@article{14356,
  abstract     = {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.},
  author       = {Lin, Sheng-Jia and Vona, Barbara and Porter, Hillary M. and Izadi, Mahmoud and Huang, Kevin and Lacassie, Yves and Rosenfeld, Jill A. and Khan, Saadullah and Petree, Cassidy and Ali, Tayyiba A. and Muhammad, Nazif and Khan, Sher A. and Muhammad, Noor and Liu, Pengfei and Haymon, Marie-Louise and Rueschendorf, Franz and Kong, Il-Keun and Schnapp, Linda and Shur, Natasha and Chorich, Lynn and Layman, Lawrence and Haaf, Thomas and Pourkarimi, Ehsan and Kim, Hyung-Goo and Varshney, Gaurav K.},
  issn         = {1059-7794},
  journal      = {Human Mutation},
  keywords     = {autosomal recessive, biallelic variants, C, elegans, translation initiation sites, tryptophanyl-tRNA synthetase 1 (WARS1), WHEP domain, zebrafish},
  number       = {10},
  pages        = {1472--1489},
  publisher    = {Wiley},
  title        = {{Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function}},
  doi          = {10.1002/humu.24435},
  volume       = {43},
  year         = {2022},
}

@article{14357,
  abstract     = {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.},
  author       = {Boegershausen, Nina and Krawczyk, Hannah E. and Jamra, Rami A. and Lin, Sheng-Jia and Yigit, Goekhan and Huening, Irina and Polo, Anna M. and Vona, Barbara and Huang, Kevin and Schmidt, Julia and Altmueller, Janine and Luppe, Johannes and Platzer, Konrad and Doergeloh, Beate B. and Busche, Andreas and Biskup, Saskia and Mendes, I, Marisa and Smith, Desiree E. C. and Salomons, Gajja S. and Zibat, Arne and Bueltmann, Eva and Nuernberg, Peter and Spielmann, Malte and Lemke, Johannes R. and Li, Yun and Zenker, Martin and Varshney, Gaurav K. and Hillen, Hauke S. and Kratz, Christian P. and Wollnik, Bernd},
  issn         = {1059-7794},
  journal      = {Human Mutation},
  keywords     = {aminoacylation, aminoacyl-tRNA synthetase, ARS, CRISPR, Cas9, intellectual disability, microcephaly, SARS1, tRNA, WARS1, zebrafish},
  number       = {10},
  pages        = {1454--1471},
  publisher    = {Wiley},
  title        = {{WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly}},
  doi          = {10.1002/humu.24430},
  volume       = {43},
  year         = {2022},
}