Mutations in mitochondrial DNA causing tubulointerstitial kidney disease

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 (2017)

Publication Type: Journal article

Publication year: 2017

Journal

PLoS Genetics Public Library of Science

Book Volume: 13

Pages Range: e1006620

Journal Issue: 3

DOI: 10.1371/journal.pgen.1006620

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.

Involved external institutions

University of Gothenburg / Göteborgs universitet SE Sweden (SE) Newcastle University GB United Kingdom (GB) University of Cambridge GB United Kingdom (GB) Royal Free Hospital GB United Kingdom (GB) University of Queensland AU Australia (AU) Oxford University Hospitals NHS Foundation Trust GB United Kingdom (GB)

How to cite

APA:

Connor, T.M., Hoer, S., Mallett, A., Gale, D.P., Gomez-Duran, A., Posse, V.,... Maxwell, P.H. (2017). Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. PLoS Genetics, 13(3), e1006620. https://dx.doi.org/10.1371/journal.pgen.1006620

MLA:

Connor, Thomas M., et al. "Mutations in mitochondrial DNA causing tubulointerstitial kidney disease." PLoS Genetics 13.3 (2017): e1006620.

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