Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function.
C. elegans
WHEP domain
autosomal recessive
biallelic variants
translation initiation sites
tryptophanyl-tRNA synthetase 1 (WARS1)
zebrafish
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
revised:
12
06
2022
received:
03
05
2022
accepted:
07
07
2022
pubmed:
12
7
2022
medline:
9
9
2022
entrez:
11
7
2022
Statut:
ppublish
Résumé
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.
Substances chimiques
RNA, Transfer
9014-25-9
Amino Acyl-tRNA Synthetases
EC 6.1.1.-
Tryptophan-tRNA Ligase
EC 6.1.1.2
WARS1 protein, human
EC 6.1.1.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1472-1489Informations de copyright
© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.
Références
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., & Sunyaev, S. R. (2010). A method and server for predicting damaging missense mutations. Nature Methods, 7(4), 248-249. https://doi.org/10.1038/nmeth0410-248
Antonellis, A., & Green, E. D. (2008). The role of aminoacyl-tRNA synthetases in genetic diseases. Annual Review of Genomics and Human Genetics, 9, 87-107. https://doi.org/10.1146/annurev.genom.9.081307.164204
Brown, S. D. M. (2021). Advances in mouse genetics for the study of human disease. Human Molecular Genetics, 30(R2), R274-R284. https://doi.org/10.1093/hmg/ddab153
Concordet, J.-P., & Haeussler, M. (2018). CRISPOR: Intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens. Nucleic Acids Research, 46(W1), W242-W245. https://doi.org/10.1093/nar/gky354
Desmet, F. O., Hamroun, D., Lalande, M., Collod-Beroud, G., Claustres, M., & Beroud, C. (2009). Human splicing finder: An online bioinformatics tool to predict splicing signals. Nucleic Acids Research, 37(9), e67. https://doi.org/10.1093/nar/gkp215
Fraser, A. G., Kamath, R. S., Zipperlen, P., Martinez-Campos, M., Sohrmann, M., & Ahringer, J. (2000). Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature, 408(6810), 325-330. https://doi.org/10.1038/35042517
Freeman, P. J., Hart, R. K., Gretton, L. J., Brookes, A. J., & Dalgleish, R. (2018). VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions. Human Mutation, 39(1), 61-68. https://doi.org/10.1002/humu.23348
Gleason, A. C., Ghadge, G., Chen, J., Sonobe, Y., & Roos, R. P. (2021). Machine learning predicts translation initiation sites in neurologic diseases with expanded repeats. bioRxiv. https://doi.org/10.1101/2021.08.17.456657
Harris, J. A., Mihalas, S., Hirokawa, K. E., Whitesell, J. D., Choi, H., Bernard, A., & Zeng, H. (2019). Hierarchical organization of cortical and thalamic connectivity. Nature, 575(7781), 195-202. https://doi.org/10.1038/s41586-019-1716-z
Harrison, S. M., Riggs, E. R., Maglott, D. R., Lee, J. M., Azzariti, D. R., Niehaus, A., & Rehm, H. L. (2016). Using ClinVar as a resource to support variant interpretation. Current Protocols in Human Genetics, 89, 8.16.1-8.16.23. https://doi.org/10.1002/0471142905.hg0816s89
Hubbard, E. J. (2007). Caenorhabditis elegansgerm line: A model for stem cell biology. Developmental Dynamics, 236(12), 3343-3357. https://doi.org/10.1002/dvdy.21335
Kamath, R. S., Fraser, A. G., Dong, Y., Poulin, G., Durbin, R., Gotta, M., & Ahringer, J. (2003). Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature, 421(6920), 231-237. https://doi.org/10.1038/nature01278
