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Nat Commun. 2019 Feb 12;10(1):708. doi: 10.1038/s41467-018-07953-w.

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

Author information

1
Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium.
2
Neurogenetics Group, Center for Molecular Neurology, VIB, University of Antwerp, Antwerp, 2610, Belgium.
3
Institute Born Bunge, University of Antwerp, Antwerp, 2610, Belgium.
4
Department of Neurology, Antwerp University Hospital, Antwerp, 2650, Belgium.
5
Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
6
Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, 2610, Belgium.
7
Department of Biochemistry, University of Vermont, Burlington, VT, 05405, USA.
8
Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
9
KRIBB School, University of Science and Technology, Daejeon, 34141, Republic of Korea.
10
Dementia DTC R&D Convergence Program, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
11
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Düsseldorf, 40225, Germany.
12
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, 01120, Israel.
13
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
14
Department of Pediatrics, Medicine, University of Louisville School of Medicine, 571S Floyd Street, Louisville, Kentucky, 40202, USA.
15
Department of Physiotherapy and Rehabilitation, Hasan Kalyoncu University, School of Health Sciences, Gaziantep, 27410, Turkey.
16
The Ohio State University Division of Human Genetics, Department of Internal Medicine, 460 W 12th Ave, Columbus, Ohio, 43210, USA.
17
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
18
Department of Genetics, University of Alabama, Birmingham, AL, 35233, USA.
19
Department of Pharmacology and Pharmacotherapy, University of Pecs, Pecs, 7622, Hungary.
20
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
21
Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
22
Texas Children's Hospital, Houston, TX, 77030, USA.
23
Institute of Human Genetics, Technische Universität München, München, 81675, Germany.
24
Luxembourg Center for Systems Biomedicine, University Luxembourg, Esch-sur-Alzette, 4365, Luxembourg.
25
Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
26
Department of Neuropediatrics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24105, Germany.
27
Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, 92656, USA.
28
Pediatric Department B' Emek Medical Center, Afula, 1834111, Israel.
29
Rappaport School of Medicine, Technion, Haifa, 3200003, Israel.
30
Northern German Epilepsy Center for Children and Adolescents, Schwentinental-Raisdorf, 24223, Germany.
31
Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA.
32
Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium. peter.dewitte@kuleuven.be.
33
Neurogenetics Group, Center for Molecular Neurology, VIB, University of Antwerp, Antwerp, 2610, Belgium. peter.dejonghe@molgen.vib-ua.be.
34
Institute Born Bunge, University of Antwerp, Antwerp, 2610, Belgium. peter.dejonghe@molgen.vib-ua.be.
35
Department of Neurology, Antwerp University Hospital, Antwerp, 2650, Belgium. peter.dejonghe@molgen.vib-ua.be.

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.

PMID:
30755616
PMCID:
PMC6372652
DOI:
10.1038/s41467-018-07953-w
[Indexed for MEDLINE]
Free PMC Article

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