biostudies-literatureAmarasekera SSCHoward Hughes Medical InstituteBio21 Mass Spectrometry and Proteomics FacilityYale Center for Mendelian GenomicsNational Heart, Lung, and Blood InstituteGSP Coordinating CenterNHGRI NIH HHSUS Department of Defense Congressionally Directed Medical Research ProgramsNational Human Genome Research InstituteVincent Chiodo Charitable Trust and the Victorian Government’s Operational Infrastructure Support ProgramAustralian National Health and Medical Research CouncilAustralian Mito FoundationRoyal Children's Hospital Foundation2441-2454https://www.ebi.ac.uk/biostudies/studies/S-EPMC10360397biostudies-literatureUnknown32(15)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 proteomics identified a specific decrease in the abundance of large but not small mitoribosomal subunitsHuman molecular geneticsMulti-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease.PMC10360397PR17039611552442009732M#UM1HG006504-05115945611135311644791140851U24 HG008956UM1 HG006504Lek MCalvo SEChristodoulou JGronborg SWWibrand FOstergaard EAmarasekera SSCStark ZAmor DJLunke SKrzesinski EIMootha VKStroud DAFahey MCHock DHLake NJThorburn DRCompton AGSimons CfalseMulti-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease.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 proteomics identified a specific decrease in the abundance of large but not small mitoribosomal subunits2023-01-01T00:00:00Z2023 Jul2026-06-03T05:07:34.681Z2026-04-24T03:14:43.737ZS-EPMC103603973713345110.1093/hmg/ddad069