{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T20:24:32Z","timestamp":1785183872442,"version":"3.55.0"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T00:00:00Z","timestamp":1599004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017210","name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela","doi-asserted-by":"publisher","award":["Pre-doctoral grant"],"award-info":[{"award-number":["Pre-doctoral grant"]}],"id":[{"id":"10.13039\/100017210","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The EARS2 nuclear gene encodes mitochondrial glutamyl-tRNA synthetase, a member of the class I family of aminoacyl-tRNA synthetases (aaRSs) that plays a crucial role in mitochondrial protein biosynthesis by catalyzing the charging of glutamate to mitochondrial tRNA(Glu). Pathogenic EARS2 variants have been associated with a rare mitochondrial disorder known as leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The targeted sequencing of 150 nuclear genes encoding respiratory chain complex subunits and proteins implicated in the oxidative phosphorylation (OXPHOS) function was performed. The oxygen consumption rate (OCR), and the extracellular acidification rate (ECAR), were measured. The enzymatic activities of Complexes I-V were analyzed spectrophotometrically. We describe a patient carrying two heterozygous EARS2 variants, c.376C&gt;T (p.Gln126*) and c.670G&gt;A (p.Gly224Ser), with infantile-onset disease and a severe clinical presentation. We demonstrate a clear defect in mitochondrial function in the patient\u2019s fibroblasts, suggesting the molecular mechanism underlying the pathogenicity of these EARS2 variants. Experimental validation using patient-derived fibroblasts allowed an accurate characterization of the disease-causing variants, and by comparing our patient\u2019s clinical presentation with that of previously reported cases, new clinical and radiological features of LTBL were identified, expanding the clinical spectrum of this disease.<\/jats:p>","DOI":"10.3390\/genes11091028","type":"journal-article","created":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T09:29:28Z","timestamp":1599038968000},"page":"1028","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1431-4644","authenticated-orcid":false,"given":"Sofia","family":"Barbosa-Gouveia","sequence":"first","affiliation":[{"name":"Diagnosis and Treatment of Congenital Metabolic Diseases Unit (UDyTEMC), Department of Pediatrics, Faculty of Medicine, Clinical University Hospital of Santiago de Compostela, University of Santiago de Compostela, CIBERER, MetabERN, Institute of Clinical Research of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emiliano","family":"Gonz\u00e1lez-Vioque","sequence":"additional","affiliation":[{"name":"Diagnosis and Treatment of Congenital Metabolic Diseases Unit (UDyTEMC), Department of Pediatrics, Faculty of Medicine, Clinical University Hospital of Santiago de Compostela, University of Santiago de Compostela, CIBERER, MetabERN, Institute of Clinical Research of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3757-262X","authenticated-orcid":false,"given":"\u00c1lvaro","family":"Hermida","sequence":"additional","affiliation":[{"name":"Diagnosis and Treatment of Congenital Metabolic Diseases Unit (UDyTEMC), Department of Pediatrics, Faculty of Medicine, Clinical University Hospital of Santiago de Compostela, University of Santiago de Compostela, CIBERER, MetabERN, Institute of Clinical Research of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8176-6750","authenticated-orcid":false,"given":"Mar\u00eda Unceta","family":"Suarez","sequence":"additional","affiliation":[{"name":"Biochemistry Laboratory (Metabolic Diseases Unit) &amp; Department of Pediatrics (Pediatric Neurology), Cruces University Hospital, 48903 Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jes\u00fas","family":"Mart\u00ednez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Biochemistry Laboratory (Metabolic Diseases Unit) &amp; Department of Pediatrics (Pediatric Neurology), Cruces University Hospital, 48903 Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9876-4348","authenticated-orcid":false,"given":"Filipa","family":"Borges","sequence":"additional","affiliation":[{"name":"Diagnosis and Treatment of Congenital Metabolic Diseases Unit (UDyTEMC), Department of Pediatrics, Faculty of Medicine, Clinical University Hospital of Santiago de Compostela, University of Santiago de Compostela, CIBERER, MetabERN, Institute of Clinical Research of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liesbeth","family":"Wintjes","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3115-8882","authenticated-orcid":false,"given":"Antonia","family":"Kappen","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5227-3527","authenticated-orcid":false,"given":"Richard","family":"Rodenburg","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4861-9905","authenticated-orcid":false,"given":"Mar\u00eda-Luz","family":"Couce","sequence":"additional","affiliation":[{"name":"Diagnosis and Treatment of Congenital Metabolic Diseases Unit (UDyTEMC), Department of Pediatrics, Faculty of Medicine, Clinical University Hospital of Santiago de Compostela, University of Santiago de Compostela, CIBERER, MetabERN, Institute of Clinical Research of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16080","DOI":"10.1038\/nrdp.2016.80","article-title":"Mitochondrial diseases","volume":"2","author":"Gorman","year":"2016","journal-title":"Nat. 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