Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing.

TitleMutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing.
Publication TypeJournal Article
Year of Publication2019
AuthorsSaoura, M, Powell, CA, Kopajtich, R, Alahmad, A, Al-Balool, HH, Albash, B, Alfadhel, M, Alston, CL, Bertini, E, Bonnen, PE, Bratkovic, D, Carrozzo, R, Donati, MA, Di Nottia, M, Ghezzi, D, Goldstein, A, Haan, E, Horvath, R, Hughes, J, Invernizzi, F, Lamantea, E, Lucas, B, Pinnock, K-G, Pujantell, M, Rahman, S, Rebelo-Guiomar, P, Santra, S, Verrigni, D, McFarland, R, Prokisch, H, Taylor, RW, Levinger, L, Minczuk, M
JournalHum Mutat
Date Published2019 May 02

Mutations in either the mitochondrial or nuclear genomes are 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, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, responsible for endonucleolytic cleavage of the 3' ends of mitochondrial pre-tRNAs. Here, we report the identification of 16 novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy (HCM), and lactic acidosis. We provide evidence for the pathogenicity of the novel missense variants by studying the RNase Z activity in an in vitro system. We also modeled the residues affected by a missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the affected individuals have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile-onset forms of HCM 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, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism.

Alternate JournalHum. Mutat.
Citation Key10.1002/humu.23777
PubMed ID31045291
Grant ListR15GM101620 / / National Institutes of Health /
MC_UU_00015/4 / / Medical Research Council / United Kingdom
203105/Z/16/Z / / Wellcome Trust / United Kingdom
MC_U105697135 / / Medical Research Council, UK /
MC_UU_00015/4 / / Medical Research Council, UK /
PD/BD/105750/2014 / / Fundação para a Ciência e a Tecnologia /
G0601943 / / MRC Center for Neuromuscular Diseases /
G016354/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
NIHR-HCS-D12-03-04 / / National Institute for Health Research (NIHR) /
109915/Z/15/Z / / Wellcome Investigator /
MR/N025431/1 / / Medical Research Council (UK) /
309548 / / European Research Council / International
UK/Turkey / / Newton Fund /
MR/N027302/1 / / Newton Fund /
GGP15041 / / Telethon Foundation /
GTB12001J / / Telethon Foundation /
/ / Great Ormond Street Hospital Children's Charity /
/ / Lily Foundation /