Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL
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Fecha de publicación
2020Título de revista
GENES
Tipo de contenido
Journal Article
DeCS
fenotipo | variación genética | tronco encefálico | tálamo | fosforilación oxidativa | consumo de oxígeno | adulto | leucoencefalopatías | ácido láctico | ARN | mitocondrias | fibroblastos | aminoacil-ARNt sintetasas | humanos | células | glutamato-ARNt ligasaMeSH
Adult | Brain Stem | Leukoencephalopathies | RNA | Genetic Variation | Phenotype | Glutamate-tRNA Ligase | Amino Acyl-tRNA Synthetases | Mitochondria | Humans | Fibroblasts | Oxidative Phosphorylation | Cells | Thalamus | Oxygen Consumption | Lactic AcidResumen
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>T (p.Gln126*) and c.670G>A (p.Gly224Ser), with infantile-onset disease and a severe clinical presentation. We demonstrate a clear defect in mitochondrial function in the patient's 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's clinical presentation with that of previously reported cases, new clinical and radiological features of LTBL were identified, expanding the clinical spectrum of this disease.
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