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Borgione, E.; Lo Giudice, M.; Santa Paola, S.; Giuliano, M.; Di Blasi, F.D.; Di Stefano, V.; Lupica, A.; Brighina, F.; Pettinato, R.; Romano, C.; et al. Mitochondrial tRNASer(UCN) Gene. Encyclopedia. Available online: https://encyclopedia.pub/entry/41476 (accessed on 17 June 2024).
Borgione E, Lo Giudice M, Santa Paola S, Giuliano M, Di Blasi FD, Di Stefano V, et al. Mitochondrial tRNASer(UCN) Gene. Encyclopedia. Available at: https://encyclopedia.pub/entry/41476. Accessed June 17, 2024.
Borgione, Eugenia, Mariangela Lo Giudice, Sandro Santa Paola, Marika Giuliano, Francesco Domenico Di Blasi, Vincenzo Di Stefano, Antonino Lupica, Filippo Brighina, Rosa Pettinato, Corrado Romano, et al. "Mitochondrial tRNASer(UCN) Gene" Encyclopedia, https://encyclopedia.pub/entry/41476 (accessed June 17, 2024).
Borgione, E., Lo Giudice, M., Santa Paola, S., Giuliano, M., Di Blasi, F.D., Di Stefano, V., Lupica, A., Brighina, F., Pettinato, R., Romano, C., & Scuderi, C. (2023, February 21). Mitochondrial tRNASer(UCN) Gene. In Encyclopedia. https://encyclopedia.pub/entry/41476
Borgione, Eugenia, et al. "Mitochondrial tRNASer(UCN) Gene." Encyclopedia. Web. 21 February, 2023.
Mitochondrial tRNASer(UCN) Gene
Edit

Mitochondrial tRNASer(UCN) is considered a hot-spot for non-syndromic and aminoglycoside-induced hearing loss. However, many patients have been described with more extensive neurological diseases, mainly including epilepsy, myoclonus, ataxia, and myopathy. 

mitochondrial DNA tRNASer(UCN) homoplasmic mutation

1. Introduction

Mitochondrial diseases are multisystemic disorders with prominent involvement of the central nervous system and the skeletal and cardiac muscles. The primary molecular defects in these diseases  are mutations in mitochondrial DNA (mtDNA). Many syndromes have been connected with specific mutations and some phenotypes can guide an easy recognition in typical patients. On the other hand, sometimes there is a high variability within the same family with different phenotypes in people carrying the same mutation. Leber hereditary optic neuropathy (LHON) is the most common mtDNA-related disorder in adults, with subacute blindness in young males due to bilateral optic atrophy. Approximately 95% of LHON cases are due to three primary mutations (m.11778G>A, m.3460G>A, m.14484T>C) affecting genes encoding complex I subunits [1]. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), caused in the most cases by A-to-G transition at nucleotide 3243 in tRNALeu(UUR) gene [2], usually presents in children and young adults after normal milestones with headache, hemiparesis, cortical blindness, and hemianopia due to infarct not corresponding to the distribution of major vessels. Myoclonus, epilepsy with ragged red fibers (MERRF), caused by A-to-G transition at nucleotide 8344 in tRNALys gene [3], is characterized by myopathy, seizures, myoclonus, and ataxia. Maternally inherited myopathy and cardiomyopathy (MMC), caused by A-to-G transition at nucleotide 3260 in tRNALeu(UUR) affect young adults [4]. Finally, maternally inherited Leigh syndrome (MILS), a severe infantile encephalopathy with symmetric lesions in the basal ganglia, and neuropathy, ataxia, and retinitis pigmentosa (NARP) are associated with the m. 8993T>G mutation in ATP6. It is interesting that this mutation is expressed as NARP when mutant mtDNA proportion is 70–90% of total mtDNA and as MILS when this proportion is >90% [1]. Also, a few families have been described with distinct mitochondrial syndromes due to mutations in the mitochondrial tRNASer(UCN) [5].
Mutations in mtDNA are transmitted by maternal inheritance because at fertilization all mitochondria are derived from the oocyte [6]. Hence, a mother carrying a mtDNA mutation will transmit it to all offspring, both males and females, but only her daughters will pass it to the progenies.
When a mtDNA pathogenic mutation affects some but not all genomes in a cell or in a tissue, the whole individual will harbor two population of mtDNA, the one normal and the other mutant, a condition known as heteroplasmy [6]. Mutations in mtDNA are usually heteroplasmic with mutant and wild type mtDNAs coexisting in tissues. It is assumed that in normal tissues all mtDNA were considered identical (homoplasmy), but it is not correct at all. Indeed, NGS techniques have revealed the coexistence of mutated mtDNA variants (among 0.2 and 2% of heteroplasmy) in unaffected individuals. Definitively, the concept of heteroplasmy is not absolute, but a minimal critical number of mutant genomes in affected tissue is needed for biochemical and clinical manifestations (threshold effect). As a consequence, even small decreases in the amount of wild type mtDNA may be sufficient to cause disease in such conditions. This might account for the high-variable clinical phenotypes involving many organs and tissues even in the same family. Furthermore, there is a possible variability in mtDNA even in the same subject at different times this may lead to phenotype progression with age and disparities among different tissues.
In this context, it is really difficult to determine the pathogenicity of novel mutations in mt-tRNA genes, particularly when are associated with dominance, segregation in a tissue or homoplasmy. However, in some conditions homoplasmic mutations have been demonstrated to have a pathogenic role.