Karczewski, K. J., Solomonson, M., Chao, K. R., Goodrich, J. K., Tiao, G., Lu, W., & Neale, B. M. (2021). Systematic single-variant and gene-based association testing of 3,700 phenotypes in 281,850 UK Biobank exomes. medRxiv. https://doi.org/10.1101/2021.06.19.21259117
Kolla, L., Kelly, M. C., Mann, Z. F., Anaya-Rocha, A., Ellis, K., Lemons, A., & Kelley, M. W. (2020). Characterization of the development of the mouse cochlear epithelium at the single-cell level. Nature Communications, 11(1), 2389. https://doi.org/10.1038/s41467-020-16113-y
Kopanos, C., Tsiolkas, V., Kouris, A., Chapple, C. E., Albarca Aguilera, M., Meyer, R., & Massouras, A. (2019). VarSome: The human genomic variant search engine. Bioinformatics, 35(11), 1978-1980. https://doi.org/10.1093/bioinformatics/bty897
LaFave, M. C., Varshney, G. K., Vemulapalli, M., Mullikin, J. C., & Burgess, S. M. (2014). A defined zebrafish line for high-throughput genetics and genomics: NHGRI-1. Genetics, 198(1), 167-170. https://doi.org/10.1534/genetics.114.166769
Lefter, M., Vis, J. K., Vermaat, M., denDunnen, J. T., Taschner, P. E. M., & Laros, J. F. J. (2021). Next generation HGVS nomenclature checker. Bioinformatics, 37(18), 2811-2817. https://doi.org/10.1093/bioinformatics/btab051
Lein, E. S., Hawrylycz, M. J., Ao, N., Ayres, M., Bensinger, A., Bernard, A., & Jones, A. R. (2007). Genome-wide atlas of gene expression in the adult mouse brain. Nature, 445(7124), 168-176. https://doi.org/10.1038/nature05453
Li, J. Q., Dong, H. L., Chen, C. X., & Wu, Z. Y. (2019). A novel WARS mutation causes distal hereditary motor neuropathy in a Chinese family. Brain, 142(9), e49. https://doi.org/10.1093/brain/awz218
Lin, S. J., Vona, B., Barbalho, P. G., Kaiyrzhanov, R., Maroofian, R., Petree, C., & Varshney, G. K. (2021). Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish. Genetics in Medicine, 23(10), 1933-1943. https://doi.org/10.1038/s41436-021-01239-1
Liu, P., Meng, L., Normand, E. A., Xia, F., Song, X., Ghazi, A., & Yang, Y. (2019). Reanalysis of clinical exome sequencing data. New England Journal of Medicine, 380(25), 2478-2480. https://doi.org/10.1056/NEJMc1812033
Malissovas, N., Griffin, L. B., Antonellis, A., & Beis, D. (2016). Dimerization is required for GARS-mediated neurotoxicity in dominant CMT disease. Human Molecular Genetics, 25(8), 1528-1542. https://doi.org/10.1093/hmg/ddw031
Mazzoli, M., Van Camp, G., Newton, V., Giarbini, N., Declau, F., & Parving, A. (2003). Recommendations for the description of genetic and audiological data for families with nonsyndromic hereditary hearing impairment. Audiological Medicine, 1(2), 148-150. https://doi.org/10.1080/16513860301713
McLaughlin, H. M., Sakaguchi, R., Liu, C., Igarashi, T., Pehlivan, D., Chu, K., & Antonellis, A. (2010). Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy. American Journal of Human Genetics, 87(4), 560-566. https://doi.org/10.1016/j.ajhg.2010.09.008
Meyer-Schuman, R., & Antonellis, A. (2017). Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease. Human Molecular Genetics, 26(R2), R114-R127. https://doi.org/10.1093/hmg/ddx231
Nam, D. E., Park, J. H., Park, C. E., Jung, N. Y., Nam, S. H., Kwon, H. M., & Chung, K. W. (2022). Variants of aminoacyl-tRNA synthetase genes in Charcot-Marie-Tooth disease: A Korean cohort study. Journal of the Peripheral Nervous System, 27(1), 38-49. https://doi.org/10.1111/jns.12476
