{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:50:55Z","timestamp":1762869055419,"version":"3.40.5"},"reference-count":22,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T00:00:00Z","timestamp":1683244800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Biallelic variants of <jats:italic>RARS1<\/jats:italic>, a gene that encodes the cytoplasmic tRNA synthetase for arginine (ArgRS), are associated with central nervous system (CNS) manifestations, such as hypomyelinating leukodystrophy\u20109 and developmental and epileptic encephalopathy (DEE). This study aimed to better understand the <jats:italic>RARS1<\/jats:italic> biallelic mutations and the associated phenotypes, particularly in patients with DEE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We identified two patients with <jats:italic>RARS1<\/jats:italic> biallelic mutations and functionally validated these mutations in vitro. Furthermore, we performed a review of the literature.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two patients with hypomyelinating leukodystrophy were found to have <jats:italic>RARS1<\/jats:italic> biallelic variants (Patient 1: c.1535G&gt;A (p.Arg512Gln) and c.1382G&gt;A (p.Arg461His); Patient 2: homozygous variants c.5A&gt;T (p.Asp2Val)). Patient 2 had a severe clinical manifestation of DEE. A review of the literature identified 27 patients from five studies. Among the 29 patients, intellectual disability, developmental delay, and hypomyelination were the common symptoms, while 13 of them exhibited DEE and malformations of cortical development. Of the 25 variants identified, c.5A&gt;G (p.Asp2Gly) was identified in 10 patients. ArgRS protein expression and stability were substantially reduced in the two newly identified patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Patients with <jats:italic>RARS1<\/jats:italic> biallelic mutations frequently exhibit DEE, a severe phenotype, along with hypomyelinating leukodystrophy. Besides its effects on the white matter, this mutation also influences cortical development. Moreover, the variants c.5A&gt;T (p.Asp2Val), c.1382G&gt;A (p.Arg461His), and c.1535G&gt;A (p.Arg512Gln) are pathogenic and affect the expression of ArgRS by reducing the protein stability.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.12751","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T09:49:47Z","timestamp":1682502587000},"page":"867-876","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<i>RARS1<\/i>\u2010related developmental and epileptic encephalopathy"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2409-3497","authenticated-orcid":false,"given":"Lin","family":"Wan","sequence":"first","affiliation":[{"name":"Department of Pediatrics, The Seventh Medical Center of PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics, The First Medical Centre Chinese PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics Medical School of Chinese People\u2019s Liberation Army  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics West China Second Hospital of Sichuan University  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhichao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Seventh Medical Center of PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics, The First Medical Centre Chinese PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics Medical School of Chinese People\u2019s Liberation Army  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinting","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Seventh Medical Center of PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics, The First Medical Centre Chinese PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics Medical School of Chinese People\u2019s Liberation Army  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Seventh Medical Center of PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics, The First Medical Centre Chinese PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics Medical School of Chinese People\u2019s Liberation Army  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huimin","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Seventh Medical Center of PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics, The First Medical Centre Chinese PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics Medical School of Chinese People\u2019s Liberation Army  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Seventh Medical Center of PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics, The First Medical Centre Chinese PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics Medical School of Chinese People\u2019s Liberation Army  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, ICCTR Biostatistics and Research Design Center, Boston Children's Hospital Harvard Medical School  Massachusetts Boston USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8622-2146","authenticated-orcid":false,"given":"Guang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Seventh Medical Center of PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics, The First Medical Centre Chinese PLA General Hospital  Beijing China"},{"name":"Department of Pediatrics Medical School of Chinese People\u2019s Liberation Army  Beijing China"},{"name":"Department of Pediatrics, The Second School of Clinical Medicine Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,5,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-022-00737-3"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12811"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-020-00432-1"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24194"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0036-1588020"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx314"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.50960"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24167"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2017.119"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0188869"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0208324"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0039-1679911"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa443"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky300"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3942"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00063.2021"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2012-302882"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181ce5d82"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A2440"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn4021"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.wneu.2021.12.011"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-020-1838-2"}],"container-title":["Epilepsia Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi4.12751","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T09:48:27Z","timestamp":1693561707000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/epi4.12751"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,5]]},"references-count":22,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2023,9]]}},"alternative-id":["10.1002\/epi4.12751"],"URL":"https:\/\/doi.org\/10.1002\/epi4.12751","archive":["Portico"],"relation":{},"ISSN":["2470-9239","2470-9239"],"issn-type":[{"type":"print","value":"2470-9239"},{"type":"electronic","value":"2470-9239"}],"subject":[],"published":{"date-parts":[[2023,5,5]]},"assertion":[{"value":"2023-03-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}