2. Mitochondrial tRNASer(UCN) Gene

A girl presenting with profound intellectual disability, spastic tetraplegia, myoclonic epilepticus status, sensorineural hearing loss and myopathy, with severe COX deficiency at muscle biopsy, carried a novel homoplasmic m.7484A>G mutation in the tRNASer(UCN) gene. Her clinical history was characterized by epilepsia partialis continua and vomiting, typical of MELAS syndrome [7], leading to generalized mioclonus epilepticus status and severe cerebral atrophy with rapid motor and cognitive deterioration. Her mother, carrying the same mutation, showed cognitive deficit, cerebellar ataxia, myoclonic epilepsy, sensorineural hearing loss and myopathy with COX deficient ragged-red fibers consistent with MERRF syndrome.
Mitochondrial tRNASer(UCN) is considered a hot-spot for non-syndromic and aminoglycoside-induced hearing loss, including the m.7444G>A, m.7445A>C, m.7445A>G, m.7510T>C, m.7511T>C mutations [8][9][10][11][12]. However, many patients have been described with more extensive neurological disease including progressive external ophthalmoplegia (PEO), epilepsy, myoclonus, ataxia, and myopathy [13][14][15][16].
Moreover, mitochondrial tRNASer(UCN) mutations were associated with non-neurological disease such as cardiovascular disease [17], hypertension [18], renal disease [19], polycystic ovary syndrome and insulin resistance [20].

Table 1 shows all of the mutations identified in the tRNASer(UCN) and the clinical phenotypes from the literature.

