---
_id: '14356'
abstract:
- lang: eng
  text: Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for faithful assignment
    of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated
    with clinically heterogeneous phenotypes in humans and follow both autosomal dominant
    or recessive inheritance patterns in many instances. Variants in tryptophanyl-tRNA
    synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor
    neuropathy and Charcot-Marie-Tooth disease. Presently, only one family with biallelic
    WARS1 variants has been described. We present three affected individuals from
    two families with biallelic variants (p.Met1? and p.(Asp419Asn)) in WARS1, showing
    varying severities of developmental delay and intellectual disability. Hearing
    impairment and microcephaly, as well as abnormalities of the brain, skeletal system,
    movement/gait, and behavior were variable features. Phenotyping of knocked down
    wars-1 in a Caenorhabditis elegans model showed depletion is associated with defects
    in germ cell development. A wars1 knockout vertebrate model recapitulates the
    human clinical phenotypes, confirms variant pathogenicity, and uncovers evidence
    implicating the p.Met1? variant as potentially impacting an exon critical for
    normal hearing. Together, our findings provide consolidating evidence for biallelic
    disruption of WARS1 as causal for an autosomal recessive neurodevelopmental syndrome
    and present a vertebrate model that recapitulates key phenotypes observed in patients.
article_processing_charge: No
article_type: original
author:
- first_name: Sheng-Jia
  full_name: Lin, Sheng-Jia
  last_name: Lin
- first_name: Barbara
  full_name: Vona, Barbara
  last_name: Vona
- first_name: Hillary M.
  full_name: Porter, Hillary M.
  last_name: Porter
- first_name: Mahmoud
  full_name: Izadi, Mahmoud
  last_name: Izadi
- first_name: Kevin
  full_name: Huang, Kevin
  id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3
  last_name: Huang
  orcid: 0000-0002-2512-7812
- first_name: Yves
  full_name: Lacassie, Yves
  last_name: Lacassie
- first_name: Jill A.
  full_name: Rosenfeld, Jill A.
  last_name: Rosenfeld
- first_name: Saadullah
  full_name: Khan, Saadullah
  last_name: Khan
- first_name: Cassidy
  full_name: Petree, Cassidy
  last_name: Petree
- first_name: Tayyiba A.
  full_name: Ali, Tayyiba A.
  last_name: Ali
- first_name: Nazif
  full_name: Muhammad, Nazif
  last_name: Muhammad
- first_name: Sher A.
  full_name: Khan, Sher A.
  last_name: Khan
- first_name: Noor
  full_name: Muhammad, Noor
  last_name: Muhammad
- first_name: Pengfei
  full_name: Liu, Pengfei
  last_name: Liu
- first_name: Marie-Louise
  full_name: Haymon, Marie-Louise
  last_name: Haymon
- first_name: Franz
  full_name: Rueschendorf, Franz
  last_name: Rueschendorf
- first_name: Il-Keun
  full_name: Kong, Il-Keun
  last_name: Kong
- first_name: Linda
  full_name: Schnapp, Linda
  last_name: Schnapp
- first_name: Natasha
  full_name: Shur, Natasha
  last_name: Shur
- first_name: Lynn
  full_name: Chorich, Lynn
  last_name: Chorich
- first_name: Lawrence
  full_name: Layman, Lawrence
  last_name: Layman
- first_name: Thomas
  full_name: Haaf, Thomas
  last_name: Haaf
- first_name: Ehsan
  full_name: Pourkarimi, Ehsan
  last_name: Pourkarimi
- first_name: Hyung-Goo
  full_name: Kim, Hyung-Goo
  last_name: Kim
- first_name: Gaurav K.
  full_name: Varshney, Gaurav K.
