title: Mutations in mitochondrial DNA causing tubulointerstitial kidney disease.
abstract: Tubulointerstitial kidney disease is an important cause of progressive renal failure whose aetiology is incompletely understood. We analysed a large pedigree with maternally inherited tubulointerstitial kidney disease and identified a homoplasmic substitution in the control region of the mitochondrial genome (m.547A>T). While mutations in mtDNA coding sequence are a well recognised cause of disease affecting multiple organs, mutations in the control region have never been shown to cause disease. Strikingly, our patients did not have classical features of mitochondrial disease. Patient fibroblasts showed reduced levels of mitochondrial tRNAPhe, tRNALeu1 and reduced mitochondrial protein translation and respiration. Mitochondrial transfer demonstrated mitochondrial transmission of the defect and in vitro assays showed reduced activity of the heavy strand promoter. We also identified further kindreds with the same phenotype carrying a homoplasmic mutation in mitochondrial tRNAPhe (m.616T>C). Thus mutations in mitochondrial DNA can cause maternally inherited renal disease, likely mediated through reduced function of mitochondrial tRNAPhe.
authors.affiliation: Oxford Kidney Unit, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Thomas M
authors.identifier: 0000-0002-5896-7084
authors.initials: TM
authors.lastname: Connor
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, United Kingdom.
authors.forename: Simon
authors.identifier: 0000-0002-6071-967X
authors.initials: S
authors.lastname: Hoer
authors.affiliation: Kidney Health Service, Royal Brisbane and Women's Hospital, School of Medicine, The University of Queensland, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mallett
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom.
authors.forename: Daniel P
authors.identifier: 0000-0002-9170-1579
authors.initials: DP
authors.lastname: Gale
authors.affiliation: MRC-Mitochondrial Biology Unit, University of Cambridge, United Kingdom.
authors.forename: Aurora
authors.identifier: 0000-0002-5895-6860
authors.initials: A
authors.lastname: Gomez-Duran
authors.affiliation: Institute of Biomedicine, University of Gothenburg, Sweden.
authors.forename: Viktor
authors.initials: V
authors.lastname: Posse
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, United Kingdom.
authors.forename: Robin
authors.identifier: 0000-0001-8608-4011
authors.initials: R
authors.lastname: Antrobus
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, United Kingdom.
authors.forename: Pablo
authors.initials: P
authors.lastname: Moreno
authors.affiliation: MRC Cancer Unit, University of Cambridge, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Sciacovelli
authors.affiliation: MRC Cancer Unit, University of Cambridge, United Kingdom.
authors.forename: Christian
authors.identifier: 0000-0002-3293-7397
authors.initials: C
authors.lastname: Frezza
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Duff
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Neil S
authors.identifier: 0000-0002-3743-2371
authors.initials: NS
authors.lastname: Sheerin
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: John A
authors.identifier: 0000-0003-1881-3782
authors.initials: JA
authors.lastname: Sayer
authors.affiliation: Department of Medicine, University of Cambridge, United Kingdom.
authors.forename: Margaret
authors.identifier: 0000-0002-0066-3707
authors.initials: M
authors.lastname: Ashcroft
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wiesener
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Hudson
authors.affiliation: Institute of Biomedicine, University of Gothenburg, Sweden.
authors.forename: Claes M
authors.initials: CM
authors.lastname: Gustafsson
authors.affiliation: MRC-Mitochondrial Biology Unit, University of Cambridge, United Kingdom.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: School of Clinical Medicine, Cambridge University, Cambridge, United Kingdom.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine; D001706:Biopsy; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D008040:Genetic Linkage; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics*; D007684:Kidney Tubules / Q000473:pathology*; D007930:Leucine / Q000737:chemistry; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D010101:Oxygen Consumption; D010375:Pedigree; D010641:Phenotype; D010649:Phenylalanine / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D052097:Quadriceps Muscle / Q000473:pathology; D012343:RNA, Transfer / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D010649:Phenylalanine; D012343:RNA, Transfer; D000118:Acetylglucosaminidase; D007930:Leucine