{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T18:42:46Z","timestamp":1763059366039,"version":"3.41.2"},"reference-count":35,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T00:00:00Z","timestamp":1747008000000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM136441"],"award-info":[{"award-number":["GM136441"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JIMD Reports"],"published-print":{"date-parts":[[2025,5]]},"abstract":"ABSTRACT<\/jats:title>Aminoacyl\u2010tRNA<\/jats:styled-content> synthetases (ARSs<\/jats:styled-content>) catalyze the formation of aminoacyl\u2010tRNA<\/jats:styled-content>, which is required for protein translation. A growing number of cases are associated with ARS<\/jats:styled-content> deficiencies. Pathogenic variants in IARS1<\/jats:italic><\/jats:styled-content> (MIM<\/jats:styled-content># 600709), encoding cytoplasmic isoleucyl\u2010tRNA<\/jats:styled-content> synthetase, have been associated with autosomal recessive growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH<\/jats:styled-content>, OMIM<\/jats:styled-content># 617093). To date, 11 GRIDHH<\/jats:styled-content> patients have been described. We identified a patient who presented with recurrent episodes of liver failure in the setting of preceding infection and neurocognitive delay, and who recently presented with a clinical picture consistent with chronic nonbacterial osteomyelitis\/chronic recurrent multifocal osteomyelitis. Exome sequencing revealed that this patient is compound heterozygous for two IARS1<\/jats:italic><\/jats:styled-content> variants: c.1193dupC<\/jats:styled-content>;p.(Cys400LeufsTer32<\/jats:styled-content>) and c.746A<\/jats:styled-content>>G;p.(Asp249Gly<\/jats:styled-content>). The frameshift variant is predicted to cause a loss of function, and functional analysis of the p.Asp249Gly<\/jats:styled-content> variant was performed using baker's yeast. Wild\u2010type human IARS1<\/jats:italic><\/jats:styled-content> has been shown to support robust yeast growth in the absence of the yeast ortholog, ILS<\/jats:italic><\/jats:styled-content>, while human IARS1<\/jats:italic><\/jats:styled-content> harboring p.Asp249Gly<\/jats:styled-content> could not, indicating a loss\u2010of\u2010function effect. The proband was treated with isoleucine supplementation with subjective clinical improvement. Overall, we expand the molecular and clinical spectra of the IARS1<\/jats:italic><\/jats:styled-content>\u2010related disorder, highlight immune dysregulation as a possible novel manifestation of this disorder, and emphasize the utility of a yeast model system for functional studies. A larger cohort of patients is required to validate these observations and evaluate the efficacy of isoleucine supplementation for patients with GRIDHH<\/jats:styled-content>.<\/jats:p>","DOI":"10.1002\/jmd2.70020","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T03:50:01Z","timestamp":1747108201000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Atypical Presentation of IARS1<\/i><\/scp>\u2010Related Disorder: Expanding the Phenotype and Genotype"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7321-307X","authenticated-orcid":false,"given":"Parith","family":"Wongkittichote","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Genetics and Genomic Medicine Washington University School of Medicine St. Louis Missouri USA"},{"name":"Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kira E.","family":"Jonatzke","sequence":"additional","affiliation":[{"name":"Department of Human Genetics University of Michigan Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin T.","family":"Hyde","sequence":"additional","affiliation":[{"name":"Department of Human Genetics University of Michigan Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2458-6678","authenticated-orcid":false,"given":"Lance W.","family":"Peterson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Rheumatology and Immunology Washington University School of Medicine St. Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mai","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology Washington University School of Medicine St. Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert C.","family":"McKinstry","sequence":"additional","affiliation":[{"name":"Mallinckrodt Institute of Radiology Washington University School of Medicine St. Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Antonellis","sequence":"additional","affiliation":[{"name":"Department of Human Genetics University of Michigan Ann Arbor Michigan USA"},{"name":"Department of Neurology University of Michigan Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1329-4100","authenticated-orcid":false,"given":"Marwan","family":"Shinawi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Genetics and Genomic Medicine Washington University School of Medicine St. Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,5,12]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genom.9.081307.164204"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2017.12.157"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436\u2010018\u20100048\u2010y"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2017.06.002"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.enz.2020.06.009"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2019.11.007"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx231"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes13122319"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.16.7435"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22629"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.05.027"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.2326"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12930"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13080"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12887\u2010022\u201003371\u20106"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v26.i15.1841"},{"key":"e_1_2_12_18_1","first-page":"94","article-title":"A Case of GRIDHH due to Mutations in the IARS Gene","volume":"29","author":"Guojie W. 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