  last_name: Varshney
citation:
  ama: Lin S-J, Vona B, Porter HM, et al. Biallelic variants in WARS1 cause a highly
    variable neurodevelopmental syndrome and implicate a critical exon for normal
    auditory function. <i>Human Mutation</i>. 2022;43(10):1472-1489. doi:<a href="https://doi.org/10.1002/humu.24435">10.1002/humu.24435</a>
  apa: Lin, S.-J., Vona, B., Porter, H. M., Izadi, M., Huang, K., Lacassie, Y., …
    Varshney, G. K. (2022). Biallelic variants in WARS1 cause a highly variable neurodevelopmental
    syndrome and implicate a critical exon for normal auditory function. <i>Human
    Mutation</i>. Wiley. <a href="https://doi.org/10.1002/humu.24435">https://doi.org/10.1002/humu.24435</a>
  chicago: Lin, Sheng-Jia, Barbara Vona, Hillary M. Porter, Mahmoud Izadi, Kevin Huang,
    Yves Lacassie, Jill A. Rosenfeld, et al. “Biallelic Variants in WARS1 Cause a
    Highly Variable Neurodevelopmental Syndrome and Implicate a Critical Exon for
    Normal Auditory Function.” <i>Human Mutation</i>. Wiley, 2022. <a href="https://doi.org/10.1002/humu.24435">https://doi.org/10.1002/humu.24435</a>.
  ieee: S.-J. Lin <i>et al.</i>, “Biallelic variants in WARS1 cause a highly variable
    neurodevelopmental syndrome and implicate a critical exon for normal auditory
    function,” <i>Human Mutation</i>, vol. 43, no. 10. Wiley, pp. 1472–1489, 2022.
  ista: Lin S-J, Vona B, Porter HM, Izadi M, Huang K, Lacassie Y, Rosenfeld JA, Khan
    S, Petree C, Ali TA, Muhammad N, Khan SA, Muhammad N, Liu P, Haymon M-L, Rueschendorf
    F, Kong I-K, Schnapp L, Shur N, Chorich L, Layman L, Haaf T, Pourkarimi E, Kim
    H-G, Varshney GK. 2022. Biallelic variants in WARS1 cause a highly variable neurodevelopmental
    syndrome and implicate a critical exon for normal auditory function. Human Mutation.
    43(10), 1472–1489.
  mla: Lin, Sheng-Jia, et al. “Biallelic Variants in WARS1 Cause a Highly Variable
    Neurodevelopmental Syndrome and Implicate a Critical Exon for Normal Auditory
    Function.” <i>Human Mutation</i>, vol. 43, no. 10, Wiley, 2022, pp. 1472–89, doi:<a
    href="https://doi.org/10.1002/humu.24435">10.1002/humu.24435</a>.
  short: S.-J. Lin, B. Vona, H.M. Porter, M. Izadi, K. Huang, Y. Lacassie, J.A. Rosenfeld,
    S. Khan, C. Petree, T.A. Ali, N. Muhammad, S.A. Khan, N. Muhammad, P. Liu, M.-L.
    Haymon, F. Rueschendorf, I.-K. Kong, L. Schnapp, N. Shur, L. Chorich, L. Layman,
    T. Haaf, E. Pourkarimi, H.-G. Kim, G.K. Varshney, Human Mutation 43 (2022) 1472–1489.
date_created: 2023-09-20T20:58:24Z
date_published: 2022-10-01T00:00:00Z
date_updated: 2023-09-25T08:54:14Z
day: '01'
ddc:
- '570'
doi: 10.1002/humu.24435
extern: '1'
file:
- access_level: open_access
  checksum: 74b01d4e4084b2f64c30ed32b18ee928
  content_type: application/pdf
  creator: dernst
  date_created: 2023-09-25T08:52:54Z
  date_updated: 2023-09-25T08:52:54Z
  file_id: '14370'
  file_name: 2022_HumanMutation_Lin.pdf
  file_size: 12131312
  relation: main_file
  success: 1
file_date_updated: 2023-09-25T08:52:54Z
has_accepted_license: '1'
intvolume: '        43'
issue: '10'
keyword:
- autosomal recessive
- biallelic variants
- C
- elegans
- translation initiation sites
- tryptophanyl-tRNA synthetase 1 (WARS1)
- WHEP domain
- zebrafish
language:
- iso: eng
month: '10'
oa: 1
oa_version: Published Version
page: 1472-1489
publication: Human Mutation
publication_identifier:
  issn:
  - 1059-7794
publication_status: published
publisher: Wiley
quality_controlled: '1'
scopus_import: '1'
status: public
title: Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome
  and implicate a critical exon for normal auditory function
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 43
year: '2022'
...
