[{"publication":"Human Mutation","file":[{"checksum":"74b01d4e4084b2f64c30ed32b18ee928","file_size":12131312,"success":1,"relation":"main_file","content_type":"application/pdf","file_id":"14370","creator":"dernst","date_updated":"2023-09-25T08:52:54Z","access_level":"open_access","date_created":"2023-09-25T08:52:54Z","file_name":"2022_HumanMutation_Lin.pdf"}],"month":"10","has_accepted_license":"1","publisher":"Wiley","file_date_updated":"2023-09-25T08:52:54Z","publication_status":"published","date_updated":"2023-09-25T08:54:14Z","_id":"14356","oa":1,"keyword":["autosomal recessive","biallelic variants","C","elegans","translation initiation sites","tryptophanyl-tRNA synthetase 1 (WARS1)","WHEP domain","zebrafish"],"author":[{"first_name":"Sheng-Jia","full_name":"Lin, Sheng-Jia","last_name":"Lin"},{"last_name":"Vona","full_name":"Vona, Barbara","first_name":"Barbara"},{"first_name":"Hillary M.","full_name":"Porter, Hillary M.","last_name":"Porter"},{"last_name":"Izadi","first_name":"Mahmoud","full_name":"Izadi, Mahmoud"},{"id":"3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3","last_name":"Huang","orcid":"0000-0002-2512-7812","first_name":"Kevin","full_name":"Huang, Kevin"},{"first_name":"Yves","full_name":"Lacassie, Yves","last_name":"Lacassie"},{"full_name":"Rosenfeld, Jill A.","first_name":"Jill A.","last_name":"Rosenfeld"},{"full_name":"Khan, Saadullah","first_name":"Saadullah","last_name":"Khan"},{"first_name":"Cassidy","full_name":"Petree, Cassidy","last_name":"Petree"},{"last_name":"Ali","first_name":"Tayyiba A.","full_name":"Ali, Tayyiba A."},{"first_name":"Nazif","full_name":"Muhammad, Nazif","last_name":"Muhammad"},{"full_name":"Khan, Sher A.","first_name":"Sher A.","last_name":"Khan"},{"last_name":"Muhammad","first_name":"Noor","full_name":"Muhammad, Noor"},{"first_name":"Pengfei","full_name":"Liu, Pengfei","last_name":"Liu"},{"full_name":"Haymon, Marie-Louise","first_name":"Marie-Louise","last_name":"Haymon"},{"last_name":"Rueschendorf","full_name":"Rueschendorf, Franz","first_name":"Franz"},{"last_name":"Kong","first_name":"Il-Keun","full_name":"Kong, Il-Keun"},{"full_name":"Schnapp, Linda","first_name":"Linda","last_name":"Schnapp"},{"last_name":"Shur","first_name":"Natasha","full_name":"Shur, Natasha"},{"last_name":"Chorich","first_name":"Lynn","full_name":"Chorich, Lynn"},{"full_name":"Layman, Lawrence","first_name":"Lawrence","last_name":"Layman"},{"full_name":"Haaf, Thomas","first_name":"Thomas","last_name":"Haaf"},{"last_name":"Pourkarimi","first_name":"Ehsan","full_name":"Pourkarimi, Ehsan"},{"full_name":"Kim, Hyung-Goo","first_name":"Hyung-Goo","last_name":"Kim"},{"last_name":"Varshney","first_name":"Gaurav K.","full_name":"Varshney, Gaurav K."}],"year":"2022","publication_identifier":{"issn":["1059-7794"]},"license":"https://creativecommons.org/licenses/by/4.0/","ddc":["570"],"status":"public","date_published":"2022-10-01T00:00:00Z","page":"1472-1489","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","article_processing_charge":"No","quality_controlled":"1","doi":"10.1002/humu.24435","oa_version":"Published Version","day":"01","type":"journal_article","citation":{"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.","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.","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.","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>","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>."},"scopus_import":"1","title":"Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function","date_created":"2023-09-20T20:58:24Z","language":[{"iso":"eng"}],"issue":"10","article_type":"original","intvolume":"        43","extern":"1","tmp":{"short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"abstract":[{"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.","lang":"eng"}],"volume":43},{"date_updated":"2023-09-25T08:43:06Z","publication_status":"published","_id":"14357","oa":1,"keyword":["aminoacylation","aminoacyl-tRNA synthetase","ARS","CRISPR","Cas9","intellectual disability","microcephaly","SARS1","tRNA","WARS1","zebrafish"],"author":[{"last_name":"Boegershausen","full_name":"Boegershausen, Nina","first_name":"Nina"},{"first_name":"Hannah E.","full_name":"Krawczyk, Hannah E.","last_name":"Krawczyk"},{"last_name":"Jamra","full_name":"Jamra, Rami A.","first_name":"Rami A."