A novel mitochondrial tRNAIle point mutation associated with chronic progressive external ophthalmoplegia and hyperCKemia

Souilem, Sihem; Chebel, S.; Mancuso, Michelangelo; Petrozzi, Lucia; Siciliano, Gabriele; Frih-Ayed, Mahbouba; Hentati, Fayçal; Amouri, Rim

doi:10.1016/j.jns.2010.08.065

Cited by 13 publications

(5 citation statements)

References 17 publications

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“…In one case report, CPEO was found to be linked to a G4308A mutation in the T-stem of mt-tRNA Ile ; this substitution disrupts a conserved GC base pair (Figure 1) (Schaller et al, 2011; Souilem et al, 2011). While there was no evidence of maternal inheritance, patient blood samples were homoplasmic for the wild type mt-tRNA Ile , and muscle tissue obtained by biopsy was heteroplasmic.…”

Section: Mitochondrial Trna Mutations and Diseasementioning

confidence: 99%

Transfer RNA and human disease

2014

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Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are “hotspots” for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing). Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.

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Section: Mitochondrial Trna Mutations and Diseasementioning

confidence: 99%

Transfer RNA and human disease

2014

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“…This mutation has been shown to be associated with a wide range of symptoms, and there is evidence the outcome is also being determined by nuclear genetic factors [ 34 ]. It is associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) [ 74 ], maternally inherited deafness and diabetes (MIDD) [ 75 ] and chronic progressive external ophthalmoplegia (CPEO) [ 76 ]. Other reported features include renal failure [ 77 ], isolated myopathy, cardiomyopathy, seizures, migraine, ataxia, cognitive impairment, bowel dysmotility and short stature [ 78 ].…”

Section: Resultsmentioning

confidence: 99%

Ancient mitochondrial DNA pathogenic variants putatively associated with mitochondrial disease

et al. 2020

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Mitochondrial DNA variants associated with diseases are widely studied in contemporary populations, but their prevalence has not yet been investigated in ancient populations. The publicly available AmtDB database contains 1443 ancient mtDNA Eurasian genomes from different periods. The objective of this study was to use this data to establish the presence of pathogenic mtDNA variants putatively associated with mitochondrial diseases in ancient populations. The clinical significance, pathogenicity prediction and contemporary frequency of mtDNA variants were determined using online platforms. The analyzed ancient mtDNAs contain six variants designated as being "confirmed pathogenic" in modern patients. The oldest of these, m.7510T>C in the MT-TS1 gene, was found in a sample from the Neolithic period, dated 5800-5400 BCE. All six have well established clinical association, and their pathogenic effect is corroborated by very low population frequencies in contemporary populations. Analysis of the geographic location of the ancient samples, contemporary epidemiological trends and probable haplogroup association indicate diverse spatiotemporal dynamics of these variants. The dynamics in the prevalence and distribution is conceivably result of de novo mutations or human migrations and subsequent evolutionary processes. In addition, ten variants designated as possibly or likely pathogenic were found, but the clinical effect of these is not yet well established and further research is warranted. All detected mutations putatively associated with mitochondrial disease in ancient mtDNA samples are in tRNA coding genes. Most of these mutations are in a mt-tRNA type (Model 2) that is characterized by loss of D-loop/T-loop interaction. Exposing pathogenic variants in ancient human populations expands our understanding of their origin and prevalence dynamics.

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“…We observed mutation levels of 97% in muscle, 45% in blood and 87% in urinary sediment. Mutant load was assessed using a described densitometric method as shown [Souilem et al, ]; and C: Expression level of respiratory chain complexes. Muscle homogenate from controls (C) and patient (Pt) were separated by SDS‐PAGE and Western blot analysis carried out using antibodies against representative subunits of CI (NDUFS3), CII (SDHA), CIII (Core2 and RISP), CIV (COX II), and CV (alpha).…”

Section: Clinical Reportmentioning

confidence: 99%

Novel MTCYB mutation in a young patient with recurrent stroke‐like episodes and status epilepticus

Mancuso

Nesti

Ienco

et al. 2014

American J of Med Genetics Pt A

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The acronym "MELAS" (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) denotes patients with histological, biochemical and/or molecular evidence of mitochondrial disease who experience stroke-like episodes. Here we report on a girl with repeated stroke-like episodes and status epilepticus, who was diagnosed with MELAS due to a novel mitochondrial cytochrome b gene (MTCYB) mutation (m.15092G>A, which predicts p.G116S). Western blotting and in silico analyses suggested that this mutation could affect the stability of complex III. Cytochrome b is the only mtDNA-encoded subunit of respiratory chain complex III. Mutations in MTCYB have been associated with isolated mitochondrial myopathy and exercise intolerance, and rarely with multisystem and/or central nervous system involvement. If the m.3243A>G and other common MELAS mutations are absent in several tissues, MTCYB should be sequenced from muscle in patients with stroke-like episodes, especially if muscle histology does not support a mitochondrial myopathy and lactic acidosis is absent.

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A novel mitochondrial tRNAIle point mutation associated with chronic progressive external ophthalmoplegia and hyperCKemia

Cited by 13 publications

References 17 publications

Transfer RNA and human disease

Transfer RNA and human disease

Ancient mitochondrial DNA pathogenic variants putatively associated with mitochondrial disease

Novel MTCYB mutation in a young patient with recurrent stroke‐like episodes and status epilepticus

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