Publication Details

Title :

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


Hum Mutat.

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Saoura M1, Powell CA2, Kopajtich R3,4, Alahmad A5,6, Al-Balool HH6, Albash B6, Alfadhel M7, Alston CL5, Bertini E8, Bonnen PE9, Bratkovic D10, Carrozzo R8, Donati MA11, Di Nottia M8, Ghezzi D12,13, Goldstein A14, Haan E10, Horvath R15, Hughes J16, Invernizzi F12, Lamantea E12, Lucas B1, Pinnock KG1, Pujantell M1, Rahman S17, Rebelo-Guiomar P2,18, Santra S19, Verrigni D8, McFarland R4, Prokisch H3,4, Taylor RW5, Levinger L1, Minczuk M2.


1 York College, The City University of New York, Jamaica, New York.

2 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.

3 Genetics of Mitochondrial Disorders, Institute of Human Genetics, Technische Universität München, Munich, Germany.

4 Genetics of Mitochondrial Disorders, Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

5 Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.

6 Kuwait Medical Genetics Center, Kuwait City, Kuwait.

7 Genetics Division, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.

8 Department of Neurosciences, Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesu’ Children’s Research Hospital, IRCCS, Rome, Italy.

9 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

10 Metabolic Clinic, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia.

11 Metabolic Unit, A. Meyer Children’s Hospital, Florence, Italy.

12 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

13 Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

14 Mitochondrial Medicine Frontier Program, Children’s Hospital of Philadelphia, Philadelphia, USA.

15 Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

16 National Centre for Inherited Metabolic Disorders, Temple Street Children’s University Hospital, Dublin, Ireland.

17 Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK.

18 Graduate Program in Areas of Basic and Applied Biology, University of Porto, Porto, Portugal.

19 Department of Clinical Inherited Metabolic Disorders, Birmingham Children’s Hospital, Birmingham, UK.

Year of Publication:





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.