MT-TK

Last updated
mitochondrially encoded tRNA lysine
Identifiers
SymbolMT-TK
Alt. symbolsMERRF, MTTK
NCBI gene 4566
HGNC 7489
RefSeq NC_001807
Other data
Locus Chr. MT

Mitochondrially encoded tRNA lysine also known as MT-TK is a transfer RNA which in humans is encoded by the mitochondrial MT-TK gene. [1]

Contents

Structure

The MT-TK gene is located on the p arm of the mitochondrial DNA at position 12 and it spans 70 base pairs. [2] The structure of a tRNA molecule is a distinctive folded structure which contains three hairpin loops and resembles a three-leafed clover. [3]

Function

MT-TK is a small 70 nucleotide RNA (human mitochondrial map position 8295-8364) that transfers the amino acid lysine to a growing polypeptide chain at the ribosome site of protein synthesis during translation.

Clinical significance

Mutations in MT-TK can result in multiple mitochondrial deficiencies and associated disorders.

Myoclonic epilepsy with ragged-red fibers (MERRF)

Mutations in the MT-TK gene are associated with myoclonic epilepsy and ragged-red fiber disease (MERRF). [4] [5] Myoclonic epilepsy with ragged-red fibers (MERRF) is a disorder that affects many parts of the body, particularly the muscles and nervous system. In most cases, the signs and symptoms of this disorder appear during childhood or adolescence. The features of MERRF vary widely among affected individuals, even among members of the same family. Common symptoms include, myoclonus, myopathy, spasticity, epilepsy, peripheral neuropathy, dementia, ataxia, atrophy and more. [6] A majority of mutations in the MT-TK gene found to cause the disease were single nucleotide substitutions, such as 8344A>G. The 8344A>G mutation has been found to disable the normal functions of the mitochondria. [7] A family of mutations 8344A>G and 16182A>C in the MT-TK gene has been found with MERRF syndrome. Another family with the syndrome exhibited mutations of 3243A>G and 16428G>A. [8]

MERRF/MELAS overlap syndrome

MELAS syndrome may also be accompanied by another mitochondrial disorder called myoclonic epilepsy with ragged-red fibers, also known as MERRF syndrome. [9] In addition to symptoms of MELAS syndrome, additional signs and symptoms may include muscle twitches (myoclonus), difficulty coordinating movement (ataxia), and abnormal muscle cells known as ragged-red fibers. The combination of MERRF and MELAS is called the MERRF/MELAS overlap syndrome. It has not been determined how mutations alter the energy production function of the mitochondria and result in symptoms of such syndromes. [7] The single nucleotide substitution 8356T>C has been found to cause the syndrome. [10]

Maternally inherited diabetes and deafness (MIDD)

A mutation in the MT-TK gene has been found in a small number of people with maternally inherited diabetes and deafness (MIDD). The disorder is characterized by diabetes combined with hearing loss, particularly of high pitches. Additional symptoms includemuscle weakness (myopathy) and various problems with a patient's eyes, heart, or kidneys. Mutations in the MT-TK gene disables the insulin release by the mitochondria. Diabetes results when the beta cells do not release enough insulin to regulate blood sugar effectively. Researchers have not determined how mutations lead to hearing loss or the other features of MIDD. [7] The single nucleotide substitution 8296A>G has been found to cause the syndrome. [11]

Leigh syndrome

The 8344A>G mutation in the MT-TK gene may also result in Leigh syndrome, a progressive brain disorder. [4] Clinical manifestations, which include vomiting, seizures, delayed development, myopathy, and problems with movement, have an early onset of infancy or early childhood. Additional symptoms include heart problems, kidney problems, and breathing difficulties. The cause of the disease has not been identified. [7]

Cardiomyopathy

The 8363G>A mutation in the MT-TK gene may also cause hypertrophic cardiomyopathy, a disorder characterized by the thickening of the heart, and hearing loss. Additional symptoms may include myopathy and ataxia. [7] A family with abundant 8363G>A mutations of MT-TK in their muscle samples exhibited symptoms of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy. [12]

Complex IV Deficiency

MT-TK mutations have been associated with complex IV deficiency of the mitochondrial respiratory chain, also known as the cytochrome c oxidase deficiency. Cytochrome c oxidase deficiency is a rare genetic condition that can affect multiple parts of the body, including skeletal muscles, the heart, the brain, or the liver. Common clinical manifestations include myopathy, hypotonia, and encephalomyopathy, lactic acidosis, and hypertrophic cardiomyopathy. [13] A patient with a 8313G>A mutation in the MT-TK gene exhibited symptoms of the deficiency accompanied by bilateral ptosis. [14] Other variants also include 8328G>A [15] and 8344G>A. [16]

Related Research Articles

Mitochondrial myopathy Medical condition

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. On biopsy, the muscle tissue of patients with these diseases usually demonstrate "ragged red" muscle fibers. These ragged-red fibers contain mild accumulations of glycogen and neutral lipids, and may show an increased reactivity for succinate dehydrogenase and a decreased reactivity for cytochrome c oxidase. Inheritance was believed to be maternal. It is now known that certain nuclear DNA deletions can also cause mitochondrial myopathy such as the OPA1 gene deletion. There are several subcategories of mitochondrial myopathies.

