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

C4RCD Research Group, AR working group of the EuroEPINOMICS RES Consortium

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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Resumé

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.

OriginalsprogEngelsk
Artikelnummer708
TidsskriftNature Communications
Vol/bind10
Antal sider15
ISSN2041-1723
DOI
StatusUdgivet - 12. feb. 2019

Fingeraftryk

Valine-tRNA Ligase
Amino Acyl-tRNA Synthetases
Microcephaly
Zebrafish
mutations
causes
epilepsy
ribonucleic acids
proteins
Mutation
yeast
Transfer RNA
Computer Simulation
Yeast
amino acids
therapy
Assays
Proteins
disorders
Amino Acids

Citer dette

C4RCD Research Group ; AR working group of the EuroEPINOMICS RES Consortium. / Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish. I: Nature Communications. 2019 ; Bind 10.
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title = "Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish",
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.",
author = "Aleksandra Siekierska and Hannah Stamberger and Tine Deconinck and Oprescu, {Stephanie N.} and Mich{\`e}le Partoens and Yifan Zhang and Jo Sourbron and Elias Adriaenssens and Patrick Mullen and Patrick Wiencek and Katia Hardies and Lee, {Jeong Soo} and Giong, {Hoi Khoanh} and Felix Distelmaier and Orly Elpeleg and Helbig, {Katherine L.} and Joseph Hersh and Sedat Isikay and Elizabeth Jordan and Ender Karaca and Angela Kecskes and Lupski, {James R.} and Reka Kovacs-Nagy and Patrick May and Vinodh Narayanan and Manuela Pendziwiat and Keri Ramsey and Sampathkumar Rangasamy and Shinde, {Deepali N.} and Ronen Spiegel and Vincent Timmerman and {von Spiczak}, Sarah and Ingo Helbig and Chris Balak and Newell Belnap and Ana Claasen and Amanda Courtright and {de Both}, Matt and Huentelman, {Matthew J.} and Marcus Naymik and Ryan Richholt and Siniard, {Ashley L.} and Szabolcs Szelinger and Craig, {David W.} and Isabelle Schrauwen and Zaid Afawi and Rudi Balling and St{\'e}phanie Baulac and Helle Hjalgrim and M{\o}ller, {Rikke S.} and {C4RCD Research Group} and {AR working group of the EuroEPINOMICS RES Consortium}",
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month = "2",
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doi = "10.1038/s41467-018-07953-w",
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Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish. / C4RCD Research Group; AR working group of the EuroEPINOMICS RES Consortium.

I: Nature Communications, Bind 10, 708, 12.02.2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

AU - Siekierska, Aleksandra

AU - Stamberger, Hannah

AU - Deconinck, Tine

AU - Oprescu, Stephanie N.

AU - Partoens, Michèle

AU - Zhang, Yifan

AU - Sourbron, Jo

AU - Adriaenssens, Elias

AU - Mullen, Patrick

AU - Wiencek, Patrick

AU - Hardies, Katia

AU - Lee, Jeong Soo

AU - Giong, Hoi Khoanh

AU - Distelmaier, Felix

AU - Elpeleg, Orly

AU - Helbig, Katherine L.

AU - Hersh, Joseph

AU - Isikay, Sedat

AU - Jordan, Elizabeth

AU - Karaca, Ender

AU - Kecskes, Angela

AU - Lupski, James R.

AU - Kovacs-Nagy, Reka

AU - May, Patrick

AU - Narayanan, Vinodh

AU - Pendziwiat, Manuela

AU - Ramsey, Keri

AU - Rangasamy, Sampathkumar

AU - Shinde, Deepali N.

AU - Spiegel, Ronen

AU - Timmerman, Vincent

AU - von Spiczak, Sarah

AU - Helbig, Ingo

AU - Balak, Chris

AU - Belnap, Newell

AU - Claasen, Ana

AU - Courtright, Amanda

AU - de Both, Matt

AU - Huentelman, Matthew J.

AU - Naymik, Marcus

AU - Richholt, Ryan

AU - Siniard, Ashley L.

AU - Szelinger, Szabolcs

AU - Craig, David W.

AU - Schrauwen, Isabelle

AU - Afawi, Zaid

AU - Balling, Rudi

AU - Baulac, Stéphanie

AU - C4RCD Research Group

AU - AR working group of the EuroEPINOMICS RES Consortium

A2 - Hjalgrim, Helle

A2 - Møller, Rikke S.

PY - 2019/2/12

Y1 - 2019/2/12

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-018-07953-w

DO - 10.1038/s41467-018-07953-w

M3 - Journal article

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 708

ER -