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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish
Genetics in Medicine, Volume 23, No. 10, Year 2021
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Description
Purpose: 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. Methods: 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. Results: 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. Conclusion: 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. © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
Authors & Co-Authors
Lin, Sheng Jia
United States, Oklahoma City
Oklahoma Medical Research Foundation
Vona, Barbara
Germany, Tubingen
Eberhard Karls Universität Tübingen
Germany, Wurzburg
Julius-maximilians-universität Würzburg
Barbalho, Patricia G.
United States, Oklahoma City
Oklahoma Medical Research Foundation
Kaiyrzhanov, Rauan
United Kingdom, London
University College London
Maroofian, Reza
United Kingdom, London
University College London
Petree, Cassidy
United States, Oklahoma City
Oklahoma Medical Research Foundation
Severino, Mariasavina
Italy, Genoa
Istituto Giannina Gaslini
Stanley, Valentina
United States, La Jolla
University of California, San Diego
Varshney, Pratishtha
United States, Oklahoma City
Oklahoma Medical Research Foundation
Bahena, Paulina
Germany, Wurzburg
Julius-maximilians-universität Würzburg
Alzahrani, Fatema
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
AlHashem, Amal M.
Saudi Arabia, Riyadh
Prince Sultan Military Medical City
Pagnamenta, Alistair T.
United Kingdom, Oxford
Nihr Oxford Biomedical Research Centre
Aubertin, Gudrun
Canada, Victoria
Victoria General Hospital
Estrada-Veras, Juvianee I.
United States, Rockville
Hjf
United States, Bethesda
Walter Reed National Military Medical Center
United States, Bethesda
Uniformed Services University of the Health Sciences
Hernández, Héctor Adrián Díaz
Mexico, Tlalpan
Instituto Nacional de la Nutrición Salvador Zubiran
Mazaheri, Neda
Iran, Ahvaz
Shahid Chamran University of Ahvaz
Iran, Kianpars
Narges Medical Genetics and Prenatal Diagnostics Laboratory
Oza, Andrea M.
United States, Boston
Harvard Medical School
Thies, Jenny M.
United States, Seattle
Seattle Children's Hospital
Renaud, Deborah L.
United States, Rochester
Mayo Medical School
Dugad, Sanmati
India, Pune
Savitribai Phule Pune University
McEvoy, Jennifer
United States, La Jolla
University of California, San Diego
Sultan, Tipu
Pakistan, Lahore
Children's Hospital Lahore
Pais, Lynn S.
United States, Cambridge
Broad Institute
Tabarki, Brahim M.
Saudi Arabia, Riyadh
Prince Sultan Military Medical City
Villalobos-Ramirez, Daniel
Germany, Wurzburg
Julius-maximilians-universität Würzburg
Rad, Aboulfazl
Germany, Tubingen
Eberhard Karls Universität Tübingen
Ambrose, John C.
United Kingdom, London
Genomics England Limited
Arumugam, Prabhu
United Kingdom, London
Genomics England Limited
Bleda, Marta
United Kingdom, London
Genomics England Limited
Boardman-Pretty, Freya
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Boustred, Christopher R.
United Kingdom, London
Genomics England Limited
Brittain, Helen K.
United Kingdom, London
Genomics England Limited
Caulfield, Mark J.
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Chan, Georgia C.
United Kingdom, London
Genomics England Limited
Fowler, Tom A.
United Kingdom, London
Genomics England Limited
Giess, Adam P.
United Kingdom, London
Genomics England Limited
Hamblin, Angela D.
United Kingdom, London
Genomics England Limited
Henderson, Shirley J.
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Hubbard, Tim J.P.
United Kingdom, London
Genomics England Limited
Jackson, Robert M.
United Kingdom, London
Genomics England Limited
Jones, Louise J.
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Kasperavičiũte, Dalia
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Kayikci, Melis
United Kingdom, London
Genomics England Limited
Kousathanas, Athanasios
United Kingdom, London
Genomics England Limited
Lahnstein, Lea
United Kingdom, London
Genomics England Limited
Leigh, Sarah E.A.
United Kingdom, London
Genomics England Limited
Leong, Ivonne Un San
United Kingdom, London
Genomics England Limited
Lopez, Frederick J.
