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

Makenzie Saoura, Christopher A Powell, Robert Kopajtich, Ahmad Alahmad, Haya H Al-Balool, Buthaina Albash, Majid Alfadhel, Charlotte L Alston, Enrico Bertini, Penelope Bonnen, Drago Bratkovic, Rosalba Carrozzo, Maria A Donati, Michela Di Nottia, Daniele Ghezzi, Amy Goldstein, Eric Haan, Rita Horvath, Joanne Hughes, Federica InvernizziEleonora Lamantea, Benjamin Lucas, Kyla-Gaye Pinnock, Maria Pujantell, Shamima Rahman, Pedro Rebelo-Guiomar, Saikat Santra, Daniela Verrigni, Robert McFarland, Holger Prokisch, Robert W Taylor, Louis Levinger, Michal Minczuk

Research output: Contribution to journalArticle

Abstract

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 sixteen novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy 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 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 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 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, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalHuman Mutation
DOIs
Publication statusE-pub ahead of print - May 2 2019

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Hypertrophic Cardiomyopathy
Transfer RNA
Mutation
RNA Precursors
Mitochondrial Diseases
Lactic Acidosis
Mitochondrial Genes
Missense Mutation
Electron Transport
Virulence
Prostatic Neoplasms
Respiration
Carcinogenesis
Fibroblasts
Genome
RNase Z
Enzymes
Genes
mitochondrial RNA

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Saoura, M., Powell, C. A., Kopajtich, R., Alahmad, A., Al-Balool, H. H., Albash, B., ... Minczuk, M. (2019). Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing. Human Mutation. https://doi.org/10.1002/humu.23777

Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing. / Saoura, Makenzie; Powell, Christopher A; Kopajtich, Robert; Alahmad, Ahmad; Al-Balool, Haya H; Albash, Buthaina; Alfadhel, Majid; Alston, Charlotte L; Bertini, Enrico; Bonnen, Penelope; Bratkovic, Drago; Carrozzo, Rosalba; Donati, Maria A; Nottia, Michela Di; Ghezzi, Daniele; Goldstein, Amy; Haan, Eric; Horvath, Rita; Hughes, Joanne; Invernizzi, Federica; Lamantea, Eleonora; Lucas, Benjamin; Pinnock, Kyla-Gaye; Pujantell, Maria; Rahman, Shamima; Rebelo-Guiomar, Pedro; Santra, Saikat; Verrigni, Daniela; McFarland, Robert; Prokisch, Holger; Taylor, Robert W; Levinger, Louis; Minczuk, Michal.

In: Human Mutation, 02.05.2019.

Research output: Contribution to journalArticle

Saoura, M, Powell, CA, Kopajtich, R, Alahmad, A, Al-Balool, HH, Albash, B, Alfadhel, M, Alston, CL, Bertini, E, Bonnen, P, Bratkovic, D, Carrozzo, R, Donati, MA, Nottia, MD, 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 2019, 'Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing', Human Mutation. https://doi.org/10.1002/humu.23777
Saoura, Makenzie ; Powell, Christopher A ; Kopajtich, Robert ; Alahmad, Ahmad ; Al-Balool, Haya H ; Albash, Buthaina ; Alfadhel, Majid ; Alston, Charlotte L ; Bertini, Enrico ; Bonnen, Penelope ; Bratkovic, Drago ; Carrozzo, Rosalba ; Donati, Maria A ; Nottia, Michela Di ; Ghezzi, Daniele ; Goldstein, Amy ; Haan, Eric ; Horvath, Rita ; Hughes, Joanne ; Invernizzi, Federica ; Lamantea, Eleonora ; Lucas, Benjamin ; Pinnock, Kyla-Gaye ; Pujantell, Maria ; Rahman, Shamima ; Rebelo-Guiomar, Pedro ; Santra, Saikat ; Verrigni, Daniela ; McFarland, Robert ; Prokisch, Holger ; Taylor, Robert W ; Levinger, Louis ; Minczuk, Michal. / Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing. In: Human Mutation. 2019.
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abstract = "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 sixteen novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy 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 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 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 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, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism This article is protected by copyright. All rights reserved.",
author = "Makenzie Saoura and Powell, {Christopher A} and Robert Kopajtich and Ahmad Alahmad and Al-Balool, {Haya H} and Buthaina Albash and Majid Alfadhel and Alston, {Charlotte L} and Enrico Bertini and Penelope Bonnen and Drago Bratkovic and Rosalba Carrozzo and Donati, {Maria A} and Nottia, {Michela Di} and Daniele Ghezzi and Amy Goldstein and Eric Haan and Rita Horvath and Joanne Hughes and Federica Invernizzi and Eleonora Lamantea and Benjamin Lucas and Kyla-Gaye Pinnock and Maria Pujantell and Shamima Rahman and Pedro Rebelo-Guiomar and Saikat Santra and Daniela Verrigni and Robert McFarland and Holger Prokisch and Taylor, {Robert W} and Louis Levinger and Michal Minczuk",
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T1 - Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing

AU - Saoura, Makenzie

AU - Powell, Christopher A

AU - Kopajtich, Robert

AU - Alahmad, Ahmad

AU - Al-Balool, Haya H

AU - Albash, Buthaina

AU - Alfadhel, Majid

AU - Alston, Charlotte L

AU - Bertini, Enrico

AU - Bonnen, Penelope

AU - Bratkovic, Drago

AU - Carrozzo, Rosalba

AU - Donati, Maria A

AU - Nottia, Michela Di

AU - Ghezzi, Daniele

AU - Goldstein, Amy

AU - Haan, Eric

AU - Horvath, Rita

AU - Hughes, Joanne

AU - Invernizzi, Federica

AU - Lamantea, Eleonora

AU - Lucas, Benjamin

AU - Pinnock, Kyla-Gaye

AU - Pujantell, Maria

AU - Rahman, Shamima

AU - Rebelo-Guiomar, Pedro

AU - Santra, Saikat

AU - Verrigni, Daniela

AU - McFarland, Robert

AU - Prokisch, Holger

AU - Taylor, Robert W

AU - Levinger, Louis

AU - Minczuk, Michal

N1 - This article is protected by copyright. All rights reserved.

PY - 2019/5/2

Y1 - 2019/5/2

N2 - 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 sixteen novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy 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 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 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 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, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism This article is protected by copyright. All rights reserved.

AB - 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 sixteen novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy 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 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 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 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, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism This article is protected by copyright. All rights reserved.

U2 - 10.1002/humu.23777

DO - 10.1002/humu.23777

M3 - Article

C2 - 31045291

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

ER -