{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:46:36Z","timestamp":1789073196203,"version":"build-2803163510"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T00:00:00Z","timestamp":1642982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Leukodystrophies constitute a heterogeneous group of inherited disorders primarily affecting the white matter of the central nervous system. Aminoacyl-tRNA synthetases (ARSs) catalyze the attachment of an amino acids to their cognate transfer RNAs (tRNAs). Pathogenic variants in both cytosolic and mitochondrial ARSs have been linked to a broad range of neurological disorders, including hypomyelinating leukodystrophies and pontocerebellar hypoplasias (PCH). Aminoacyl tRNA synthetase-interacting multifunctional protein 2 (AIMP2), one of the three non-catalytic components of multi ARS complex, harbors anti-proliferative activity and functions as a proapoptotic factor thus promoting cell death. We report a case of a 7-month-old infant with a complex clinical presentation, including weight loss, severe anemia, skeletal abnormalities, microcephaly and MR imaging features of leukodystrophy with a novel mutation in AIMP2.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Whole-exome sequencing (WES) was performed on the proband. Parental samples were analyzed by PCR amplification and Sanger sequencing.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Whole-exome sequencing revealed a novel variant c.A463T in the homozygous state in exon 3 (NM_001,326,607) of AIMP2 [p.(K155X)] in the proband. Parental carrier status was confirmed by target sequencing.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Here, we present an Iranian case with leukodystrophy with a novel AIMP2 mutation. This finding broadens the mutational and phenotypic spectra of AIMP2-related leukodystrophy and offers guidance for proper genetic counselling for pre- and post-natal screenings as well as for disease management.<\/jats:p>","DOI":"10.3389\/fgene.2022.816987","type":"journal-article","created":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T06:37:48Z","timestamp":1643006268000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Case Report: Mutation in AIMP2\/P38, the Scaffold for the Multi-Trna Synthetase Complex, and Association With Progressive Neurodevelopmental Disorders"],"prefix":"10.3389","volume":"13","author":[{"given":"Mahta","family":"Mazaheri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahdie","family":"Yavari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadi","family":"Zare Marzouni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Stufano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Lovreglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"D'Amore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid Reza","family":"Jahantigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1007\/s10048-019-00572-7","article-title":"Pathogenic Variants in AIMP1 Cause Pontocerebellar Hypoplasia","volume":"20","author":"Accogli","year":"2019","journal-title":"Neurogenetics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.braindev.2017.01.001","article-title":"Childhood Leukodystrophies: a Literature Review of Updates on New Definitions, Classification, Diagnostic Approach and Management","volume":"39","author":"Ashrafi","year":"2017","journal-title":"Brain Dev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1080\/14737175.2020.1699060","article-title":"An Update on Clinical, Pathological, Diagnostic, and Therapeutic Perspectives of Childhood Leukodystrophies","volume":"20","author":"Ashrafi","year":"2020","journal-title":"Expert Rev. Neurother."},{"key":"B4","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1212\/wnl.0b013e3181eee46b","article-title":"The burden of Inherited Leukodystrophies in Children","volume":"75","author":"Bonkowsky","year":"2010","journal-title":"Neurology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1101\/pdb.prot083659","article-title":"Whole-exome Enrichment with the Agilent Sureselect Human All Exon Platform","volume":"2015","author":"Chen","year":"2015","journal-title":"Cold Spring Harb. Protoc."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1093\/carcin\/bgp170","article-title":"Multidirectional Tumor-Suppressive Activity of AIMP2\/p38 and the Enhanced Susceptibility of AIMP2 Heterozygous Mice to Carcinogenesis","volume":"30","author":"Choi","year":"2009","journal-title":"Carcinogenesis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.braindev.2012.03.005","article-title":"An Atypical Patient with Cowden Syndrome and PTEN Gene Mutation Presenting with Cortical Malformation and Focal Epilepsy","volume":"34","author":"Elia","year":"2012","journal-title":"Brain Dev."},{"key":"B8","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1007\/128_2013_479","article-title":"Protein-Protein Interactions and Multi-Component Complexes of Aminoacyl-tRNA Synthetases","volume":"344","author":"Kim","year":"2013","journal-title":"Top Curr. Chem."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.3390\/ma12071064","article-title":"Fluorescence-based Analysis of Noncanonical Functions of Aminoacyl-tRNA Synthetase-Interacting Multifunctional Proteins (AIMPs) in Peripheral Nerves","volume":"12","author":"Kim","year":"2019","journal-title":"Materials"},{"key":"B10","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1007\/s00415-014-7263-5","article-title":"Epidemiological, Clinical, and Genetic Landscapes of Hypomyelinating Leukodystrophies","volume":"261","author":"Numata","year":"2014","journal-title":"J. Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11064-021-03451-6","article-title":"Knockdown of Golgi Stress-Responsive Caspase-2 Ameliorates HLD17-Associated AIMP2 Mutant-Mediated Inhibition of Oligodendroglial Cell Morphological Differentiation","author":"Ochiai","year":"2021","journal-title":"Neurochem. Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1080\/15476286.2017.1330245","article-title":"Human Aminoacyl-tRNA Synthetases in Diseases of the Nervous System","volume":"15","author":"Ognjenovi\u0107","year":"2018","journal-title":"RNA Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1016\/j.ymgme.2014.12.434","article-title":"A Clinical Approach to the Diagnosis of Patients with Leukodystrophies and Genetic Leukoencephelopathies","volume":"114","author":"Parikh","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"B14","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/j.tibs.2005.08.004","article-title":"Functional Expansion of Aminoacyl-tRNA Synthetases and Their Interacting Factors: New Perspectives on Housekeepers","volume":"30","author":"Park","year":"2005","journal-title":"Trends Biochem. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1002\/iub.324","article-title":"Aminoacyl-tRNA Synthetase-Interacting Multifunctional Proteins (AIMPs): a Triad for Cellular Homeostasis","volume":"62","author":"Park","year":"2010","journal-title":"IUBMB life"},{"key":"B16","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/s10038-017-0363-1","article-title":"Homozygosity for a Nonsense Variant in AIMP2 Is Associated with a Progressive Neurodevelopmental Disorder with Microcephaly, Seizures, and Spastic Quadriparesis","volume":"63","author":"Shukla","year":"2018","journal-title":"J. Hum. Genet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1002\/ana.24251","article-title":"Clinical Whole Exome Sequencing in Child Neurology Practice","volume":"76","author":"Srivastava","year":"2014","journal-title":"Ann. Neurol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1148\/radiology.213.1.r99se01121","article-title":"Defining and Categorizing Leukoencephalopathies of Unknown Origin: MR Imaging Approach","volume":"213","author":"Van Der Knaap","year":"1999","journal-title":"Radiology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/j.ymgme.2015.01.006","article-title":"Case Definition and Classification of Leukodystrophies and Leukoencephalopathies","volume":"114","author":"Vanderver","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"B21","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1212\/con.0000000000000338","article-title":"Genetic Leukoencephalopathies in Adults","volume":"22","author":"Vanderver","year":"2016","journal-title":"Continuum: Lifelong Learn. Neurol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.816987\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T10:18:14Z","timestamp":1645525094000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.816987\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,24]]},"references-count":21,"alternative-id":["10.3389\/fgene.2022.816987"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.816987","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,24]]},"article-number":"816987"}}