|
|||||
|
|
Uniparental isodisomy of chromosome 2 causing MRPL44-related multisystem mitochondrial disease |
|
| Authors: | Horga Alejandro Manole Andreea Mitchell Alice L Bugiardini Enrico Hargreaves Iain P Mowafi Walied Bettencourt Conceição Blakely Emma L He Langping Polke James M Woodward Catherine E Dalla Rosa Ilaria Shah Sachit Pittman Alan M Quinlivan Ros Reilly Mary M Taylor Robert W Holt Ian J Hanna Michael G Pitceathly Robert D S Spinazzola Antonella Houlden Henry |
| Institution: | 1.MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK ;2.Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK ;3.Neuromuscular Diseases Unit, Department of Neurology, Hospital Clínico San Carlos and Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040, Madrid, Spain ;4.Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK ;5.Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Royal Free Campus, London, NW3 2PF, UK ;6.Neurometabolic Unit, the National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK ;7.Neurosciences Department, Calderdale Royal Hospital, Halifax, HX3 0PW, UK ;8.Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, WC1N 1PJ, UK ;9.Institute of Neuroscience, Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK ;10.Neurogenetic Unit, the National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK ;11.Lysholm Department of Neuroradiology, the National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK ;12.Biodonostia Health Research Institute, 20014, San Sebastián, Spain ;13.Ikerbasque, Basque Foundation for Science, 48013, Bilbao, Spain ; |
| Abstract: | Mutations in nuclear-encoded protein subunits of the mitochondrial ribosome are an increasingly recognised cause of oxidative phosphorylation system (OXPHOS) disorders. Among them, mutations in the MRPL44 gene, encoding a structural protein of the large subunit of the mitochondrial ribosome, have been identified in four patients with OXPHOS defects and early-onset hypertrophic cardiomyopathy with or without additional clinical features. A 23-year-old individual with cardiac and skeletal myopathy, neurological involvement, and combined deficiency of OXPHOS complexes in skeletal muscle was clinically and genetically investigated. Analysis of whole-exome sequencing data revealed a homozygous mutation in MRPL44 (c.467 T?>?G), which was not present in the biological father, and a region of homozygosity involving most of chromosome 2, raising the possibility of uniparental disomy. Short-tandem repeat and genome-wide SNP microarray analyses of the family trio confirmed complete maternal uniparental isodisomy of chromosome 2. Mitochondrial ribosome assembly and mitochondrial translation were assessed in patient derived-fibroblasts. These studies confirmed that c.467 T?>?G affects the stability or assembly of the large subunit of the mitochondrial ribosome, leading to impaired mitochondrial protein synthesis and decreased levels of multiple OXPHOS components. This study provides evidence of complete maternal uniparental isodisomy of chromosome 2 in a patient with MRPL44-related disease, and confirms that MRLP44 mutations cause a mitochondrial translation defect that may present as a multisystem disorder with neurological involvement. |
| Keywords: | |
| 本文献已被 SpringerLink 等数据库收录！ | |