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Uniparental isodisomy of chromosome 2 causing MRPL44-related multisystem mitochondrial disease

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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.

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Acknowledgements

We are indebted to the family members who participated in this study. We are grateful to Dr Christopher Carroll and Professor Anu Suomalainen for the information kindly provided for Western blot analysis of MRPL44.

Funding

AS is supported by a UK Medical Research Council Senior Non-Clinical Fellowship (MC_PC_13029). IJH is supported by the Ikerbasque Science Foundation, the Carlos III Health Program and the Biodonostia Research Institute. RWT is supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease, the Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, the MRC/EPSRC Molecular Pathology Node and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children (http://www.newcastle-mitochondria.com/). CB is supported by the MSA Trust (JH61030/18).

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Authors and Affiliations

  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

    Alejandro Horga, Andreea Manole, Enrico Bugiardini, Ros Quinlivan, Mary M. Reilly, Michael G. Hanna, Robert D. S. Pitceathly, Antonella Spinazzola & Henry Houlden

  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

    Alejandro Horga, Enrico Bugiardini, Ros Quinlivan, Mary M. Reilly, Michael G. Hanna, Robert D. S. Pitceathly & Henry Houlden

  3. Neuromuscular Diseases Unit, Department of Neurology, Hospital Clínico San Carlos and Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040, Madrid, Spain

    Alejandro Horga

  4. Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Andreea Manole, Alan M. Pittman & Henry Houlden

  5. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Royal Free Campus, London, NW3 2PF, UK

    Alice L. Mitchell, Ilaria Dalla Rosa, Ian J. Holt & Antonella Spinazzola

  6. Neurometabolic Unit, the National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK

    Iain P. Hargreaves

  7. Neurosciences Department, Calderdale Royal Hospital, Halifax, HX3 0PW, UK

    Walied Mowafi

  8. Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, WC1N 1PJ, UK

    Conceição Bettencourt

  9. Institute of Neuroscience, Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

    Emma L. Blakely, Langping He & Robert W. Taylor

  10. Neurogenetic Unit, the National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK

    James M. Polke & Catherine E. Woodward

  11. Lysholm Department of Neuroradiology, the National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK

    Sachit Shah

  12. Biodonostia Health Research Institute, 20014, San Sebastián, Spain

    Ian J. Holt

  13. Ikerbasque, Basque Foundation for Science, 48013, Bilbao, Spain

    Ian J. Holt

Authors
  1. Alejandro Horga
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  2. Andreea Manole
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  22. Henry Houlden
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Contributions

AH, AM, ARM, AS and HH designed and conceptualised the study. AH, AM, ARM, EB, IPH, WM, CB, ELB, LH, JMP, CEW, IDR, SS, AMP, RQ, MMR, RWT, IJH, MGH, RDSP, AS and HH performed analysis and interpreted the data. AH, AS and HH drafted the manuscript. All authors critically revised the manuscript, contributed significantly to this work and declare to meet the ICMJE criteria for authorship.

Corresponding authors

Correspondence to Alejandro Horga or Henry Houlden.

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Informed consent was obtained from all individual participants included in the study.

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Horga, A., Manole, A., Mitchell, A.L. et al. Uniparental isodisomy of chromosome 2 causing MRPL44-related multisystem mitochondrial disease. Mol Biol Rep 48, 2093–2104 (2021). https://doi.org/10.1007/s11033-021-06188-1

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