Table 1. Clinical phenotypes and the genetic characteristics of the cases reported from literature.
Locus Mutation Homoplasmy Heteroplasmy Status MitoTIP Disease First Report
MT-COI/
MT-TS1 precursor
m.7443A>G + - Reported - Hearing loss Pandya et al., 1999 [9]
MT-COI/
MT-TS1 precursor
m.7444G>A + - Reported - Aminoglycoside-induced deafness and non syndromic hearing loss Zhu et al., 2006 [8]
m.7444G>A (with m.3460G>A or m.14484T>C) LHON Brown et al., 1995 [21]
m.7444G>A (with m.1555A>G) Hearing loss Pandya et al., 1999 [9]
Aminoglycoside-induced deafness Yuan et al., 2005 [22]
m.7444G>A (with m.1494C>T) Aminoglycoside-induced and non syndromic hearing loss Yuan et al., 2007 [23]
m.7444G>A (with m.6498C>A) Non syndromic hearing loss, diabetes and congenital visual loss Mkaouar-Rebai et al., 2013 [24]
MT-TS1 precursor m.7445A>C + - Reported - Hearing loss Pandya et al., 1999 [9]
MT-TS1 precursor m.7445A>G + + Confirmed - Sensorineural hearing loss Reid et al., 1994 [10]
Progressive hearing loss and palmoplantar keratoderma Sevior et al., 1998 [25]
Sensorineural deafness and NEPPK Martin et al., 2000 [26]
MT-TS1 precursor m.7445A>T + - Reported - Sensorineural hearing loss Chen et al., 2008 [27]
MT-TS1 m.7451A>T - + Reported 80.70% C-PEO, ptosis Blakely et al., 2013 [28]
MT-TS1 m.7453G>A + - Reported 68.00% Fatal neonatal lactic acidosis Gotz et al., 2012 [29]
Neonatal lactic acidosis, exercise intolerance, mild ID Riley et al., 2020 [30]
MT-TS1 m.7456A>G + - Unclear 16.00% Deafness Jacobs et al., 2005 [31]
MT-TS1 m.7458G>A - + Reported 86.00% PEO Souilem et al., 2010 [32]
MT-TS1 m.7462C>T + - Reported 11.20% Hearing loss Uehara et al., 2010 [33]
MT-TS1 m.7471del nd nd Reported 4.30% Maternally inherited hypertension Yang et al., 2020 [34]
Deafness Tang et al., 2015 [35]
MT-TS1 m.7471_7472insC
(reported as m.7472insC)
+ + Confirmed - Hearing loss, ataxia, dysarthria and, occasionally, peripheral sensory neuropathy and focal myoclonus Tiranti et al., 1995 [36]
Sensorineural hearing loss, myoclonic epilepsy, ataxia, MR Jaksch et al., 1998 [15]
Epilepsia partialis continua, ataxia, lactic acidosis, myopathy, sensorineural hearing loss, severe headaches, and MR Schuelke et al., 1998 [16]
Non syndromic sensorineural hearing loss and monomelic amyotrophic Fetoni et al., 2004 [37]
Non syndromic sensorineural hearing loss Hutchin et al., 2001 [38]
MT-TS1 m.7472A>C (with m.7471_7472insC) + + Reported 3.2% Early onset myopathy and execise intollerance Pulkes et al., 2005 [39]
Bilateral hearing loss, MR, fatal neurodegeneration with cognitive decline, epilepsia partialis continua, myopathy, lactic acidosis and ataxia Cardaioli et al., 2006 [40]
MT-TS1 m.7474A>G nd nd Reported 0.00% Hearing loss Zheng et al., 2020 [41]
MT-TS1 m.7474del nd nd Reported 34.80% Hearing loss and epilepsy Zhao et al., 2008 [14]
MT-TS1 m.7480T>C - + Reported 46.60% Progressive mitochondrial myopathy, deafness, dementia and ataxia Bidooki et al., 2004 [42]
MT-TS1 m.7486G>A - + Reported 50.50% C-PEO Bacalhau et al., 2018 [43]
MT-TS1 m.7492C>T + - Reported 0.10% Hypertension Liu et al., 2014 [18]
Hearing loss Peng et al., 2020 [44]
Polycystic ovary syndrome-insulin resistance Dyng et al., 2017 [20]
MT-TS1 m.7496T>C nd nd Reported 58.30% Hearing Loss Tang et al., 2015 [35]
MT-TS1 m.7497G>A + + Confirmed Pathogenic Severe progressive myopathy, muscle weakness and increase exercise intolerance Jaksch et al., 1998 [5]
Exercise intolerance, muscle pain and lactic acidemia Grafakou et al., 2003 [45]
Muscular weakness, atrophy and severe dystrophic myopathy Muller et al., 2005 [46]
MT-TS1 m.7501T>A nd nd Reported 1.90% Cardiovascular disease Zaragoza et al., 2010 [17]
Renal disease patient Imasawa et al., 2014 [19]
MT-TS1 m.7502C>T nd nd Reported 8.20% Tic disorder Jiang et al., 2020 [47]