Kearns–Sayre syndrome (KSS), oculocraniosomatic disorder or oculocranionsomatic neuromuscular disorder with ragged red fibers is a mitochondrial myopathy with a typical onset before 20 years of age. KSS is a more severe syndromic variant of chronic progressive external ophthalmoplegia, a syndrome that is characterized by isolated involvement of the muscles controlling movement of the eyelid and eye. This results in ptosis and ophthalmoplegia respectively. KSS involves a combination of the already described CPEO as well as pigmentary retinopathy in both eyes and cardiac conduction abnormalities. Other symptoms may include cerebellar ataxia, proximal muscle weakness, deafness, diabetes mellitus, growth hormone deficiency, hypoparathyroidism, and other endocrinopathies. In both of these diseases, muscle involvement may begin unilaterally but always develops into a bilateral deficit, and the course is progressive. This discussion is limited specifically to the more severe and systemically involved variant.

MELAS syndrome Medical condition

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent.

<span class="mw-page-title-main">MERRF syndrome</span> Medical condition

MERRF syndrome is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the muscles and nervous system. The signs and symptoms of this disorder appear at an early age, generally childhood or adolescence. The causes of MERRF syndrome are difficult to determine, but because it is a mitochondrial disorder, it can be caused by the mutation of nuclear DNA or mitochondrial DNA. The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category. The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy, and ragged red fibers (RRF) on muscle biopsy, leading to the disease's name. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, or multiple lipomata. Mitochondrial disorders, including MERRFS, may present at any age.

Progressive Myoclonic Epilepsies (PME) are a rare group of inherited neurodegenerative diseases characterized by myoclonus, resistance to treatment, and neurological deterioration. The cause of PME depends largely on the type of PME. Most PMEs are caused by autosomal dominant or recessive and mitochondrial mutations. The location of the mutation also affects the inheritance and treatment of PME. Diagnosing PME is difficult due to their genetic heterogeneity and the lack of a genetic mutation identified in some patients. The prognosis depends largely on the worsening symptoms and failure to respond to treatment. There is no current cure for PME and treatment focuses on managing myoclonus and seizures through antiepileptic medication (AED).

Mitochondrially encoded tRNA leucine 1 (UUA/G) also known as MT-TL1 is a transfer RNA which in humans is encoded by the mitochondrial MT-TL1 gene.

Mitochondrially encoded tRNA histidine, also known as MT-TH, is a transfer RNA which, in humans, is encoded by the mitochondrial MT-TH gene.

Mitochondrially encoded tRNA valine also known as MT-TV is a transfer RNA which in humans is encoded by the mitochondrial MT-TV gene.

Mitochondrially encoded tRNA aspartic acid also known as MT-TD is a transfer RNA which in humans is encoded by the mitochondrial MT-TD gene.

Mitochondrially encoded tRNA glutamic acid also known as MT-TE is a transfer RNA which in humans is encoded by the mitochondrial MT-TE gene. MT-TE is a small 69 nucleotide RNA that transfers the amino acid glutamic acid to a growing polypeptide chain at the ribosome site of protein synthesis during translation.

Mitochondrially encoded tRNA phenylalanine also known as MT-TF is a transfer RNA which in humans is encoded by the mitochondrial MT-TF gene.

Mitochondrially encoded tRNA glycine also known as MT-TG is a transfer RNA which in humans is encoded by the mitochondrial MT-TG gene.

Mitochondrially encoded tRNA isoleucine also known as MT-TI is a transfer RNA which in humans is encoded by the mitochondrial MT-TI gene.

Mitochondrially encoded tRNA leucine 2 (CUN) also known as MT-TL2 is a transfer RNA which in humans is encoded by the mitochondrial MT-TL2 gene.

Mitochondrially encoded tRNA asparagine also known as MT-TN is a transfer RNA which in humans is encoded by the mitochondrial MT-TN gene.

Mitochondrially encoded tRNA arginine also known as MT-TR is a transfer RNA which in humans is encoded by the mitochondrial MT-TR gene.

Mitochondrially encoded tRNA threonine also known as MT-TT is a transfer RNA which in humans is encoded by the mitochondrial MT-TT gene.

Mitochondrially encoded tRNA tryptophan also known as MT-TW is a transfer RNA which in humans is encoded by the mitochondrial MT-TW gene.

