Journal article
Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome
NJ Lake, BD Webb, DA Stroud, TR Richman, B Ruzzenente, AG Compton, HS Mountford, J Pulman, C Zangarelli, M Rio, N Bodaert, Z Assouline, MD Sherpa, EE Schadt, SM Houten, J Byrnes, EM McCormick, Z Zolkipli-Cunningham, K Haude, Z Zhang Show all
American Journal of Human Genetics | CELL PRESS | Published : 2017
Abstract
The synthesis of all 13 mitochondrial DNA (mtDNA)-encoded protein subunits of the human oxidative phosphorylation (OXPHOS) system is carried out by mitochondrial ribosomes (mitoribosomes). Defects in the stability of mitoribosomal proteins or mitoribosome assembly impair mitochondrial protein translation, causing combined OXPHOS enzyme deficiency and clinical disease. Here we report four autosomal-recessive pathogenic mutations in the gene encoding the small mitoribosomal subunit protein, MRPS34, in six subjects from four unrelated families with Leigh syndrome and combined OXPHOS defects. Whole-exome sequencing was used to independently identify all variants. Two splice-site mutations were i..
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Awarded by National Institute of Child Health and Human Development
Funding Acknowledgements
This project was supported by Australian National Health and Medical Research Council (NHMRC) fellowships and project grants to D.R.T., A.G.C., A.F., and D.A.S. (1022896, 1068409, 1068056, 1058442, 1078273, 1125390, 1107094, 1070916), the Australian Research Council (DP170103000 to A.F.), the Jaxson Flynt Research Fund (M.J.F. and J.B.), the Joseph and Pat Holveck Research Fund (M.J.F. and Z.Z.-C.), an Australian Postgraduate Award (N.J.L.), a NHMRC scholarship (1017174 to H.S.M.), Australian Mitochondrial Disease Foundation scholarship (N.J.L. and H.S.M.), the Victorian Government's Operational Infrastructure Support Program (D.R.T. and A.G.C.), the Icahn Institute for Genomics and Multiscale Biology, NIH National Institute of Child Health and Human Development (NICHD) (grant K08HD086827 to B.D.W.), the NIH (R01GM077465 and 1R35GM122455 to V.K.M.), the French Muscular Dystrophy Association (AFM grant #19876 to M.D.M.), and Genomit (01GML1207 to A.R.). We acknowledge the use of bioresources of the Necker Imagine DNA biobank (BB-033-00065). We thank the subjects, families, and multi-disciplinary clinical care providers for their involvement. The authors acknowledge the GeneMatcher tool, which enabled the identification of two of the families described in this study, and the Monash Biomedical Proteomics Facility, Monash University, for the provision of instrumentation, training, and technical support. We thank Associate Professor Susan Donath for her expert advice on appropriate statistical analyses. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.