MT-TS1 m.7505T>C + - Reported 58.60% Maternally inherited hearing loss Tang et al., 2010 [48]
MT-TS1 m.7506G>A - + Reported 81.40% PEO and hearing loss Cardaioli et al., 2007 [13]
MT-TS1 m.7507A>G + - Reported - Cardio-respiratory failure and fatal lactic acidosis, severe hearing loss and progressive exercise intolerance McCann et al., 2015 [49]
MT-TS1 m.7510T>C - + Confirmed Pathogenic Non syndromic sensorineural hearing loss Hutchin et al., 2000 [11]
MT-TS1 m.7511T>C + + Confirmed Pathogenic Non syndromic hearing loss Sue et al., 1999 [12]
MT-TS1 m.7512T>C + + Reported 64.20% MERRF/MELAS overlap syndrome Nakamura et al., 1995 [50]
Sensorineural hearing loss, myoclonic epilepsy, ataxia, MR Jaksch et al., 1998 [15]
Sensorineural hearing loss, myoclonus epilepsy, ataxia, severe psychomotor retardation, short stature, and diabetes mellitus Ramelli et al., 2006 [51]
MELAS syndrome Lindberg et al., 2008 [52]
Legend—LHON (Leber hereditary optic neuropathy); NEPPK (non-epidermolytic palmoplantar keratoderma); C-PEO (chronic-progressive external ophthalmoplegia), ID (intellectual disability); MR (mental retardation), MERRF (myoclonic epilepsy with ragged-red fibers); MELAS (myopathy with encephalopathy, lactic acidosis and stroke-like episodes); nd (not determined).
First, the mutation was absent in 56910 mtDNA genomes according to the website Mitomap and in our 162 Italian individuals (normal and disease control subjects), indicating that it is unlikely in the general population or in association with other known pathogenic mtDNA mutations. In addition, it was associated with abnormal morphological and biochemical mitochondrial features in the proband and in her mother. Moreover, a marked decrease in level of four mtDNA-encoded polypeptides was observed using a western blot analysis, supporting a correlation of the m.7484A>G mutation with the impairment of mitochondrial protein synthesis.
This change disrupts the highly conserved third base of the anticodon triplet of tRNASer(UCN), that may compromise its function as tRNA identity determinant. In fact, many anticondon sequences are recognized by their cognate aminoacyl tRNA synthetase for specific amino acid addition [53][54] and one single base change may lead to noncharging [55], resulting in a lack of functional tRNASer(UCN) which is necessary for protein synthesis.
Furthermore, heteroplasmy has been traditionally considered important evidence for the pathogenicity of a mtDNA mutation, and an important determinant of the clinical phenotype [56], while homoplasmic changes generally tend to be underestimated.
However, the mutation found, although homoplasmic in the proband and her mother, is pathogenic. Indeed this is strongly supported by literature with the increasing evidence that pathogenic homoplasmic mtDNA defects are more common than previously thought [57], in particular in the tRNASer(UCN) gene [5][8][9][10][12][15][16][29]. In fact, such mutations are often homoplasmic or at high levels of heteroplasmy, suggesting that high threshold of the mutated mtDNA must accumulate for pathogenicity [24].
Mutations affecting the anticodon triplet of tRNAs, are hypothetically likely to be pathogenic because interfere with the decoding process of a tRNA. Suppositionally these variants are incompatible with early developmental stages or lethal in embryogenesis and for this reason are rarely reported [58]; in fact, only seven previous mutations have been described associated to different phenotypes, especially encephalomyopathies [59][60][61][62][63][64][65].
Finally, the possibility that this mutation might represent a neutral polymorphism, is not supported by the absence of mutations in the exome.

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