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Mutations in mitochondrial DNA causing tubulointerstitial kidney disease

Lookup NU author(s): Dr Jennifer Duff, Professor Neil SheerinORCiD, Professor John SayerORCiD, Professor Gavin Hudson, Professor Patrick Chinnery

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Abstract

© 2017 Connor et al. 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, tRNALeu1and 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.

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Author(s): 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

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2017

Volume: 13

Issue: 3

Online publication date: 07/03/2017

Acceptance date: 07/02/2017

Date deposited: 04/07/2017

ISSN (print): 1553-7390

ISSN (electronic): 1553-7404

Publisher: Public Library of Science

URL: https://doi.org/10.1371/journal.pgen.1006620

DOI: 10.1371/journal.pgen.1006620

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