---
_id: '14357'
abstract:
- lang: eng
text: 'Aminoacylation of transfer RNA (tRNA) is a key step in protein biosynthesis,
carried out by highly specific aminoacyl-tRNA synthetases (ARSs). ARSs have been
implicated in autosomal dominant and autosomal recessive human disorders. Autosomal
dominant variants in tryptophanyl-tRNA synthetase 1 (WARS1) are known to cause
distal hereditary motor neuropathy and Charcot-Marie-Tooth disease, but a recessively
inherited phenotype is yet to be clearly defined. Seryl-tRNA synthetase 1 (SARS1)
has rarely been implicated in an autosomal recessive developmental disorder. Here,
we report five individuals with biallelic missense variants in WARS1 or SARS1,
who presented with an overlapping phenotype of microcephaly, developmental delay,
intellectual disability, and brain anomalies. Structural mapping showed that the
SARS1 variant is located directly within the enzyme’s active site, most likely
diminishing activity, while the WARS1 variant is located in the N-terminal domain.
We further characterize the identified WARS1 variant by showing that it negatively
impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9
wars1 knockout zebrafish model. In summary, we describe two overlapping autosomal
recessive syndromes caused by variants in WARS1 and SARS1, present functional
insights into the pathogenesis of the WARS1-related syndrome and define an emerging
disease spectrum: ARS-related developmental disorders with or without microcephaly.'
article_processing_charge: No
article_type: original
author:
- first_name: Nina
full_name: Boegershausen, Nina
last_name: Boegershausen
- first_name: Hannah E.
full_name: Krawczyk, Hannah E.
last_name: Krawczyk
- first_name: Rami A.
full_name: Jamra, Rami A.
last_name: Jamra
- first_name: Sheng-Jia
full_name: Lin, Sheng-Jia
last_name: Lin
- first_name: Goekhan
full_name: Yigit, Goekhan
last_name: Yigit
- first_name: Irina
full_name: Huening, Irina
last_name: Huening
- first_name: Anna M.
full_name: Polo, Anna M.
last_name: Polo
- first_name: Barbara
full_name: Vona, Barbara
last_name: Vona
- first_name: Kevin
full_name: Huang, Kevin
id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3
last_name: Huang
orcid: 0000-0002-2512-7812
- first_name: Julia
full_name: Schmidt, Julia
last_name: Schmidt
- first_name: Janine
full_name: Altmueller, Janine
last_name: Altmueller
- first_name: Johannes
full_name: Luppe, Johannes
last_name: Luppe
- first_name: Konrad
full_name: Platzer, Konrad
last_name: Platzer
- first_name: Beate B.
full_name: Doergeloh, Beate B.
last_name: Doergeloh
- first_name: Andreas
full_name: Busche, Andreas
last_name: Busche
- first_name: Saskia
full_name: Biskup, Saskia
last_name: Biskup
- first_name: Marisa
full_name: Mendes, I, Marisa
last_name: Mendes, I
- first_name: Desiree E. C.
full_name: Smith, Desiree E. C.
last_name: Smith
- first_name: Gajja S.
full_name: Salomons, Gajja S.
last_name: Salomons
- first_name: Arne
full_name: Zibat, Arne
last_name: Zibat
- first_name: Eva
full_name: Bueltmann, Eva
last_name: Bueltmann
- first_name: Peter
full_name: Nuernberg, Peter
last_name: Nuernberg
- first_name: Malte
full_name: Spielmann, Malte
last_name: Spielmann
- first_name: Johannes R.
full_name: Lemke, Johannes R.
last_name: Lemke
- first_name: Yun
full_name: Li, Yun
last_name: Li
- first_name: Martin
full_name: Zenker, Martin
last_name: Zenker
- first_name: Gaurav K.
full_name: Varshney, Gaurav K.
last_name: Varshney
- first_name: Hauke S.
full_name: Hillen, Hauke S.
last_name: Hillen
- first_name: Christian P.
full_name: Kratz, Christian P.
last_name: Kratz
- first_name: Bernd
full_name: Wollnik, Bernd
last_name: Wollnik
citation:
ama: 'Boegershausen N, Krawczyk HE, Jamra RA, et al. WARS1 and SARS1: Two tRNA synthetases
implicated in autosomal recessive microcephaly. Human Mutation. 2022;43(10):1454-1471.
