@article{14368,
  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.},
  author       = {Accogli, Andrea and Lin, Sheng-Jia and Severino, Mariasavina and Kim, Sung-Hoon and Huang, Kevin and Rocca, Clarissa and Landsverk, Megan and Zaki, Maha S. and Al-Maawali, Almundher and Srinivasan, Varunvenkat M. and Al-Thihli, Khalid and Schaefer, G. Bradly and Davis, Monica and Tonduti, Davide and Doneda, Chiara and Marten, Lara M. and Mühlhausen, Chris and Gomez, Maria and Lamantea, Eleonora and Mena, Rafael and Nizon, Mathilde and Procaccio, Vincent and Begtrup, Amber and Telegrafi, Aida and Cui, Hong and Schulz, Heidi L. and Mohr, Julia and Biskup, Saskia and Loos, Mariana Amina and Aráoz, Hilda Verónica and Salpietro, Vincenzo and Keppen, Laura Davis and Chitre, Manali and Petree, Cassidy and Raymond, Lucy and Vogt, Julie and Sawyer, Lindsey B. and Basinger, Alice A. and Pedersen, Signe Vandal and Pearson, Toni S. and Grange, Dorothy K. and Lingappa, Lokesh and McDunnah, Paige and Horvath, Rita and Cognè, Benjamin and Isidor, Bertrand and Hahn, Andreas and Gripp, Karen W. and Jafarnejad, Seyed Mehdi and Østergaard, Elsebet and Prada, Carlos E. and Ghezzi, Daniele and Gowda, Vykuntaraju K. and Taylor, Robert W. and Sonenberg, Nahum and Houlden, Henry and Sissler, Marie and Varshney, Gaurav K. and Maroofian, Reza},
  issn         = {1098-3600},
  journal      = {Genetics in Medicine},
  keywords     = {Genetics (clinical)},
  number       = {11},
  publisher    = {Elsevier},
  title        = {{Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder}},
  doi          = {10.1016/j.gim.2023.100938},
  volume       = {25},
  year         = {2023},
}

@article{14355,
  abstract     = {Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.},
  author       = {Cali, Elisa and Lin, Sheng-Jia and Rocca, Clarissa and Sahin, Yavuz and Al Shamsi, Aisha and El Chehadeh, Salima and Chaabouni, Myriam and Mankad, Kshitij and Galanaki, Evangelia and Efthymiou, Stephanie and Sudhakar, Sniya and Athanasiou-Fragkouli, Alkyoni and Celik, Tamer and Narli, Nejat and Bianca, Sebastiano and Murphy, David and Moreira, Francisco Martins De Carvalho and Accogli, Andrea and Petree, Cassidy and Huang, Kevin and Monastiri, Kamel and Edizadeh, Masoud and Nardello, Rosaria and Ognibene, Marzia and De Marco, Patrizia and Ruggieri, Martino and Zara, Federico and Striano, Pasquale and Sahin, Yavuz and Al-Gazali, Lihadh and Warde, Marie Therese Abi and Gerard, Benedicte and Zifarelli, Giovanni and Beetz, Christian and Fortuna, Sara and Soler, Miguel and Valente, Enza Maria and Varshney, Gaurav and Maroofian, Reza and Salpietro, Vincenzo and Houlden, Henry and Grp, SYNaPS Study},
  issn         = {1098-3600},
  journal      = {Genetics in Medicine},
  keywords     = {Human mediator complex, MED11, MEDopathies},
  number       = {10},
  pages        = {2194--2203},
  publisher    = {Elsevier},
  title        = {{A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease}},
  doi          = {10.1016/j.gim.2022.07.013},
  volume       = {24},
  year         = {2022},
}