Ng, P. C., & Henikoff, S. (2001). Predicting deleterious amino acid substitutions. Genome Research, 11(5), 863-874. https://doi.org/10.1101/gr.176601
Oh, S. W., Harris, J. A., Ng, L., Winslow, B., Cain, N., Mihalas, S., & Zeng, H. (2014). A mesoscale connectome of the mouse brain. Nature, 508(7495), 207-214. https://doi.org/10.1038/nature13186
Okamoto, N., Miya, F., Tsunoda, T., Kanemura, Y., Saitoh, S., Kato, M., & Kosaki, K. (2022). Four pedigrees with aminoacyl-tRNA synthetase abnormalities. Neurological Science, 43(4), 2765-2774. https://doi.org/10.1007/s10072-021-05626-z
Orvis, J., Gottfried, B., Kancherla, J., Adkins, R. S., Song, Y., Dror, A. A., & Hertzano, R. (2021). gEAR: Gene expression analysis resource portal for community-driven, multi-omic data exploration. Nature methods, 18(8), 843-844. https://doi.org/10.1038/s41592-021-01200-9
Pertea, M., Lin, X., & Salzberg, S. L. (2001). GeneSplicer: A new computational method for splice site prediction. Nucleic Acids Research, 29(5), 1185-1190. https://doi.org/10.1093/nar/29.5.1185
Ranum, P. T., Goodwin, A. T., Yoshimura, H., Kolbe, D. L., Walls, W. D., Koh, J. Y., & Smith, R. J. H. (2019). Insights into the biology of hearing and deafness revealed by single-cell RNA sequencing. Cell Reports, 26(11), 3160-3171. https://doi.org/10.1016/j.celrep.2019.02.053
Ray, P. S., Sullivan, J. C., Jia, J., Francis, J., Finnerty, J. R., & Fox, P. L. (2011). Evolution of function of a fused metazoan tRNA synthetase. Molecular Biology and Evolution, 28(1), 437-447. https://doi.org/10.1093/molbev/msq246
Reese, M. G., Eeckman, F. H., Kulp, D., & Haussler, D. (1997). Improved splice site detection in genie. Journal of Computational Biology, 4(3), 311-323. https://doi.org/10.1089/cmb.1997.4.311
Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J., & Kircher, M. (2019). CADD: Predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Research, 47(D1), D886-D894. https://doi.org/10.1093/nar/gky1016
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., & Committee, A. L. Q. A. (2015). Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genetics in Medicine, 17(5), 405-424. https://doi.org/10.1038/gim.2015.30
Santos-Cortez, R. L., Lee, K., Azeem, Z., Antonellis, P. J., Pollock, L. M., Khan, S., & Leal, S. M. (2013). Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89. American Journal of Human Genetics, 93(1), 132-140. https://doi.org/10.1016/j.ajhg.2013.05.018
Schwarz, J. M., Cooper, D. N., Schuelke, M., & Seelow, D. (2014). MutationTaster2: Mutation prediction for the deep-sequencing age. Nature methods, 11(4), 361-362. https://doi.org/10.1038/nmeth.2890
Scott, E. M., Halees, A., Itan, Y., Spencer, E. G., He, Y., Azab, M. A., & Gleeson, J. G. (2016). Characterization of greater middle eastern genetic variation for enhanced disease gene discovery. Nature Genetics, 48(9), 1071-1076. https://doi.org/10.1038/ng.3592
Shen, N., Guo, L., Yang, B., Jin, Y., & Ding, J. (2006). Structure of human tryptophanyl-tRNA synthetase in complex with tRNATrp reveals the molecular basis of tRNA recognition and specificity. Nucleic Acids Research, 34(11), 3246-3258. https://doi.org/10.1093/nar/gkl441
Siekierska, A., Stamberger, H., Deconinck, T., Oprescu, S. N., Partoens, M., & Zhang, Y., C4RCD Research Group, AR working group of the EuroEPINOMICS RES Consortium.(2019). Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish. Nature Communications, 10(1), 708. https://doi.org/10.1038/s41467-018-07953-w
