MRPS25 mutations impair mitochondrial translation and cause encephalomyopathy

Hum Mol Genet. 2019 Aug 15;28(16):2711-2719. doi: 10.1093/hmg/ddz093.

Enrico Bugiardini ¹ ², Alice L Mitchell ³, Ilaria Dalla Rosa ³, Hue-Tran Horning-Do ⁴, Alan M Pitmann ², Olivia V Poole ¹ ², Janice L Holton ¹, Sachit Shah ¹, Cathy Woodward ⁵, Iain Hargreaves ⁶, Rosaline Quinlivan ¹, Alexey Amunts ⁷ ⁸, Rudolf J Wiesner ⁴, Henry Houlden ², Ian J Holt ³ ⁹ ¹⁰ ¹¹, Michael G Hanna ¹ ², Robert D S Pitceathly ¹ ², Antonella Spinazzola ¹ ³

Affiliations

1 MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
2 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
3 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Royal Free Campus, London NW3 2PF, UK.
4 Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Köln, 50931 Köln, Germany.
5 Neurogenetic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
6 Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
7 Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, 17165 Solna, Sweden.
8 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
9 Biodonostia Health Research Institute, 20014 San Sebastián, Spain.
10 IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
11 CIBERNED (Center for Networked Biomedical Research on Neurodegenerative Diseases, Ministry of Economy and Competitiveness, Institute Carlos III), Madrid, Spain.

PMID: 31039582 DOI: 10.1093/hmg/ddz093

Abstract

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.

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