Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL

Barbosa-Gouveia, Sofia; González-Vioque, Emiliano; Hermida, Álvaro; Suarez, María Unceta; Martínez-González, María Jesús; Borges, Filipa; Wintjes, Liesbeth; Kappen, Antonia; Rodenburg, Richard; Couce, María-Luz

doi:10.3390/genes11091028

Open AccessArticle

Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL

by

Sofia Barbosa-Gouveia

^1,*

,

Emiliano González-Vioque

¹,

Álvaro Hermida

¹

,

María Unceta Suarez

²

,

María Jesús Martínez-González

²,

Filipa Borges

¹

,

Liesbeth Wintjes

³,

Antonia Kappen

³

,

Richard Rodenburg

⁴

and

María-Luz Couce

¹

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

²

Biochemistry Laboratory (Metabolic Diseases Unit) & Department of Pediatrics (Pediatric Neurology), Cruces University Hospital, 48903 Bizkaia, Spain

³

Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands

⁴

Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands

^*

Author to whom correspondence should be addressed.

Genes 2020, 11(9), 1028; https://doi.org/10.3390/genes11091028

Submission received: 17 July 2020 / Revised: 21 August 2020 / Accepted: 31 August 2020 / Published: 2 September 2020

(This article belongs to the Special Issue The Value of Genetics in the Identification of Treatable Rare Diseases. The Paradigm of Inborn Errors of Metabolism)

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Abstract

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.

Keywords: mitochondrial disorders; aminoacyl-tRNA synthetases; EARS2; LTBL

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MDPI and ACS Style

Barbosa-Gouveia, S.; González-Vioque, E.; Hermida, Á.; Suarez, M.U.; Martínez-González, M.J.; Borges, F.; Wintjes, L.; Kappen, A.; Rodenburg, R.; Couce, M.-L. Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL. Genes 2020, 11, 1028. https://doi.org/10.3390/genes11091028

AMA Style

Barbosa-Gouveia S, González-Vioque E, Hermida Á, Suarez MU, Martínez-González MJ, Borges F, Wintjes L, Kappen A, Rodenburg R, Couce M-L. Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL. Genes. 2020; 11(9):1028. https://doi.org/10.3390/genes11091028

Chicago/Turabian Style

Barbosa-Gouveia, Sofia, Emiliano González-Vioque, Álvaro Hermida, María Unceta Suarez, María Jesús Martínez-González, Filipa Borges, Liesbeth Wintjes, Antonia Kappen, Richard Rodenburg, and María-Luz Couce. 2020. "Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL" Genes 11, no. 9: 1028. https://doi.org/10.3390/genes11091028

APA Style

Barbosa-Gouveia, S., González-Vioque, E., Hermida, Á., Suarez, M. U., Martínez-González, M. J., Borges, F., Wintjes, L., Kappen, A., Rodenburg, R., & Couce, M.-L. (2020). Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL. Genes, 11(9), 1028. https://doi.org/10.3390/genes11091028

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Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL

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