Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder.
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Accogli Andrea, Lin Sheng-Jia, Severino Mariasavina, Kim Sung-Hoon, Huang Kevin, Rocca Clarissa, Landsverk Megan, Zaki Maha S, Al-Maawali Almundher, Srinivasan Varunvenkat M, Al-Thihli Khalid, Schaefer G Bradly, Davis Monica, Tonduti Davide, Doneda Chiara, Marten Lara M, Mühlhausen Chris, Gomez Maria, Lamantea Eleonora, Mena Rafael, Nizon Mathilde, Procaccio Vincent, Begtrup Amber, Telegrafi Aida, Cui Hong, Schulz Heidi L, Mohr Julia, Biskup Saskia, Loos Mariana Amina, Aráoz Hilda Verónica, Salpietro Vincenzo, Keppen Laura Davis, Chitre Manali, Petree Cassidy, Raymond Lucy, Vogt Julie, Sawyer Lindsey B, Basinger Alice A, Pedersen Signe Vandal, Pearson Toni S, Grange Dorothy K, Lingappa Lokesh, McDunnah Paige, Horvath Rita, Cognè Benjamin, Isidor Bertrand, Hahn Andreas, Gripp Karen W, Jafarnejad Seyed Mehdi, Østergaard Elsebet, Prada Carlos E, Ghezzi Daniele, Gowda Vykuntaraju K, Taylor Robert W, Sonenberg Nahum, Houlden Henry, Sissler Marie, Varshney Gaurav K, Maroofian Reza
Аннотация
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.