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


Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
12 02 2019
Historique:
received: 20 12 2017
accepted: 03 10 2018
entrez: 14 2 2019
pubmed: 14 2 2019
medline: 12 4 2019
Statut: epublish

Résumé

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.

Identifiants

pubmed: 30755616
doi: 10.1038/s41467-018-07953-w
pii: 10.1038/s41467-018-07953-w
pmc: PMC6372652
doi:

Substances chimiques

Valine-tRNA Ligase EC 6.1.1.9

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

708

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM054899
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM118647
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS105078
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States

Investigateurs

Chris Balak (C)
Newell Belnap (N)
Ana Claasen (A)
Amanda Courtright (A)
Matt de Both (M)
Matthew J Huentelman (MJ)
Marcus Naymik (M)
Ryan Richholt (R)
Ashley L Siniard (AL)
Szabolcs Szelinger (S)
David W Craig (DW)
Isabelle Schrauwen (I)
Zaid Afawi (Z)
Rudi Balling (R)
Stéphanie Baulac (S)
Nina Barišić (N)
Hande S Caglayan (HS)
Dana Craiu (D)
Rosa Guerrero-López (R)
Renzo Guerrini (R)
Helle Hjalgrim (H)
Johanna Jähn (J)
Karl Martin Klein (KM)
Eric Leguern (E)
Johannes R Lemke (JR)
Holger Lerche (H)
Carla Marini (C)
Rikke S Møller (RS)
Hiltrud Muhle (H)
Felix Rosenow (F)
Jose Serratosa (J)
Arvid Suls (A)
Ulrich Stephani (U)
Katalin Štěrbová (K)
Pasquale Striano (P)
Federico Zara (F)

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Auteurs

Aleksandra Siekierska (A)

Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium.

Hannah Stamberger (H)

Neurogenetics Group, Center for Molecular Neurology, VIB, University of Antwerp, Antwerp, 2610, Belgium.
Institute Born Bunge, University of Antwerp, Antwerp, 2610, Belgium.
Department of Neurology, Antwerp University Hospital, Antwerp, 2650, Belgium.

Tine Deconinck (T)

Neurogenetics Group, Center for Molecular Neurology, VIB, University of Antwerp, Antwerp, 2610, Belgium.
Institute Born Bunge, University of Antwerp, Antwerp, 2610, Belgium.

Stephanie N Oprescu (SN)

Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.

Michèle Partoens (M)

Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium.

Yifan Zhang (Y)

Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium.

Jo Sourbron (J)

Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium.

Elias Adriaenssens (E)

Institute Born Bunge, University of Antwerp, Antwerp, 2610, Belgium.
Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, 2610, Belgium.

Patrick Mullen (P)

Department of Biochemistry, University of Vermont, Burlington, VT, 05405, USA.

Patrick Wiencek (P)

Department of Biochemistry, University of Vermont, Burlington, VT, 05405, USA.

Katia Hardies (K)

Neurogenetics Group, Center for Molecular Neurology, VIB, University of Antwerp, Antwerp, 2610, Belgium.
Institute Born Bunge, University of Antwerp, Antwerp, 2610, Belgium.

Jeong-Soo Lee (JS)

Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
KRIBB School, University of Science and Technology, Daejeon, 34141, Republic of Korea.
Dementia DTC R&D Convergence Program, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.

Hoi-Khoanh Giong (HK)

Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
KRIBB School, University of Science and Technology, Daejeon, 34141, Republic of Korea.
Dementia DTC R&D Convergence Program, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.

Felix Distelmaier (F)

Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Düsseldorf, 40225, Germany.

Orly Elpeleg (O)

Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, 01120, Israel.

Katherine L Helbig (KL)

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.

Joseph Hersh (J)

Department of Pediatrics, Medicine, University of Louisville School of Medicine, 571S Floyd Street, Louisville, Kentucky, 40202, USA.

Sedat Isikay (S)

Department of Physiotherapy and Rehabilitation, Hasan Kalyoncu University, School of Health Sciences, Gaziantep, 27410, Turkey.

Elizabeth Jordan (E)

The Ohio State University Division of Human Genetics, Department of Internal Medicine, 460 W 12th Ave, Columbus, Ohio, 43210, USA.

Ender Karaca (E)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Department of Genetics, University of Alabama, Birmingham, AL, 35233, USA.

Angela Kecskes (A)

Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium.
Department of Pharmacology and Pharmacotherapy, University of Pecs, Pecs, 7622, Hungary.

James R Lupski (JR)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
Texas Children's Hospital, Houston, TX, 77030, USA.

Reka Kovacs-Nagy (R)

Institute of Human Genetics, Technische Universität München, München, 81675, Germany.

Patrick May (P)

Luxembourg Center for Systems Biomedicine, University Luxembourg, Esch-sur-Alzette, 4365, Luxembourg.

Vinodh Narayanan (V)

Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.

Manuela Pendziwiat (M)

Department of Neuropediatrics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24105, Germany.

Keri Ramsey (K)

Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.

Sampathkumar Rangasamy (S)

Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.

Deepali N Shinde (DN)

Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, 92656, USA.

Ronen Spiegel (R)

Pediatric Department B' Emek Medical Center, Afula, 1834111, Israel.
Rappaport School of Medicine, Technion, Haifa, 3200003, Israel.

Vincent Timmerman (V)

Institute Born Bunge, University of Antwerp, Antwerp, 2610, Belgium.
Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, 2610, Belgium.

Sarah von Spiczak (S)

Department of Neuropediatrics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24105, Germany.
Northern German Epilepsy Center for Children and Adolescents, Schwentinental-Raisdorf, 24223, Germany.

Ingo Helbig (I)

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
Department of Neuropediatrics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24105, Germany.

Sarah Weckhuysen (S)

Neurogenetics Group, Center for Molecular Neurology, VIB, University of Antwerp, Antwerp, 2610, Belgium.
Institute Born Bunge, University of Antwerp, Antwerp, 2610, Belgium.
Department of Neurology, Antwerp University Hospital, Antwerp, 2650, Belgium.

Christopher Francklyn (C)

Department of Biochemistry, University of Vermont, Burlington, VT, 05405, USA.

Anthony Antonellis (A)

Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA.

Peter de Witte (P)

Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium. peter.dewitte@kuleuven.be.

Peter De Jonghe (P)

Neurogenetics Group, Center for Molecular Neurology, VIB, University of Antwerp, Antwerp, 2610, Belgium. peter.dejonghe@molgen.vib-ua.be.
Institute Born Bunge, University of Antwerp, Antwerp, 2610, Belgium. peter.dejonghe@molgen.vib-ua.be.
Department of Neurology, Antwerp University Hospital, Antwerp, 2650, Belgium. peter.dejonghe@molgen.vib-ua.be.

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