Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy
Robert Kopajtich
(1)
,
Thomas Nicholls
(2)
,
Joanna Rorbach
(2)
,
Metodi d. Metodiev
(3)
,
Peter Freisinger
(4)
,
Hanna Mandel
(5)
,
Arnaud Vanlander
(6)
,
Daniele Ghezzi
(7)
,
Rosalba Carrozzo
(8)
,
Robert w. Taylor
(9)
,
Klaus Marquard
(10)
,
Kei Murayama
(11)
,
Thomas Wieland
(12)
,
Thomas Schwarzmayr
(12)
,
Johannes a. Mayr
(13)
,
Sarah f. Pearce
(2)
,
Christopher a. Powell
(2)
,
Ann Saada
(14)
,
Akira Ohtake
(15)
,
Federica Invernizzi
(7)
,
Eleonora Lamantea
(7)
,
Ewen w. Sommerville
(9)
,
Angela Pyle
(9)
,
Patrick f. Chinnery
(9)
,
Ellen Crushell
(16)
,
Yasushi Okazaki
(17)
,
Masakazu Kohda
(17)
,
Yoshihito Kishita
(17)
,
Yoshimi Tokuzawa
(17)
,
Zahra Assouline
(18)
,
Marlène Rio
(18)
,
François Feillet
(19, 20)
,
Bénédict Mousson de camaret
(21)
,
Dominique Chrétien
(3)
,
Arnold Munnich
(3, 18)
,
Björn Menten
(22)
,
Tom Sante
(22)
,
Joél Smet
(6)
,
Luc Régal
(23)
,
Abraham Lorber
(5)
,
Asaad Khoury
(5)
,
Massimo Zeviani
(2, 7)
,
Tim m. Strom
(12)
,
Thomas Meitinger
(24, 25, 26)
,
Enrico s. Bertini
(8)
,
Rudy Van coster
(6)
,
Thomas Klopstock
(26, 27, 28)
,
Agnès Rötig
(3)
,
Tobias b. Haack
(12)
,
Michal Minczuk
(2)
,
Holger Prokisch
(12)
1
HMGU -
Helmholtz Zentrum München = German Research Center for Environmental Health
2 MRC Mitochondrial Biology Unit
3 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
4 Reutlingen University
5 Rambam Health Care Campus
6 Department of Pediatric Neurology and Metabolism [Ghent]
7 Fondazione IRCCS Istituto Neurologico "Carlo Besta"
8 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
9 Wellcome Trust Centre for Mitochondrial Research
10 Klinikum Stuttgart
11 Department of Metabolism [Chiba]
12 Institute of Human Genetics
13 Paracelsus Medical University and Universitätsklinikum Salzburg
14 Department of Genetics and Metabolic Diseases and the Monique and Jacques Roboh Department of Genetic Research
15 Saitama Medical University
16 National Centre for Inherited Metabolic Disorders [Dublin]
17 Saitama University
18 Service de Génétique Médicale [CHU Necker]
19 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
20 Service de Médecine Infantile I [CHRU Nancy]
21 Service des Maladies Héréditaires du Métabolisme
22 Center for Medical Genetics [Ghent]
23 Hôpitaux universitaires de Louvain
24 DZHK - German Center for Cardiovascular Research
25 Munich Heart Alliance
26 SyNergy - Munich Cluster for systems neurology [Munich]
27 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
28 Friedrich-Baur Institute
2 MRC Mitochondrial Biology Unit
3 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
4 Reutlingen University
5 Rambam Health Care Campus
6 Department of Pediatric Neurology and Metabolism [Ghent]
7 Fondazione IRCCS Istituto Neurologico "Carlo Besta"
8 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
9 Wellcome Trust Centre for Mitochondrial Research
10 Klinikum Stuttgart
11 Department of Metabolism [Chiba]
12 Institute of Human Genetics
13 Paracelsus Medical University and Universitätsklinikum Salzburg
14 Department of Genetics and Metabolic Diseases and the Monique and Jacques Roboh Department of Genetic Research
15 Saitama Medical University
16 National Centre for Inherited Metabolic Disorders [Dublin]
17 Saitama University
18 Service de Génétique Médicale [CHU Necker]
19 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
20 Service de Médecine Infantile I [CHRU Nancy]
21 Service des Maladies Héréditaires du Métabolisme
22 Center for Medical Genetics [Ghent]
23 Hôpitaux universitaires de Louvain
24 DZHK - German Center for Cardiovascular Research
25 Munich Heart Alliance
26 SyNergy - Munich Cluster for systems neurology [Munich]
27 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
28 Friedrich-Baur Institute
Ann Saada
- Fonction : Auteur
- PersonId : 922366
François Feillet
- Fonction : Auteur
- PersonId : 763712
- IdRef : 070690626
Michal Minczuk
- Fonction : Auteur
- PersonId : 785881
- ORCID : 0000-0001-8242-1420
- IdRef : 231400705
Résumé
Respiratory chain deficiencies exhibit a wide variety of clinical phenotypes resulting from defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mtDNA or mutations in nuclear genes coding for mitochondrial proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial physiology. By whole-exome and candidate gene sequencing, we identified 11 individuals from 9 families carrying compound heterozygous or homozygous mutations in GTPBP3, encoding the mitochondrial GTP-binding protein 3. Affected individuals from eight out of nine families presented with combined respiratory chain complex deficiencies in skeletal muscle. Mutations in GTPBP3 are associated with a severe mitochondrial translation defect, consistent with the predicted function of the protein in catalyzing the formation of 5-taurinomethyluridine (τm(5)U) in the anticodon wobble position of five mitochondrial tRNAs. All case subjects presented with lactic acidosis and nine developed hypertrophic cardiomyopathy. In contrast to individuals with mutations in MTO1, the protein product of which is predicted to participate in the generation of the same modification, most individuals with GTPBP3 mutations developed neurological symptoms and MRI involvement of thalamus, putamen, and brainstem resembling Leigh syndrome. Our study of a mitochondrial translation disorder points toward the importance of posttranscriptional modification of mitochondrial tRNAs for proper mitochondrial function.