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Mutations in mitochondrial DNA causing tubulointerstitial kidney disease

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Connor, TM 
Mallett, A 
Gale, DP 
Gomez Duran, A 


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.



Acetylglucosaminidase, Biopsy, DNA, Mitochondrial, Female, Fibroblasts, Genetic Linkage, Humans, Kidney Diseases, Kidney Tubules, Leucine, Male, Mitochondria, Mutation, Oxygen Consumption, Pedigree, Phenotype, Phenylalanine, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Quadriceps Muscle, RNA, Transfer

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PLoS Genetics

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Medical Research Council (MR/K002201/2)
MRC (unknown)
Medical Research Council (MC_UU_12022/6)
Wellcome Trust (101876/Z/13/Z)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (096956/Z/11/Z)
This study was supported by a Wellcome Trust Senior Investigator Award to PHM [19710], by the National Institute for Health Research Cambridge and Imperial Biomedical Research Centres, and a Medical Research Council Clinical Training Fellowship awarded to TMC. The core facilities at CIMR were funded by a Wellcome Trust strategic award [100140]. PFC is a Wellcome Trust Senior Fellow in Clinical Science [101876/Z/13/Z] within the Medical Research Council Mitochondrial Biology Unit [MC_UP_1501/2]. CMG was supported by The Swedish Medical Research Council and The Knut and Alice Wallenberg Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.