RT Journal Article SR Electronic T1 Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3’-end processing JF bioRxiv FD Cold Spring Harbor Laboratory SP 378448 DO 10.1101/378448 A1 Makenzie Saoura A1 Christopher A. Powell A1 Robert Kopajtich A1 Ahmad Alahmad A1 Haya H. AL-Balool A1 Buthaina Albash A1 Majid Alfadhel A1 Charlotte L. Alston A1 Enrico Bertini A1 Penelope Bonnen A1 Drago Bratkovic A1 Rosalba Carrozzo A1 Maria A. Donati A1 Michela Di Nottia A1 Daniele Ghezzi A1 Amy Goldstein A1 Eric Haan A1 Rita Horvath A1 Joanne Hughes A1 Federica Invernizzi A1 Eleonora Lamantea A1 Benjamin Lucas A1 Kyla-Gaye Pinnock A1 Maria Pujantell A1 Shamima Rahman A1 Pedro Rebelo-Guiomar A1 Saikat Santra A1 Daniela Verrigni A1 Robert McFarland A1 Holger Prokisch A1 Robert W. Taylor A1 Louis Levinger A1 Michal Minczuk YR 2018 UL http://biorxiv.org/content/early/2018/08/08/378448.abstract AB Dysfunction of mitochondrial gene expression, caused by mutations in either the mitochondrial or nuclear genomes, is associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism. For instance, pathogenic mutations have been identified in the genes encoding enzymes involved in the precursor transcript processing, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, which is responsible for endonucleolytic cleavage of the 3’ ends of mitochondrial pre-tRNAs. Here, we report the identification of sixteen novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy and lactic acidosis. We provided further evidence for the pathogenicity of the three previously reported variants by studying the RNase Z activity in an in vitro system and applied this recombinant system to investigate all novel missense variants, confirming the pathogenic role of these new ELAC2 mutations. We also modelled the residues affected by missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the individuals with novel ELAC2 variants have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile-onset forms of hypertrophic cardiomyopathy and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, possibly indicating a functional link between tumorigenesis and mitochondrial RNA metabolism.