Mutations in mitochondrial DNA causing tubulointerstitial kidney disease.

TitleMutations in mitochondrial DNA causing tubulointerstitial kidney disease.
Publication TypeJournal Article
Year of Publication2017
AuthorsConnor, 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
JournalPLoS Genet
Volume13
Issue3
Paginatione1006620
Date Published2017 Mar
ISSN1553-7404
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.

DOI10.1371/journal.pgen.1006620
Alternate JournalPLoS Genet.
Citation Key10.1371/journal.pgen.1006620
PubMed ID28267784
PubMed Central IDPMC5360345
Grant ListMR/K002201/1 / / Medical Research Council / United Kingdom
G0802266 / / Medical Research Council / United Kingdom
G0701320 / / Medical Research Council / United Kingdom
MR/K002201/2 / / Medical Research Council / United Kingdom
G1002528 / / Medical Research Council / United Kingdom