Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish.
Alleles
Animals
Brain Diseases
/ enzymology
Cell Line
Disease Models, Animal
Epilepsy
/ enzymology
Female
Fibroblasts
Gene Knockout Techniques
Genetic Predisposition to Disease
Humans
Loss of Function Mutation
Male
Microcephaly
/ enzymology
Models, Molecular
Neurodevelopmental Disorders
/ enzymology
Pedigree
Prosencephalon
/ pathology
Valine-tRNA Ligase
/ genetics
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
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
708Subventions
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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