Mutations in mitochondrial DNA causing tubulointerstitial kidney disease.
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 mitochondri...
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| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-03-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006620&type=printable |
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| author | Thomas M Connor Simon Hoer Andrew Mallett Daniel P Gale Aurora Gomez-Duran Viktor Posse Robin Antrobus Pablo Moreno Marco Sciacovelli Christian Frezza Jennifer Duff Neil S Sheerin John A Sayer Margaret Ashcroft Michael S Wiesener Gavin Hudson Claes M Gustafsson Patrick F Chinnery Patrick H Maxwell |
| author_facet | Thomas M Connor Simon Hoer Andrew Mallett Daniel P Gale Aurora Gomez-Duran Viktor Posse Robin Antrobus Pablo Moreno Marco Sciacovelli Christian Frezza Jennifer Duff Neil S Sheerin John A Sayer Margaret Ashcroft Michael S Wiesener Gavin Hudson Claes M Gustafsson Patrick F Chinnery Patrick H Maxwell |
| author_sort | Thomas M Connor |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6685dd0c725b4fedbc65cf57e4a7ebde |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2017-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-6685dd0c725b4fedbc65cf57e4a7ebde2025-08-20T02:03:16ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-03-01133e100662010.1371/journal.pgen.1006620Mutations in mitochondrial DNA causing tubulointerstitial kidney disease.Thomas M ConnorSimon HoerAndrew MallettDaniel P GaleAurora Gomez-DuranViktor PosseRobin AntrobusPablo MorenoMarco SciacovelliChristian FrezzaJennifer DuffNeil S SheerinJohn A SayerMargaret AshcroftMichael S WiesenerGavin HudsonClaes M GustafssonPatrick F ChinneryPatrick H MaxwellTubulointerstitial 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006620&type=printable |
| spellingShingle | Thomas M Connor Simon Hoer Andrew Mallett Daniel P Gale Aurora Gomez-Duran Viktor Posse Robin Antrobus Pablo Moreno Marco Sciacovelli Christian Frezza Jennifer Duff Neil S Sheerin John A Sayer Margaret Ashcroft Michael S Wiesener Gavin Hudson Claes M Gustafsson Patrick F Chinnery Patrick H Maxwell Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. PLoS Genetics |
| title | Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. |
| title_full | Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. |
| title_fullStr | Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. |
| title_full_unstemmed | Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. |
| title_short | Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. |
| title_sort | mutations in mitochondrial dna causing tubulointerstitial kidney disease |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006620&type=printable |
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