Connor, TM; Hoer, S; Mallett, A; Gale, DP; Gomez-Duran, A; Posse, V; Antrobus, R; ... Maxwell, PH; + view all 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; - view fewer (2017) Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. PLOS Genetics , 13 (3) , Article e1006620. 10.1371/journal.pgen.1006620.

Preview

Text Gale_journal.pgen.1006620.pdf - Published Version Download (2MB) | Preview

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.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as JSONXMLCSV

Downloads by country - last 12 months

Export as CSVXMLJSON

Archive Staff Only

View Item