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

Andrea Accogli, Sheng Jia Lin, Mariasavina Severino, Sung Hoon Kim, Kevin Huang, Clarissa Rocca, Megan Landsverk, Maha S. Zaki, Almundher Al-Maawali, Varunvenkat M. Srinivasan, Khalid Al-Thihli, G. Bradly Schaefer, Monica Davis, Davide Tonduti, Chiara Doneda, Lara M. Marten, Chris Mühlhausen, Maria Gomez, Eleonora Lamantea, Rafael MenaMathilde Nizon, Vincent Procaccio, Amber Begtrup, Aida Telegrafi, Hong Cui, Heidi L. Schulz, Julia Mohr, Saskia Biskup, Mariana Amina Loos, Hilda Verónica Aráoz, Vincenzo Salpietro, Laura Davis Keppen, Manali Chitre, Cassidy Petree, Lucy Raymond, Julie Vogt, Lindsey B. Sawyer, Alice A. Basinger, Signe Vandal Pedersen, Toni S. Pearson, Dorothy K. Grange, Lokesh Lingappa, Paige McDunnah, Rita Horvath, Benjamin Cognè, Bertrand Isidor, Andreas Hahn, Karen W. Gripp, Seyed Mehdi Jafarnejad, Elsebet Østergaard, Carlos E. Prada, Daniele Ghezzi, Vykuntaraju K. Gowda, Robert W. Taylor, Nahum Sonenberg, Henry Houlden, Marie Sissler, Gaurav K. Varshney, Reza Maroofian

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish
Article number100938
JournalGenetics in Medicine
Volume25
Issue number11
DOIs
StatePublished - Nov 2023

Keywords

  • Cerebellar atrophy
  • Mitochondrial dysfunction
  • Mitochondrial threonyl-tRNA-synthetase
  • TARS2
  • mTORC1 signaling

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