United Kingdom, London
Genomics England Limited
Maleady-Crowe, Fiona
United Kingdom, London
Genomics England Limited
Moutsianas, Loukas
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Mueller, Michael C.
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Murugaesu, Nirupa
United Kingdom, London
Genomics England Limited
Need, Anna C.
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
O’Donovan, Peter
United Kingdom, London
Genomics England Limited
Odhams, Christopher A.
United Kingdom, London
Genomics England Limited
Patch, Christine
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Perez-Gil, Daniel
United Kingdom, London
Genomics England Limited
Pereira, Mariana Buongermino
United Kingdom, London
Genomics England Limited
Pullinger, John
United Kingdom, London
Genomics England Limited
Rahim, Tahrima
United Kingdom, London
Genomics England Limited
Rendon, Augusto
United Kingdom, London
Genomics England Limited
Savage, Kevin
United Kingdom, London
Genomics England Limited
Sawant, Kushmita
United Kingdom, London
Genomics England Limited
Scott, Richard H.
United Kingdom, London
Genomics England Limited
Siddiq, Afshan
United Kingdom, London
Genomics England Limited
Sieghart, Alexander
United Kingdom, London
Genomics England Limited
Smith, Samuel C.
United Kingdom, London
Genomics England Limited
Sosinsky, Alona
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Stuckey, Alexander
United Kingdom, London
Genomics England Limited
Tanguy, Mélanie
United Kingdom, London
Genomics England Limited
Thomas, Ellen R.A.
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Thompson, Simon R.
United Kingdom, London
Genomics England Limited
Tucci, Arianna
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Walsh, Emma
United Kingdom, London
Genomics England Limited
Welland, Matthew J.
United Kingdom, London
Genomics England Limited
Williams, Eleanor P.
United Kingdom, London
Genomics England Limited
Witkowska, Katarzyna A.
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Wood, Suzanne M.
United Kingdom, London
Genomics England Limited
United Kingdom, London
Queen Mary University of London
Galehdari, Hamid
Mexico, Tlalpan
Instituto Nacional de la Nutrición Salvador Zubiran
Ashrafzadeh, Farah
Iran, Mashhad
Mashhad University of Medical Sciences
Sahebzamani, Afsaneh
Iran, Kerman
Kerman Welfare Organization
Saeidi, Kolsoum
Iran, Kerman
Kerman University of Medical Sciences
Torti, Erin E.
United States, Gaithersburg
Genedx, Inc.
Elloumi, Houda Zghal
United States, Gaithersburg
Genedx, Inc.
Mora, Sara
United States, Gaithersburg
Genedx, Inc.
Palculict, Timothy Blake
United States, Gaithersburg
Genedx, Inc.
Yang, Hui
United States, Gaithersburg
Genedx, Inc.
Wren, Jonathan D.
United States, Oklahoma City
Oklahoma Medical Research Foundation
Ben Fowler,
United States, Oklahoma City
Oklahoma Medical Research Foundation
Joshi, Manali
India, Pune
Savitribai Phule Pune University
Behra, Martine
Puerto Rico, San Juan
Universidad de Puerto Rico
Burgess, Shawn Michael
United States, Bethesda
National Institutes of Health Nih
Nath, Swapan K.
United States, Oklahoma City
Oklahoma Medical Research Foundation
Hanna, Michael G.
United Kingdom, London
University College London
Kenna, Margaret A.
United States, Boston
Harvard Medical School
Merritt, John Lawrence
United States, Seattle
University of Washington
Houlden, Henry H.
United Kingdom, London
University College London
Karimiani, Ehsan Ghayoor
United Kingdom, London
St George’s, University of London
Iran, Mashhad
Innovative Medical Research Center
Zaki, Maha S.
Egypt, Giza
National Research Centre
Haaf, Thomas
Germany, Wurzburg
Julius-maximilians-universität Würzburg
Alkuraya., Fowzan S.
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Saudi Arabia, Riyadh
Prince Sultan Military Medical City
Gleeson, Joseph G.
United States, La Jolla
University of California, San Diego
Varshney, Gaurav Kumar
United States, Oklahoma City
Oklahoma Medical Research Foundation
Statistics
Citations: 11
Authors: 104
Affiliations: 34
Identifiers
Doi:
10.1038/s41436-021-01239-1
ISSN:
10983600
Research Areas
Cancer
Disability
Genetics And Genomics