},{"first_name":"Sheng-Jia","full_name":"Lin, Sheng-Jia","last_name":"Lin"},{"last_name":"Yigit","first_name":"Goekhan","full_name":"Yigit, Goekhan"},{"first_name":"Irina","full_name":"Huening, Irina","last_name":"Huening"},{"full_name":"Polo, Anna M.","first_name":"Anna M.","last_name":"Polo"},{"full_name":"Vona, Barbara","first_name":"Barbara","last_name":"Vona"},{"last_name":"Huang","id":"3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3","orcid":"0000-0002-2512-7812","first_name":"Kevin","full_name":"Huang, Kevin"},{"last_name":"Schmidt","first_name":"Julia","full_name":"Schmidt, Julia"},{"first_name":"Janine","full_name":"Altmueller, Janine","last_name":"Altmueller"},{"full_name":"Luppe, Johannes","first_name":"Johannes","last_name":"Luppe"},{"last_name":"Platzer","full_name":"Platzer, Konrad","first_name":"Konrad"},{"last_name":"Doergeloh","first_name":"Beate B.","full_name":"Doergeloh, Beate B."},{"last_name":"Busche","first_name":"Andreas","full_name":"Busche, Andreas"},{"first_name":"Saskia","full_name":"Biskup, Saskia","last_name":"Biskup"},{"full_name":"Mendes, I, Marisa","first_name":"Marisa","last_name":"Mendes, I"},{"last_name":"Smith","full_name":"Smith, Desiree E. C.","first_name":"Desiree E. C."},{"first_name":"Gajja S.","full_name":"Salomons, Gajja S.","last_name":"Salomons"},{"last_name":"Zibat","first_name":"Arne","full_name":"Zibat, Arne"},{"last_name":"Bueltmann","full_name":"Bueltmann, Eva","first_name":"Eva"},{"full_name":"Nuernberg, Peter","first_name":"Peter","last_name":"Nuernberg"},{"last_name":"Spielmann","full_name":"Spielmann, Malte","first_name":"Malte"},{"full_name":"Lemke, Johannes R.","first_name":"Johannes R.","last_name":"Lemke"},{"last_name":"Li","first_name":"Yun","full_name":"Li, Yun"},{"full_name":"Zenker, Martin","first_name":"Martin","last_name":"Zenker"},{"full_name":"Varshney, Gaurav K.","first_name":"Gaurav K.","last_name":"Varshney"},{"full_name":"Hillen, Hauke S.","first_name":"Hauke S.","last_name":"Hillen"},{"first_name":"Christian P.","full_name":"Kratz, Christian P.","last_name":"Kratz"},{"full_name":"Wollnik, Bernd","first_name":"Bernd","last_name":"Wollnik"}],"external_id":{"pmid":["35790048"]},"page":"1454-1471","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","article_processing_charge":"No","publication_identifier":{"issn":["1059-7794"]},"year":"2022","license":"https://creativecommons.org/licenses/by-nc-nd/4.0/","status":"public","ddc":["570"],"date_published":"2022-10-01T00:00:00Z","publication":"Human Mutation","pmid":1,"month":"10","file":[{"file_name":"2022_HumanMutation_Boegershausen.pdf","date_created":"2023-09-25T08:41:23Z","file_id":"14367","date_updated":"2023-09-25T08:41:23Z","creator":"dernst","access_level":"open_access","success":1,"content_type":"application/pdf","relation":"main_file","checksum":"c31fc91e0445c35b9da83eb911a9b552","file_size":4863605}],"has_accepted_license":"1","publisher":"Wiley","file_date_updated":"2023-09-25T08:41:23Z","scopus_import":"1","title":"WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly","date_created":"2023-09-20T20:59:33Z","language":[{"iso":"eng"}],"extern":"1","article_type":"original","issue":"10","intvolume":"        43","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)"},"abstract":[{"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.","lang":"eng"}],"volume":43,"quality_controlled":"1","doi":"10.1002/humu.24430","oa_version":"Published Version","citation":{"ieee":"N. Boegershausen <i>et al.</i>, “WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly,” <i>Human Mutation</i>, vol. 43, no. 10. Wiley, pp. 1454–1471, 2022.","ama":"Boegershausen N, Krawczyk HE, Jamra RA, et al. WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly. <i>Human Mutation</i>. 2022;43(10):1454-1471. doi:<a href=\"https://doi.org/10.1002/humu.24430\">10.1002/humu.24430</a>","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.","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.","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.” <i>Human Mutation</i>. Wiley, 2022. <a href=\"https://doi.org/10.1002/humu.24430\">https://doi.org/10.1002/humu.24430</a>.","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. <i>Human Mutation</i>. Wiley. <a href=\"https://doi.org/10.1002/humu.24430\">https://doi.org/10.1002/humu.24430</a>","mla":"Boegershausen, Nina, et al. “WARS1 and SARS1: Two TRNA Synthetases Implicated in Autosomal Recessive Microcephaly.” <i>Human Mutation</i>, vol. 43, no. 10, Wiley, 2022, pp. 1454–71, doi:<a href=\"https://doi.org/10.1002/humu.24430\">10.1002/humu.24430</a>."},"type":"journal_article","day":"01"}]