--- _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. Human Mutation. 2022;43(10):1472-1489. doi:10.1002/humu.24435 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. Human Mutation. Wiley. https://doi.org/10.1002/humu.24435 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.” Human Mutation. Wiley, 2022. https://doi.org/10.1002/humu.24435. ieee: S.-J. Lin et al., “Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function,” Human Mutation, 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.” Human Mutation, vol. 43, no. 10, Wiley, 2022, pp. 1472–89, doi:10.1002/humu.24435. 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: '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' ...