic heterogeneity. J. Neurol. Neurosurg. Psychiat. 65: 512-517, 1998. [PubMed: 9771776] [Full Text: https://doi.org/10.1136/jnnp.65.4.512]
Ling, J., Roy, H., Qin, D., Rubio, M. A. T., Alfonzo, J. D., Fredrick, K., Ibba, M. Pathogenic mechanism of a human mitochondrial tRNA-Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome. Proc. Nat. Acad. Sci. 104: 15299-15304, 2007. [PubMed: 17878308] [Full Text: https://doi.org/10.1073/pnas.0704441104]
Mancuso, M., Filosto, M., Mootha, V. K., Rocchi, A., Pistolesi, S., Murri, L., DiMauro, S., Siciliano, G. A novel mitochondrial tRNA-phe mutation causes MERRF syndrome. Neurology 62: 2119-2121, 2004. [PubMed: 15184630] [Full Text: https://doi.org/10.1212/01.wnl.0000127608.48406.f1]
Pavlakis, S. G., Phillips, P. C., DiMauro, S., De Vivo, D. C., Rowland, L. P. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann. Neurol. 16: 481-488, 1984. [PubMed: 6093682] [Full Text: https://doi.org/10.1002/ana.410160409]
Shapira, Y., Cederbaum, S. D., Cancilla, P. A., Nielsen, D., Lippe, B. M. Familial poliodystrophy, mitochondrial myopathy, and lactic acidemia. Neurology 25: 614-621, 1975. [PubMed: 1171391] [Full Text: https://doi.org/10.1212/wnl.25.7.614]
Tzen, C.-Y., Tsai, J.-D., Wu, T.-Y., Chen, B.-F., Chen, M.-L., Lin, S.-P., Chen, S.-C. Tubulointerstitial nephritis associated with a novel mitochondrial point mutation. Kidney Int. 59: 846-854, 2001. [PubMed: 11231339] [Full Text: https://doi.org/10.1046/j.1523-1755.2001.059003846.x]
Young, T. M., Blakely, E. L., Swalwell, H., Carter, J. E., Kartsounis, L. D., O'Donovan, D. G., Turnbull, D. M., Taylor, R. W., de Silva, R. N. Mitochondrial transfer RNA(Phe) mutation associated with a progressive neurodegenerative disorder characterized by psychiatric disturbance, dementia, and akinesia-rigidity. Arch. Neurol. 67: 1399-1402, 2010. [PubMed: 21060018] [Full Text: https://doi.org/10.1001/archneurol.2010.283]
Zaganelli, S., Rebelo-Guiomar, P., Maundrell, K., Rozanska, A., Pierredon, S., Powell, C. A., Jourdain, A. A., Hulo, N., Lightowlers, R. N., Chrzanowska-Lightowlers, Z. M., Minczuk, M., Martinou, J.-C. The pseudouridine synthase RPUSD4 is an essential component of mitochondrial RNA granules. J. Biol. Chem. 292: 4519-4532, 2017. [PubMed: 28082677] [Full Text: https://doi.org/10.1074/jbc.M116.771105]
Zsurka, G., Hampel, K. G., Nelson, I., Jardel, C., Mirandola, S. R., Sassen, R., Kornblum, C., Marcorelles, P., Lavoue, S., Lombes, A., Kunz, W. S. Severe epilepsy as the major symptom of new mutations in the mitochondrial tRNA(Phe) gene. Neurology 74: 507-512, 2010. [PubMed: 20142618] [Full Text: https://doi.org/10.1212/WNL.0b013e3181cef7ab]