Mitochondrially encoded tRNA tyrosine, also known as MT-TY, is a transfer RNA which in humans is encoded by the mitochondrial MT-TY gene.

References

  1. ↑ Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG (April 1981). "Sequence and organization of the human mitochondrial genome". Nature. 290 (5806): 457–65. Bibcode:1981Natur.290..457A. doi:10.1038/290457a0. PMID   7219534. S2CID   4355527.
  2. ↑ "MT-TK mitochondrially encoded tRNA lysine [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  3. ↑ "tRNA / transfer RNA". Learn Science at Scitable.
  4. 1 2 Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC (June 1990). "Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation". Cell. 61 (6): 931–7. doi:10.1016/0092-8674(90)90059-N. PMID   2112427. S2CID   6101099.
  5. ↑ Yoneda M, Tanno Y, Horai S, Ozawa T, Miyatake T, Tsuji S (August 1990). "A common mitochondrial DNA mutation in the t-RNA(Lys) of patients with myoclonus epilepsy associated with ragged-red fibers". Biochemistry International. 21 (5): 789–96. PMID   2124116.
  6. ↑ "Myoclonic epilepsy with ragged-red fibers". Genetics Home Reference. U.S. National Library of Medicine.PD-icon.svgThis article incorporates text from this source, which is in the public domain .
  7. 1 2 3 4 5 Reference, Genetics Home. "MT-TK gene". Genetics Home Reference.PD-icon.svgThis article incorporates text from this source, which is in the public domain .
  8. ↑ Zsurka G, Hampel KG, Kudina T, Kornblum C, Kraytsberg Y, Elger CE, Khrapko K, Kunz WS (February 2007). "Inheritance of mitochondrial DNA recombinants in double-heteroplasmic families: potential implications for phylogenetic analysis". American Journal of Human Genetics. 80 (2): 298–305. doi:10.1086/511282. PMC   1785346 . PMID   17236134.
  9. ↑ Melone MA, Tessa A, Petrini S, Lus G, Sampaolo S, di Fede G, Santorelli FM, Cotrufo R (February 2004). "Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERFF phenotype". Archives of Neurology. 61 (2): 269–72. doi: 10.1001/archneur.61.2.269 . PMID   14967777.
  10. ↑ Silvestri G, Moraes CT, Shanske S, Oh SJ, DiMauro S (December 1992). "A new mtDNA mutation in the tRNA(Lys) gene associated with myoclonic epilepsy and ragged-red fibers (MERRF)". American Journal of Human Genetics. 51 (6): 1213–7. PMC   1682905 . PMID   1361099.
  11. ↑ Kameoka K, Isotani H, Tanaka K, Azukari K, Fujimura Y, Shiota Y, Sasaki E, Majima M, Furukawa K, Haginomori S, Kitaoka H, Ohsawa N (April 1998). "Novel mitochondrial DNA mutation in tRNA(Lys) (8296A-->G) associated with diabetes". Biochemical and Biophysical Research Communications. 245 (2): 523–7. doi:10.1006/bbrc.1998.8437. PMID   9571188.
  12. ↑ Santorelli FM, Mak SC, El-Schahawi M, Casali C, Shanske S, Baram TZ, Madrid RE, DiMauro S (May 1996). "Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA(Lys) gene (G8363A)". American Journal of Human Genetics. 58 (5): 933–9. PMC   1914622 . PMID   8651277.
  13. ↑ Reference, Genetics Home. "Cytochrome c oxidase deficiency". Genetics Home Reference.PD-icon.svgThis article incorporates text from this source, which is in the public domain .
  14. ↑ O'Rourke K, Buddles MR, Farrell M, Howley R, Sukuraman S, Connolly S, Turnbull DM, Hutchinson M, Taylor RW (October 2009). "Phenotypic diversity associated with the mitochondrial m.8313G>A point mutation". Muscle & Nerve. 40 (4): 648–51. doi:10.1002/mus.21342. PMID   19618438. S2CID   5872401.
  15. ↑ Houshmand M, Lindberg C, Moslemi AR, Oldfors A, Holme E (1999). "A novel heteroplasmic point mutation in the mitochondrial tRNA(Lys) gene in a sporadic case of mitochondrial encephalomyopathy: de novo mutation and no transmission to the offspring". Human Mutation. 13 (3): 203–9. doi:10.1002/(SICI)1098-1004(1999)13:3<203::AID-HUMU4>3.0.CO;2-3. PMID   10090475. S2CID   29433711.
  16. ↑ Mancuso M, Petrozzi L, Filosto M, Nesti C, Rocchi A, Choub A, Pistolesi S, Massetani R, Fontanini G, Siciliano G (March 2007). "MERRF syndrome without ragged-red fibers: the need for molecular diagnosis". Biochemical and Biophysical Research Communications. 354 (4): 1058–60. doi:10.1016/j.bbrc.2007.01.099. PMID   17275787.

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