eprintid: 1545215 rev_number: 25 eprint_status: archive userid: 608 dir: disk0/01/54/52/15 datestamp: 2017-04-06 15:44:37 lastmod: 2021-09-19 23:59:44 status_changed: 2017-04-06 15:44:37 type: article metadata_visibility: show creators_name: Connor, TM creators_name: Hoer, S creators_name: Mallett, A creators_name: Gale, DP creators_name: Gomez-Duran, A creators_name: Posse, V creators_name: Antrobus, R creators_name: Moreno, P creators_name: Sciacovelli, M creators_name: Frezza, C creators_name: Duff, J creators_name: Sheerin, NS creators_name: Sayer, JA creators_name: Ashcroft, M creators_name: Wiesener, MS creators_name: Hudson, G creators_name: Gustafsson, CM creators_name: Chinnery, PF creators_name: Maxwell, PH title: Mutations in mitochondrial DNA causing tubulointerstitial kidney disease ispublished: pub divisions: UCL divisions: B02 divisions: C10 divisions: D17 divisions: G93 note: © 2017 Connor et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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. date: 2017-03-07 date_type: published official_url: http://doi.org/10.1371/journal.pgen.1006620 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_id: 1212965 doi: 10.1371/journal.pgen.1006620 pii: PGENETICS-D-16-02568 lyricists_name: Gale, Daniel lyricists_id: DGALE18 actors_name: Tsochatzis, Emmanouil actors_name: Laslett, David actors_id: ETSOC40 actors_id: DLASL34 actors_role: owner actors_role: impersonator full_text_status: public publication: PLOS Genetics volume: 13 number: 3 article_number: e1006620 event_location: United States issn: 1553-7404 citation: Connor, TM; Hoer, S; Mallett, A; Gale, DP; Gomez-Duran, A; Posse, V; Antrobus, R; ... Maxwell, PH; + view all <#> Connor, TM; Hoer, S; Mallett, A; Gale, DP; Gomez-Duran, A; Posse, V; Antrobus, R; Moreno, P; Sciacovelli, M; Frezza, C; Duff, J; Sheerin, NS; Sayer, JA; Ashcroft, M; Wiesener, MS; Hudson, G; Gustafsson, CM; Chinnery, PF; Maxwell, PH; - view fewer <#> (2017) Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. PLOS Genetics , 13 (3) , Article e1006620. 10.1371/journal.pgen.1006620 <https://doi.org/10.1371/journal.pgen.1006620>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1545215/1/Gale_journal.pgen.1006620.pdf