المؤلفون: Rosaline Quinlivan, Mohammed Y Khanji, Luis R. Lopes, Daniel M Jones, Perry M. Elliott

المصدر: European Heart Journal. 40:397-398

مصطلحات موضوعية: Male, medicine.medical_specialty, MCARDLE DISEASE, business.industry, Heart Ventricles, MEDLINE, Magnetic Resonance Imaging, Cine, Cardiomyopathy, Hypertrophic, medicine.disease, Electrocardiography, Internal medicine, medicine, Glycogen Storage Disease Type V, Humans, Muscle, Skeletal, Cardiology and Cardiovascular Medicine, business, Glycogen storage disease type V, Aged

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6d0f166d4a18f9f66e6e18899a440e94Test
https://doi.org/10.1093/eurheartj/ehy783Test

المؤلفون: Henry Houlden, Ian Holt, Enrico Bugiardini, Hue-Tran Horning-Do, Alexey Amunts, Janice L. Holton, Cathy E. Woodward, Alice L Mitchell, Sachit Shah, Michael G. Hanna, Rosaline Quinlivan, Rudolf J. Wiesner, Alan M Pitmann, Antonella Spinazzola, Robert D S Pitceathly, Ilaria Dalla Rosa, Olivia V. Poole, Iain P. Hargreaves

المصدر: Human Molecular Genetics

مصطلحات موضوعية: Adult, Male, Ribosomal Proteins, RM, Mitochondrial translation, Mitochondrial disease, Protein subunit, Respiratory chain, Biology, Mitochondrion, Ribosome, Models, Biological, Mitochondrial Proteins, 03 medical and health sciences, 0302 clinical medicine, Mitochondrial myopathy, Mitochondrial Encephalomyopathies, Exome Sequencing, Genetics, medicine, Mitochondrial ribosome, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Homozygote, General Medicine, Fibroblasts, medicine.disease, Magnetic Resonance Imaging, Mitochondria, Pedigree, Phenotype, Protein Biosynthesis, Mutation, General Article, 030217 neurology & neurosurgery, Biomarkers

الوصف: Mitochondrial disorders are clinically and genetically heterogeneous and are associated with a variety of disease mechanisms. Defects of mitochondrial protein synthesis account for the largest subgroup of disorders manifesting with impaired respiratory chain capacity; yet, only a few have been linked to dysfunction in the protein components of the mitochondrial ribosomes. Here, we report a subject presenting with dyskinetic cerebral palsy and partial agenesis of the corpus callosum, while histochemical and biochemical analyses of skeletal muscle revealed signs of mitochondrial myopathy. Using exome sequencing, we identified a homozygous variant c.215C>T in MRPS25, which encodes for a structural component of the 28S small subunit of the mitochondrial ribosome (mS25). The variant segregated with the disease and substitutes a highly conserved proline residue with leucine (p.P72L) that, based on the high-resolution structure of the 28S ribosome, is predicted to compromise inter-protein contacts and destabilize the small subunit. Concordant with the in silico analysis, patient’s fibroblasts showed decreased levels of MRPS25 and other components of the 28S subunit. Moreover, assembled 28S subunits were scarce in the fibroblasts with mutant mS25 leading to impaired mitochondrial translation and decreased levels of multiple respiratory chain subunits. Crucially, these abnormalities were rescued by transgenic expression of wild-type MRPS25 in the mutant fibroblasts. Collectively, our data demonstrate the pathogenicity of the p.P72L variant and identify MRPS25 mutations as a new cause of mitochondrial translation defect.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::62b4cd36ca2d1a1d119ca863faac8c23Test
https://researchonline.ljmu.ac.uk/id/eprint/11032/1/enrico.pdfTest