---
_id: '6161'
abstract:
- lang: eng
  text: 'The tra-1 gene is a terminal regulator of somatic sex in Caenorhabditis elegans:
    high tra-1 activity elicits female development, low tra-1 activity elicits male
    development. To investigate the function and evolution of tra- 1, we examined
    the tra-1 gene from the closely related nematode C. briggsae. Ce-tra-1 and Cb-tra-1
    are unusually divergent. Each gene generates two transcripts, but only one of
    these is present in both species. This common transcript encodes TRA-1A, which
    shows only 44% amino acid identity between the species, a figure much lower than
    that for previously compared genes. A Cb-tra-1 transgene rescues many tissues
    of tra-1(null) mutants of C. elegans but not the somatic gonad or germ line. This
    transgene also causes nongonadal feminization of XO animals, indicating incorrect
    sexual regulation. Alignment of Ce-TRA-1A and Cb-TRA-1A defined several conserved
    regions likely to be important for tra-1 function. The phenotype differences between
    Ce-tra- 1(null) mutants rescued by Cb-tra-1 transgenes and wild-type C. elegans
    indicate significant divergence of regulatory regions. These molecular and functional
    studies suggest that evolution of sex determination in nematodes is rapid and
    genetically complex.'
author:
- first_name: Mario
  full_name: de Bono, Mario
  id: 4E3FF80E-F248-11E8-B48F-1D18A9856A87
  last_name: de Bono
  orcid: 0000-0001-8347-0443
- first_name: J.
  full_name: Hodgkin, J.
  last_name: Hodgkin
citation:
  ama: 'de Bono M, Hodgkin J. Evolution of sex determination in Caenorhabditis: Unusually
    high divergence of tra-1 and its functional consequences. <i>Genetics</i>. 1996;144(2):587-595.'
  apa: 'de Bono, M., &#38; Hodgkin, J. (1996). Evolution of sex determination in Caenorhabditis:
    Unusually high divergence of tra-1 and its functional consequences. <i>Genetics</i>.
    Genetics Society of America.'
  chicago: 'Bono, Mario de, and J. Hodgkin. “Evolution of Sex Determination in Caenorhabditis:
    Unusually High Divergence of Tra-1 and Its Functional Consequences.” <i>Genetics</i>.
    Genetics Society of America, 1996.'
  ieee: 'M. de Bono and J. Hodgkin, “Evolution of sex determination in Caenorhabditis:
    Unusually high divergence of tra-1 and its functional consequences,” <i>Genetics</i>,
    vol. 144, no. 2. Genetics Society of America, pp. 587–595, 1996.'
  ista: 'de Bono M, Hodgkin J. 1996. Evolution of sex determination in Caenorhabditis:
    Unusually high divergence of tra-1 and its functional consequences. Genetics.
    144(2), 587–595.'
  mla: 'de Bono, Mario, and J. Hodgkin. “Evolution of Sex Determination in Caenorhabditis:
    Unusually High Divergence of Tra-1 and Its Functional Consequences.” <i>Genetics</i>,
    vol. 144, no. 2, Genetics Society of America, 1996, pp. 587–95.'
  short: M. de Bono, J. Hodgkin, Genetics 144 (1996) 587–595.
date_created: 2019-03-21T11:50:37Z
date_published: 1996-10-01T00:00:00Z
date_updated: 2021-01-12T08:06:28Z
day: '01'
extern: '1'
external_id:
  pmid:
  - '8889522'
intvolume: '       144'
issue: '2'
keyword:
- amino acid sequence
- article
- caenorhabditis elegans
- evolution
- genetic variability
- nonhuman
- priority journal
- sex determination
- Amino Acid Sequence
- Animals
- Animals
- Genetically Modified
- Base Sequence
- Caenorhabditis
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- DNA
- Helminth
- DNA-Binding Proteins
- Evolution
- Molecular
- Female
- Helminth Proteins
- Membrane Proteins
- Molecular Sequence Data
- Mutagenesis
- RNA
- Messenger
- Sequence Homology
- Amino Acid
- Sex Determination (Analysis)
- Transcription Factors
- Transgenes
- Turner Syndrome
- Animalia
- Caenorhabditis
- Caenorhabditis briggsae
- Caenorhabditis elegans
- Nematoda
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1207552/
month: '10'
oa: 1
oa_version: Published Version
page: 587-595
pmid: 1
publication: Genetics
publication_identifier:
  issn:
  - '00166731'
publication_status: published
publisher: Genetics Society of America
quality_controlled: '1'
status: public
title: 'Evolution of sex determination in Caenorhabditis: Unusually high divergence
  of tra-1 and its functional consequences'
type: journal_article
user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87
volume: 144
year: '1996'
...