doi:10.1002/humu.24430'
apa: 'Boegershausen, N., Krawczyk, H. E., Jamra, R. A., Lin, S.-J., Yigit, G., Huening,
I., … Wollnik, B. (2022). WARS1 and SARS1: Two tRNA synthetases implicated in
autosomal recessive microcephaly. Human Mutation. Wiley. https://doi.org/10.1002/humu.24430'
chicago: 'Boegershausen, Nina, Hannah E. Krawczyk, Rami A. Jamra, Sheng-Jia Lin,
Goekhan Yigit, Irina Huening, Anna M. Polo, et al. “WARS1 and SARS1: Two TRNA
Synthetases Implicated in Autosomal Recessive Microcephaly.” Human Mutation.
Wiley, 2022. https://doi.org/10.1002/humu.24430.'
ieee: 'N. Boegershausen et al., “WARS1 and SARS1: Two tRNA synthetases implicated
in autosomal recessive microcephaly,” Human Mutation, vol. 43, no. 10.
Wiley, pp. 1454–1471, 2022.'
ista: 'Boegershausen N, Krawczyk HE, Jamra RA, Lin S-J, Yigit G, Huening I, Polo
AM, Vona B, Huang K, Schmidt J, Altmueller J, Luppe J, Platzer K, Doergeloh BB,
Busche A, Biskup S, Mendes, I M, Smith DEC, Salomons GS, Zibat A, Bueltmann E,
Nuernberg P, Spielmann M, Lemke JR, Li Y, Zenker M, Varshney GK, Hillen HS, Kratz
CP, Wollnik B. 2022. WARS1 and SARS1: Two tRNA synthetases implicated in autosomal
recessive microcephaly. Human Mutation. 43(10), 1454–1471.'
mla: 'Boegershausen, Nina, et al. “WARS1 and SARS1: Two TRNA Synthetases Implicated
in Autosomal Recessive Microcephaly.” Human Mutation, vol. 43, no. 10,
Wiley, 2022, pp. 1454–71, doi:10.1002/humu.24430.'
short: N. Boegershausen, H.E. Krawczyk, R.A. Jamra, S.-J. Lin, G. Yigit, I. Huening,
A.M. Polo, B. Vona, K. Huang, J. Schmidt, J. Altmueller, J. Luppe, K. Platzer,
B.B. Doergeloh, A. Busche, S. Biskup, M. Mendes, I, D.E.C. Smith, G.S. Salomons,
A. Zibat, E. Bueltmann, P. Nuernberg, M. Spielmann, J.R. Lemke, Y. Li, M. Zenker,
G.K. Varshney, H.S. Hillen, C.P. Kratz, B. Wollnik, Human Mutation 43 (2022) 1454–1471.
date_created: 2023-09-20T20:59:33Z
date_published: 2022-10-01T00:00:00Z
date_updated: 2023-09-25T08:43:06Z
day: '01'
ddc:
- '570'
doi: 10.1002/humu.24430
extern: '1'
external_id:
pmid:
- '35790048'
file:
- access_level: open_access
checksum: c31fc91e0445c35b9da83eb911a9b552
content_type: application/pdf
creator: dernst
date_created: 2023-09-25T08:41:23Z
date_updated: 2023-09-25T08:41:23Z
file_id: '14367'
file_name: 2022_HumanMutation_Boegershausen.pdf
file_size: 4863605
relation: main_file
success: 1
file_date_updated: 2023-09-25T08:41:23Z
has_accepted_license: '1'
intvolume: ' 43'
issue: '10'
keyword:
- aminoacylation
- aminoacyl-tRNA synthetase
- ARS
- CRISPR
- Cas9
- intellectual disability
- microcephaly
- SARS1
- tRNA
- WARS1
- zebrafish
language:
- iso: eng
license: https://creativecommons.org/licenses/by-nc-nd/4.0/
month: '10'
oa: 1
oa_version: Published Version
page: 1454-1471
pmid: 1
publication: Human Mutation
publication_identifier:
issn:
- 1059-7794
publication_status: published
publisher: Wiley
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly'
tmp:
image: /images/cc_by_nc_nd.png
legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
(CC BY-NC-ND 4.0)
short: CC BY-NC-ND (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 43
year: '2022'
...