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Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish

2021; Elsevier BV; Volume: 23; Issue: 10 Linguagem: Inglês

10.1038/s41436-021-01239-1

1530-0366

Sheng‐Jia Lin, Barbara Vona, Patrícia Gonçalves Barbalho, Rauan Kaiyrzhanov, Reza Maroofian, Cassidy Petree, Mariasavina Severino, Valentina Stanley, Pratishtha Varshney, Paulina Bahena, Fatema Alzahrani, Amal Alhashem, Alistair T. Pagnamenta, Gudrun Aubertin, Juvianee Estrada‐Veras, Héctor Adrián Díaz Hernández, Neda Mazaheri, Andrea M. Oza, Jenny Thies, Deborah L. Renaud, Sanmati Dugad, Jennifer McEvoy, Tipu Sultan, Lynn Pais, Brahim Tabarki, Daniel Villalobos-Ramirez, Abolfazl Rad, John C. Ambrose, Prabhu Arumugam, Marta Bleda, F. Boardman-Pretty, C. R. Boustred, Helen Brittain, Mark J. Caulfield, G. C. Chan, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim Hubbard, Richard V. Jackson, J. Louise Jones, Dalia Kasperavičiūtė, Melis Kayikci, Athanasios Kousathanas, L. Lahnstein, S. E. A. Leigh, I. U. S. Leong, Fabrice Lopez, F. Maleady-Crowe, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Chris A. Odhams, Christine Patch, D. Perez-Gil, Mariana Buongermino Pereira, J. Pullinger, T. Rahim, Augusto Rendon, Tim Rogers, K. Savage, K. Sawant, Richard H. Scott, Afshan Siddiq, A. Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, M. Tanguy, Ellen Thomas, Simon R. Thompson, Arianna Tucci, Elizabeth T. Walsh, M. J. Welland, E. G. Williams, Katarzyna Witkowska, Shalandra Wood, Hamid Galehdari, Farah Ashrafzadeh, Afsaneh Sahebzamani, Kolsoum Saeidi, Erin Torti, Houda Zghal Elloumi, Sara Mora, Timothy Blake Palculict, Hui Yang, Jonathan D. Wren, Ben Fowler, Manali Joshi, Martine Behra, Shawn M. Burgess, Swapan K. Nath, Michael G. Hanna, Margaret A. Kenna, J. Lawrence Merritt, Henry Houlden, Ehsan Ghayoor Karimiani, Maha S. Zaki, Thomas Haaf, Fowzan S. Alkuraya, Joseph G. Gleeson, Gaurav K. Varshney,

RNA and protein synthesis mechanisms

Pathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo.Through international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish.We identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1-/- knockouts.Our work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets.