title: A mutation in MT-TW causes a tRNA processing defect and reduced mitochondrial function in a family with Leigh syndrome.
abstract: Leigh syndrome (LS) is a progressive mitochondrial neurodegenerative disorder, whose symptoms most commonly include psychomotor delay with regression, lactic acidosis and a failure to thrive. Here we describe three siblings with LS, but with additional manifestations including hypertrophic cardiomyopathy, hepatosplenomegaly, cholestatic hepatitis, and seizures. All three affected siblings were found to be homoplasmic for an m. 5559A>G mutation in the T stem of the mitochondrial DNA-encoded MT-TW by next generation sequencing. The m.5559A>G mutation causes a reduction in the steady state levels of tRNA(Trp) and this decrease likely affects the stability of other mitochondrial RNAs in the patient fibroblasts. We observe accumulation of an unprocessed transcript containing tRNA(Trp), decreased de novo protein synthesis and consequently lowered steady state levels of mitochondrial DNA-encoded proteins that compromise mitochondrial respiration. Our results show that the m.5559A>G mutation at homoplasmic levels causes LS in association with severe multi-organ disease (LS-plus) as a consequence of dysfunctional mitochondrial RNA metabolism.
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Western Australia 6009, Australia.
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Duff
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Western Australia 6009, Australia.
authors.forename: Anne-Marie J
authors.initials: AM
authors.lastname: Shearwood
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Western Australia 6009, Australia.
authors.forename: Judith
authors.initials: J
authors.lastname: Ermer
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Western Australia 6009, Australia.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gooding
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Western Australia 6009, Australia.
authors.forename: Tara R
authors.initials: TR
authors.lastname: Richman
authors.affiliation: Metabolic Unit, Department of Pediatric and Adolescent Medicine, Princess Margaret Hospital, 6008 Perth, Western Australia, Australia.
authors.forename: Shanti
authors.initials: S
authors.lastname: Balasubramaniam
authors.affiliation: Murdoch Childrens Research Institute and Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Western Australia 6009, Australia; School of Chemistry and Biochemistry, The University of Western Australia, Western Australia 6009, Australia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Rackham
authors.affiliation: Neurogenetic unit, Department of Neurology, Royal Perth Hospital, Western Australia, Australia.
authors.forename: Phillipa J
authors.initials: PJ
authors.lastname: Lamont
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Western Australia 6009, Australia; School of Chemistry and Biochemistry, The University of Western Australia, Western Australia 6009, Australia. Electronic address: aleksandra.filipovska@uwa.edu.au.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Filipovska
mesh_terms: D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007888:Leigh Disease / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation; D012323:RNA Processing, Post-Transcriptional; D012364:RNA, Transfer, Trp / Q000235:genetics* / Q000378:metabolism*; D035781:Siblings
chemical_list: D012364:RNA, Transfer, Trp
keywords: Leigh syndrome; MT-TW; Mitochondrial disease; Multi-organ mitochondrial disease; OXPHOS; tRNA; tRNA tryptophan