Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder

Abstract Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA ami...

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Autores principales:	Marisa W. Friederich, Sharita Timal, Christopher A. Powell, Cristina Dallabona, Alina Kurolap, Sara Palacios-Zambrano, Drago Bratkovic, Terry G. J. Derks, David Bick, Katelijne Bouman, Kathryn C. Chatfield, Nadine Damouny-Naoum, Megan K. Dishop, Tzipora C. Falik-Zaccai, Fuad Fares, Ayalla Fedida, Ileana Ferrero, Renata C. Gallagher, Rafael Garesse, Micol Gilberti, Cristina González, Katherine Gowan, Clair Habib, Rebecca K. Halligan, Limor Kalfon, Kaz Knight, Dirk Lefeber, Laura Mamblona, Hanna Mandel, Adi Mory, John Ottoson, Tamar Paperna, Ger J. M. Pruijn, Pedro F. Rebelo-Guiomar, Ann Saada, Bruno Sainz, Hayley Salvemini, Mirthe H. Schoots, Jan A. Smeitink, Maciej J. Szukszto, Hendrik J. ter Horst, Frans van den Brandt, Francjan J. van Spronsen, Joris A. Veltman, Eric Wartchow, Liesbeth T. Wintjes, Yaniv Zohar, Miguel A. Fernández-Moreno, Hagit N. Baris, Claudia Donnini, Michal Minczuk, Richard J. Rodenburg, Johan L. K. Van Hove
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Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Science Q
Acceso en línea:	https://doaj.org/article/5e2c03b6081043e5add48aba3812d059
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spelling	oai:doaj.org-article:5e2c03b6081043e5add48aba3812d0592021-12-02T14:39:26ZPathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder10.1038/s41467-018-06250-w2041-1723https://doaj.org/article/5e2c03b6081043e5add48aba3812d0592018-10-01T00:00:00Zhttps://doi.org/10.1038/s41467-018-06250-whttps://doaj.org/toc/2041-1723Abstract Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients’ fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.Marisa W. FriederichSharita TimalChristopher A. PowellCristina DallabonaAlina KurolapSara Palacios-ZambranoDrago BratkovicTerry G. J. DerksDavid BickKatelijne BoumanKathryn C. ChatfieldNadine Damouny-NaoumMegan K. DishopTzipora C. Falik-ZaccaiFuad FaresAyalla FedidaIleana FerreroRenata C. GallagherRafael GaresseMicol GilbertiCristina GonzálezKatherine GowanClair HabibRebecca K. HalliganLimor KalfonKaz KnightDirk LefeberLaura MamblonaHanna MandelAdi MoryJohn OttosonTamar PapernaGer J. M. PruijnPedro F. Rebelo-GuiomarAnn SaadaBruno SainzHayley SalveminiMirthe H. SchootsJan A. SmeitinkMaciej J. SzuksztoHendrik J. ter HorstFrans van den BrandtFrancjan J. van SpronsenJoris A. VeltmanEric WartchowLiesbeth T. WintjesYaniv ZoharMiguel A. Fernández-MorenoHagit N. BarisClaudia DonniniMichal MinczukRichard J. RodenburgJohan L. K. Van HoveNature PortfolioarticleScienceQENNature Communications, Vol 9, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Science Q
spellingShingle	Science Q Marisa W. Friederich Sharita Timal Christopher A. Powell Cristina Dallabona Alina Kurolap Sara Palacios-Zambrano Drago Bratkovic Terry G. J. Derks David Bick Katelijne Bouman Kathryn C. Chatfield Nadine Damouny-Naoum Megan K. Dishop Tzipora C. Falik-Zaccai Fuad Fares Ayalla Fedida Ileana Ferrero Renata C. Gallagher Rafael Garesse Micol Gilberti Cristina González Katherine Gowan Clair Habib Rebecca K. Halligan Limor Kalfon Kaz Knight Dirk Lefeber Laura Mamblona Hanna Mandel Adi Mory John Ottoson Tamar Paperna Ger J. M. Pruijn Pedro F. Rebelo-Guiomar Ann Saada Bruno Sainz Hayley Salvemini Mirthe H. Schoots Jan A. Smeitink Maciej J. Szukszto Hendrik J. ter Horst Frans van den Brandt Francjan J. van Spronsen Joris A. Veltman Eric Wartchow Liesbeth T. Wintjes Yaniv Zohar Miguel A. Fernández-Moreno Hagit N. Baris Claudia Donnini Michal Minczuk Richard J. Rodenburg Johan L. K. Van Hove Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder
description	Abstract Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients’ fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.
format	article
author	Marisa W. Friederich Sharita Timal Christopher A. Powell Cristina Dallabona Alina Kurolap Sara Palacios-Zambrano Drago Bratkovic Terry G. J. Derks David Bick Katelijne Bouman Kathryn C. Chatfield Nadine Damouny-Naoum Megan K. Dishop Tzipora C. Falik-Zaccai Fuad Fares Ayalla Fedida Ileana Ferrero Renata C. Gallagher Rafael Garesse Micol Gilberti Cristina González Katherine Gowan Clair Habib Rebecca K. Halligan Limor Kalfon Kaz Knight Dirk Lefeber Laura Mamblona Hanna Mandel Adi Mory John Ottoson Tamar Paperna Ger J. M. Pruijn Pedro F. Rebelo-Guiomar Ann Saada Bruno Sainz Hayley Salvemini Mirthe H. Schoots Jan A. Smeitink Maciej J. Szukszto Hendrik J. ter Horst Frans van den Brandt Francjan J. van Spronsen Joris A. Veltman Eric Wartchow Liesbeth T. Wintjes Yaniv Zohar Miguel A. Fernández-Moreno Hagit N. Baris Claudia Donnini Michal Minczuk Richard J. Rodenburg Johan L. K. Van Hove
author_facet	Marisa W. Friederich Sharita Timal Christopher A. Powell Cristina Dallabona Alina Kurolap Sara Palacios-Zambrano Drago Bratkovic Terry G. J. Derks David Bick Katelijne Bouman Kathryn C. Chatfield Nadine Damouny-Naoum Megan K. Dishop Tzipora C. Falik-Zaccai Fuad Fares Ayalla Fedida Ileana Ferrero Renata C. Gallagher Rafael Garesse Micol Gilberti Cristina González Katherine Gowan Clair Habib Rebecca K. Halligan Limor Kalfon Kaz Knight Dirk Lefeber Laura Mamblona Hanna Mandel Adi Mory John Ottoson Tamar Paperna Ger J. M. Pruijn Pedro F. Rebelo-Guiomar Ann Saada Bruno Sainz Hayley Salvemini Mirthe H. Schoots Jan A. Smeitink Maciej J. Szukszto Hendrik J. ter Horst Frans van den Brandt Francjan J. van Spronsen Joris A. Veltman Eric Wartchow Liesbeth T. Wintjes Yaniv Zohar Miguel A. Fernández-Moreno Hagit N. Baris Claudia Donnini Michal Minczuk Richard J. Rodenburg Johan L. K. Van Hove
author_sort	Marisa W. Friederich
title	Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder
title_short	Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder
title_full	Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder
title_fullStr	Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder
title_full_unstemmed	Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder
title_sort	pathogenic variants in glutamyl-trnagln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/5e2c03b6081043e5add48aba3812d059
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Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder

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