Clinical, neuroradiological and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder

July 13, 2023

Andrea Accogli 1, Sheng-Jia Lin 2, Mariasavina Severino 3, Sung-Hoon Kim 4, Kevin Huang 2, Clarissa Rocca 5, Megan Landsverk 6, Maha Zaki 7, Almundher Al-Maawali 8, Varunvenkat M Srinivasan 9, Khalid Al-Thihli 8, G Bradly Schaefer 10, Monica Davis 10, Davide Tonduti 11, Chiara Doneda 12, Lara M Marten 13, Chris Mühlhausen 13, Maria Gomez 14, Eleonora Lamantea 15, Rafael Mena 16, Mathilde Nizon 17, Vincent Procaccio 18, Amber Begtrup 19, Aida Telegrafi 19, Hong Cui 19, Heidi L Schulz 20, Julia Mohr 20, Saskia Biskup 21, Mariana Amina Loos 22, Hilda Verónica Aráoz 23, Vincenzo Salpietro 24, Laura Davis Keppen 6, Manali Chitre 25, Cassidy Petree 2, Lucy Raymond 25, Julie Vogt 26, Lindsey B Swayer 27, Alice A Basinger 27, Signe Vandal Pedersen 28, Toni S Pearson 29, Dorothy K Grange 30, Lokesh Lingapp 31, Paige McDunnah 32, Rita Horvath 33, Benjamin Cogne 17, Bertrand Isidor 34, Andreas Hahn 35, Karen Gripp 32, Seyed Mehdi Jafarnejad 36, Elsebet Ostergaard 37, Carlos E Prada 38, Daniele Ghezzi 39, Vykuntaraju K Gowda 9, Robert W Taylor 40, Nahum Sonenberg 4, Henry Houlden 5, Marie Sissler 41, Gaurav K Varshney 42, Reza Maroofian 43

Abstract

Purpose: Biallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype, but with limited neuroradiological data and insufficient evidence for causality of the variants.

Methods: Exome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays, and a zebrafish model.

Results: We report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs and increased blood lactate. In vitro studies showed that variants within the TARS2301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model.

Conclusion: We define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity.

Keywords: TARS2; cerebellar atrophy; mTORC1 signaling; mitochondrial dysfunction; mitochondrial threonyl-tRNA-synthetase; white matter.

  1. Division of Medical Genetics, Department of Specialized Medicine, Montreal Children’s Hospital, McGill University Health Centre (MUHC), Montreal, QC, H4A 3J1, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.
  2. Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
  3. Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  4. Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
  5. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom.
  6. University of South Dakota Sanford School of Medicine Sioux Falls, SD 57105; Sanford Research, Pediatrics and Rare Diseases Group, Sioux Falls, South Dakota 57104, USA.
  7. Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
  8. Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman; Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Oman.
  9. Indira Gandhi institute of child health, Bangalore, India.
  10. Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
  11. Pediatric Radiology and Neuroradiology Department, Buzzi Children’s Hospital, Milan, Italy; Department of Biomedical and Clinical Sciences, University of Milan.
  12. Pediatric Radiology and Neuroradiology Department, Children’s Hospital Vittore Buzzi, Milan, Italy.
  13. Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen.
  14. Centro de Obsetricia y Ginecologia & Centro Medico Moderno, Santo Domingo, Dominican Republic.
  15. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Libero Temolo 4, Milan, Italy.
  16. Division of Neonatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA; Centro de Obsetricia y Ginecologia, Santo Domingo, Dominican Republic.
  17. Service de Génétique Médicale, CHU de Nantes, Nantes Université, Nantes, France; Nantes Université, CNRS, INSERM, l’Institut du Thorax, Nantes, France.
  18. University of Angers, MitoLab Team, Unité MitoVasc, UMR CNRS 6015, INSERM U1083, SFR ICAT, Angers, France; Department of Genetics, CHU Angers, Angers, F-49000, France.
  19. GeneDx, Gaithersburg, MD 20877, USA.
  20. Human Genetic center Tübingen, Baden-Württemberg, Germany.
  21. Human Genetic center Tübingen, Baden-Württemberg, Germany; CeGaT GmbH, Germany.
  22. Department of Neurology, Hospital de Pediatría Juan P. Garrahan,Buenos Aires 1245, Argentina.
  23. Genomics Laboratory, Hospital de Pediatría Juan P. Garrahan,Buenos Aires 1245, Argentina.
  24. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom; Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100, L’Aquila, Italy.
  25. Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.
  26. West Midlands Regional Genetics Service, Birmingham Women and Children’s Hospital NHS Foundation Trust, Birmingham, United Kingdom.
  27. Children’s Hospital of the King’s Daughters, Norfolk, Virginia, VA.
  28. Department of Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
  29. Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
  30. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA; Center for the Investigation of Membrane Excitability Diseases (CIMED), St. Louis, Missouri, USA.
  31. Rainbow Children Hospital, Hyderabad, India.
  32. Division of Medical Genetics, Nemours/A I duPont Hospital for Children, Wilmington, DE 19803, USA.
  33. Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
  34. Service de Génétique Médicale, CHU de Nantes, Nantes Université, Nantes, France.
  35. Department of Child Neurology, University Hospital, Gießen, Germany.
  36. Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK.
  37. Department of Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
  38. Division of Genetics, Genomics, and Metabolism, Ann & Robert Lurie Children’s Hospital of Chicago, Chicago, USA; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, USA; Fundacion Cardiovascular de Colombia, Floridablanca, Colombia.
  39. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Libero Temolo 4, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza 35, Milan, Italy.
  40. Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; NHS Highly Specialized Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle University, Newcastle upon Tyne, NE1 4LP, UK.
  41. ARNA – UMR5320 CNRS – U1212 INSERM, Université de Bordeaux, IECB, F-33600 Pessac, France.
  42. Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. Electronic address: gaurav-varshney@omrf.org.
  43. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom. Electronic address: r.maroofian@ucl.ac.uk.