Stenson, P. D., Mort, M., Ball, E. V., Chapman, M., Evans, K., Azevedo, L., & Cooper, D. N. (2020). The human gene mutation database (HGMD((R))): Optimizing its use in a clinical diagnostic or research setting. Human Genetics, 139(10), 1197-1207. https://doi.org/10.1007/s00439-020-02199-3
Sulston, J. E., & Horvitz, H. R. (1977). Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Developmental Biology, 56(1), 110-156. https://doi.org/10.1016/0012-1606(77)90158-0
Sulston, J. E., Schierenberg, E., White, J. G., & Thomson, J. N. (1983). The embryonic cell lineage of the nematode Caenorhabditis elegans. Developmental Biology, 100(1), 64-119. https://doi.org/10.1016/0012-1606(83)90201-4
Thisse, C., & Thisse, B. (2008). High-resolution in situ hybridization to whole-mount zebrafish embryos. Nature Protocols, 3(1), 59-69. https://doi.org/10.1038/nprot.2007.514
Tsai, P. C., Soong, B. W., Mademan, I., Huang, Y. H., Liu, C. R., Hsiao, C. T., & Lee, Y. C. (2017). A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy. Brain, 140(5), 1252-1266. https://doi.org/10.1093/brain/awx058
Varshney, G. K., Carrington, B., Pei, W., Bishop, K., Chen, Z., Fan, C., & Burgess, S. M. (2016). A high-throughput functional genomics workflow based on CRISPR/Cas9-mediated targeted mutagenesis in zebrafish. Nature Protocols, 11(12), 2357-2375. https://doi.org/10.1038/nprot.2016.141
Waldron, A., Wilcox, C., Francklyn, C., & Ebert, A. (2019). Knock-Down of Histidyl-tRNA synthetase causes cell cycle arrest and apoptosis of neuronal progenitor cells in vivo. Frontiers in Cell and Developmental Biology, 7, 67. https://doi.org/10.3389/fcell.2019.00067
Walker, M. B., & Kimmel, C. B. (2007). A two-color acid-free cartilage and bone stain for zebrafish larvae. Biotechnic and Histochemistry, 82(1), 23-28. https://doi.org/10.1080/10520290701333558
Wang, B., Li, X., Huang, S., Zhao, H., Liu, J., Hu, Z., & Zhang, R. (2019). A novel WARS mutation (p.Asp314Gly) identified in a Chinese distal hereditary motor neuropathy family. Clinical Genetics, 96(2), 176-182. https://doi.org/10.1111/cge.13563
Westerfield, M. (1993). The zebrafish book: A guide for the laboratory use of zebrafish (Brachydanio rerio). M. Westerfield.
Xiao, T., Roeser, T., Staub, W., & Baier, H. (2005). A GFP-based genetic screen reveals mutations that disrupt the architecture of the zebrafish retinotectal projection. Development, 132(13), 2955-2967. https://doi.org/10.1242/dev.01861
Yang, J., Yan, R., Roy, A., Xu, D., Poisson, J., & Zhang, Y. (2015). The I-TASSER suite: Protein structure and function prediction. Nature Methods, 12(1), 7-8. https://doi.org/10.1038/nmeth.3213
Yang, Y., Muzny, D. M., Xia, F., Niu, Z., Person, R., Ding, Y., & Eng, C. M. (2014). Molecular findings among patients referred for clinical whole-exome sequencing. Journal of the American Medical Association, 312(18), 1870-1879. https://doi.org/10.1001/jama.2014.14601
Yao, Z., vanVelthoven, C. T. J., Nguyen, T. N., Goldy, J., Sedeno-Cortes, A. E., Baftizadeh, F., & Zeng, H. (2021). A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell, 184(12), 3222-3241. https://doi.org/10.1016/j.cell.2021.04.021
Yeo, G., & Burge, C. B. (2004). Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. Journal of Computational Biology, 11(2-3), 377-394. https://doi.org/10.1089/1066527041410418