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Lookup NU author(s): Ahmad Alahmad, Haya AL-Balool, Dr Charlotte Alston, Professor Rita HorvathORCiD, Professor Robert Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc. 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.
Author(s): Saoura 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
Publication type: Article
Publication status: Published
Journal: Human Mutation
Year: 2019
Volume: 40
Issue: 10
Pages: 1731-1748
Print publication date: 01/10/2019
Online publication date: 02/05/2019
Acceptance date: 29/04/2019
Date deposited: 07/10/2019
ISSN (print): 1059-7794
ISSN (electronic): 1098-1004
Publisher: John Wiley & Sons, Inc.
URL: https://doi.org/10.1002/humu.23777
DOI: 10.1002/humu.23777
PubMed id: 31045291
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