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

July 13, 2023

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


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.