Journal article
Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease
SSC Amarasekera, DH Hock, NJ Lake, SE Calvo, SW Grønborg, EI Krzesinski, DJ Amor, MC Fahey, C Simons, F Wibrand, VK Mootha, M Lek, S Lunke, Z Stark, E Østergaard, J Christodoulou, DR Thorburn, DA Stroud, AG Compton
Human Molecular Genetics | OXFORD UNIV PRESS | Published : 2023
DOI: 10.1093/hmg/ddad069
Abstract
MRPL39 encodes one of 52 proteins comprising the large subunit of the mitochondrial ribosome (mitoribosome). In conjunction with 30 proteins in the small subunit, the mitoribosome synthesizes the 13 subunits of the mitochondrial oxidative phosphorylation (OXPHOS) system encoded by mitochondrial Deoxyribonucleic acid (DNA). We used multi-omics and gene matching to identify three unrelated individuals with biallelic variants in MRPL39 presenting with multisystem diseases with severity ranging from lethal, infantile-onset (Leigh syndrome spectrum) to milder with survival into adulthood. Clinical exome sequencing of known disease genes failed to diagnose these patients; however quantitative prot..
View full abstractRelated Projects (2)
Grants
Awarded by National Institutes of Health
Funding Acknowledgements
This research was supported by grants and fellowships from the Australian National Health and Medical Research Council (1140851, 1164479, 1159456, 1155244, 2009732 plus 111353 to the Australian Genomics Health Alliance), plus grants from the US Department of Defense Congressionally Directed Medical Research Programs PR170396, the Australian Mito Foundation, the Vincent Chiodo Charitable Trust and the Victorian Government's Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to JC is generously supported by The Royal Children's Hospital Foundation. We acknowledge the Bio21 Mass Spectrometry and Proteomics Facility (MMSPF) for the provision of instrumentation, training, and technical support. The Yale Center for Mendelian Genomics (NIH M#UM1HG006504-05) is funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. DHH is supported by a Melbourne International Research Scholarship and the Mito Foundation PhD Top-up Scholarship. VKM is an Investigator at the Howard Hughes Medical Institute.