Mutations in mitochondrial DNA causing tubulointerstitial kidney disease

Connor, Thomas M., Hoer, Simon, Mallett, Andrew, Gale, Daniel P., Gomez-Duran, Aurora, Posse, Viktor, Antrobus, Robin, Moreno, Pablo, Sciacovelli, Marco, Frezza, Christian, Duff, Jennifer, Sheerin, Neil S., Sayer, John A., Ashcroft, Margaret, Wiesener, Michael S., Hudson, Gavin, Gustafsson, Claes M., Chinnery, Patrick F., and Maxwell, Patrick H. (2017) Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. PLoS Genetics, 13. e1006620.

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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.

Item ID: 67885
Item Type: Article (Research - C1)
ISSN: 1553-7404
Copyright Information: © 2017 Connoret al. This is an open access article distributed underthe 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.
Funders: Wellcome Trust (WT), National Institute for Health Research (NIHR), Cambridge and Imperial Biomedical Research Centres, Medical Research Council
Projects and Grants: WT 19710
Date Deposited: 14 Jul 2021 05:22
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320213 Medical genetics (excl. cancer genetics) @ 30%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320214 Nephrology and urology @ 70%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 100%
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