Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Aleksandra Siekierska, Hannah Stamberger, Tine Deconinck, Stephanie N. Oprescu, Michèle Partoens, Yifan Zhang, Jo Sourbron, Elias Adriaenssens, Patrick Mullen, Patrick Wiencek, Katia Hardies, Jeong-Soo Lee, Hoi-Khoanh Giong, Felix Distelmaier, Orly Elpeleg, Katherine L. Helbig, Joseph Hersh, Sedat Isikay, Elizabeth Jordan, Ender Karaca, Angela Kecskes, James R. Lupski, Reka Kovacs-Nagy, Patrick May, Vinodh Narayanan, Manuela Pendziwiat, Keri Ramsey, Sampathkumar Rangasamy, Deepali N. Shinde, Ronen Spiegel, Vincent Timmerman, Sarah von Spiczak, Ingo Helbig, Sarah Weckhuysen, Christopher Francklyn, Anthony Antonellis, Peter de Witte () and Peter De Jonghe ()
Additional contact information
Aleksandra Siekierska: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven
Hannah Stamberger: University of Antwerp
Tine Deconinck: University of Antwerp
Stephanie N. Oprescu: University of Michigan
Michèle Partoens: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven
Yifan Zhang: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven
Jo Sourbron: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven
Elias Adriaenssens: University of Antwerp
Patrick Mullen: University of Vermont
Patrick Wiencek: University of Vermont
Katia Hardies: University of Antwerp
Jeong-Soo Lee: Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology
Hoi-Khoanh Giong: Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology
Felix Distelmaier: University Childrenʼs Hospital, Heinrich-Heine-University Düsseldorf
Orly Elpeleg: Hadassah-Hebrew University Medical Center
Katherine L. Helbig: Division of Neurology, Childrenʼs Hospital of Philadelphia
Joseph Hersh: University of Louisville School of Medicine
Sedat Isikay: Hasan Kalyoncu University, School of Health Sciences
Elizabeth Jordan: Department of Internal Medicine
Ender Karaca: Baylor College of Medicine
Angela Kecskes: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven
James R. Lupski: Baylor College of Medicine
Reka Kovacs-Nagy: Technische Universität München
Patrick May: Luxembourg Center for Systems Biomedicine, University Luxembourg
Vinodh Narayanan: The Translational Genomics Research Institute
Manuela Pendziwiat: Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein
Keri Ramsey: The Translational Genomics Research Institute
Sampathkumar Rangasamy: The Translational Genomics Research Institute
Deepali N. Shinde: Division of Clinical Genomics, Ambry Genetics
Ronen Spiegel: Pediatric Department B’ Emek Medical Center
Vincent Timmerman: University of Antwerp
Sarah von Spiczak: Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein
Ingo Helbig: Division of Neurology, Childrenʼs Hospital of Philadelphia
Sarah Weckhuysen: University of Antwerp
Christopher Francklyn: University of Vermont
Anthony Antonellis: University of Michigan
Peter de Witte: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven
Peter De Jonghe: University of Antwerp

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.

Date: 2019
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DOI: 10.1038/s41467-018-07953-w

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