Contribution of a mitochondrial tyrosyl-tRNA synthetase mutation to the phenotypic expression of the deafness-associated tRNASer(UCN) 7511A>G mutation Molecular Bases of Disease

Nuclear modifier genes have been proposed to modify the phenotypic expression of mitochondrial DNA mutations. Using a targeted exome-sequencing approach, here we found that the p.191Gly>Val mutation in mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) interacts with the tRNASer(UCN) 7511A>G mutation in causing deafness. Strikingly, members of a Chinese family bearing both the YARS2 p.191Gly>Val and m.7511A>G mutations displayed much higher penetrance of deafness than those pedigrees carrying only the m.7511A>G mutation. The m.7511A>G mutation changed the A4:U69 base-pairing to G4:U69 pairing at the aminoacyl acceptor stem of tRNASer(UCN) and perturbed tRNASer(UCN) structure and function, including an increased melting temperature, altered conformation, instability, and aberrant aminoacylation of mutant tRNA. Using lymphoblastoid cell lines derived from symptomatic and asymptomatic members of these Chinese families and control subjects, we show that cell lines harboring only the m.7511A>G or p.191Gly>Val mutation revealed relatively mild defects in tRNASer(UCN) or tRNATyr metabolism, respectively. However, cell lines harboring both m.7511A>G and p.191Gly>Val mutations displayed more severe defective aminoacylations and lower tRNASer(UCN) and tRNATyr levels, aberrant aminoacylation, and lower levels of other tRNAs, including tRNAThr, tRNALys, tRNALeu(UUR), and tRNASer(AGY), than those in the cell lines carrying only the m.7511A>G or p.191Gly>Va...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: RNA Source Type: research

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The deafness-associated m.12201T>C mutation affects the A5-U68 base-pairing within the acceptor stem of mitochondrial tRNAHis. The primary defect in this mutation is an alteration in tRNAHis aminoacylation. Here, we further investigate the molecular mechanism of the deafness-associated tRNAHis 12201T>C mutation and test whether the overexpression of the human mitochondrial histidyl-tRNA synthetase gene (HARS2) in cytoplasmic hybrid (cybrid) cells carrying the m.12201T>C mutation reverses mitochondrial dysfunctions. Using molecular dynamics simulations, we demonstrate that the m.12201T>C mutation perturbs the tR...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: RNA Source Type: research
In this study, by adenovirus-mediated delivery and inducible transgenic mouse models, we demonstrate the proliferation of both HCs and SCs by combined Notch1 and Myc activation in in vitro and in vivo inner ear adult mouse models. These proliferating mature SCs and HCs maintain their respective identities. Moreover, when presented with HC induction signals, reprogrammed adult SCs transdifferentiate into HC-like cells both in vitro and in vivo. Finally, our data suggest that regenerated HC-like cells likely possess functional transduction channels and are able to form connections with adult auditory neurons. Epige...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Apoptosis-Inducing Factor Mitochondria-associated-1 gene (AIFM1) encodes a mitochondrial flavin adenine dinucleotide-dependent nicotinamide oxidoreductase, which has a biological role in oxidative phosphorylation (OXPHOS) and in apoptosis pathway [1]. AIFM1 mutations have been reported to be associated with various neurological diseases, including Cowchock syndrome (OMIM 310490) [2], X-linked recessive Charcot-Marie-Tooth disease-4 (CMTX4), X-linked deafness-5 (DFNX5; OMIM 300614) [3], and hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) [4].
Source: Journal of the Neurological Sciences - Category: Neurology Authors: Tags: Letter to the Editor Source Type: research
ConclusionsGrowth differentiation factor-15 can be used not only for the diagnosis of mitochondrial disease, but as an indicator of its acute exacerbation. A stroke-like episode of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes reflects a drastic derangement of multiple amino acids. The involvement of aspartic acid in the episodes should be explored in future studies.
Source: Journal of Medical Case Reports - Category: General Medicine Source Type: research
This study emphasizes the frequency of ALAS2 and SLC25A38 mutations and provides the largest comprehensive analysis to date of genotype/phenotype correlations in CSA. Further studies of CSA patients with data recorded in an international registry would be helpful to improve patient management and establish standardized guidelines. PMID: 31338833 [PubMed - as supplied by publisher]
Source: Hamostaseologie - Category: Hematology Authors: Tags: Br J Haematol Source Type: research
Gulcin Tezcan1, Ekaterina V. Martynova1, Zarema E. Gilazieva1, Alan McIntyre2, Albert A. Rizvanov1 and Svetlana F. Khaiboullina1,3* 1Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia 2Centre for Cancer Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom 3Department of Microbiology and Immunology, University of Nevada, Reno, Reno, NV, United States Inflammation has a crucial role in protection against various pathogens. The inflammasome is an intracellular multiprotein signaling complex that is linked to pathogen sensing and...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Conclusion To conclude, this study suggests a preserved plasticity in the skeletal muscle of a patient with MELAS. More importantly, Resistance Training appears to be a safe and effective method to increase skeletal muscle function in this patient population, and this effect is mediated by both neuromuscular and mitochondrial adaptations. However, particular attention and caution is needed in the interpretation of the data of this single case study and further studies are warranted including larger sample of patients. Ethics Statement For this case study the participant caregiver provided written informed consent. Auth...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
Conclusions: We have shown that severity of MWS symptoms gradually increased with age toward distinct generation-specific phenotypes. A uniform trajectory of disease evolution has encouraged us to postpone institution of IL-1 blockade in affected oligosymptomatic children. This report illustrates importance of close interdisciplinary collaboration. Introduction Cryopyrinopathies (Cryopyrin Associated Periodic Syndromes, CAPS) belong to autoinflammatory disorders with autosomal dominant inheritance caused by the gain-of-function point mutation of NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) gene which en...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
We present the case of a 6-year-old boy with both Kniest dysplasia and underlying mitochondrial disease for examination under anesthesia before cataract surgery. Successful anesthetic management of a patient with Kniest dysplasia and a mitochondrial myopathy is discussed.
Source: A&A Case Reports - Category: Anesthesiology Tags: Case Reports Source Type: research
Publication date: Available online 22 March 2019Source: MitochondrionAuthor(s): Periyasamy Govindaraj, Bindu Rani, Pandarisamy Sundaravadivel, Ayyasamy Vanniarajan, K.P. Indumathi, Nahid Akthar Khan, Perundurai S. Dhandapany, Deepa Selvi Rani, Rakesh Tamang, Ajay Bahl, Calambur Narasimhan, Dharma Rakshak, Andiappan Rathinavel, Kumpati Premkumar, Madhu Khullar, Kumarasamy ThangarajAbstractIdiopathic dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. The aim of this study was to assess the role of mitochondrial DNA (mtDNA) variations and haplogroups in Indian DCM patients. Whole mtDNA ...
Source: Mitochondrion - Category: Biochemistry Source Type: research
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