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Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency

Pathogenic variants in the mitochondrial tyrosyl-tRNA synthetase gene (YARS2) were associated with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). However, patients can present mitochondrial myopathy, with exercise intolerance and muscle weakness, leading from mild to lethal phenotypes....

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Autores principales: Carreño-Gago, Lidia, Juárez-Flores, Diana Luz, Grau, Josep Maria, Ramón, Javier, Lozano, Ester, Vila-Julià, Ferran, Martí, Ramon, Garrabou, Glòria, Garcia-Arumí, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397107/
https://www.ncbi.nlm.nih.gov/pubmed/34441767
http://dx.doi.org/10.3390/jcm10163471
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author Carreño-Gago, Lidia
Juárez-Flores, Diana Luz
Grau, Josep Maria
Ramón, Javier
Lozano, Ester
Vila-Julià, Ferran
Martí, Ramon
Garrabou, Glòria
Garcia-Arumí, Elena
author_facet Carreño-Gago, Lidia
Juárez-Flores, Diana Luz
Grau, Josep Maria
Ramón, Javier
Lozano, Ester
Vila-Julià, Ferran
Martí, Ramon
Garrabou, Glòria
Garcia-Arumí, Elena
author_sort Carreño-Gago, Lidia
collection PubMed
description Pathogenic variants in the mitochondrial tyrosyl-tRNA synthetase gene (YARS2) were associated with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). However, patients can present mitochondrial myopathy, with exercise intolerance and muscle weakness, leading from mild to lethal phenotypes. Genes implicated in mtDNA replication were studied by Next Generation Sequencing (NGS) and whole exome sequence with the TruSeq Rapid Exome kit (Illumina, San Diego, CA, USA). Mitochondrial protein translation was studied following the Sasarman and Shoubridge protocol and oxygen consumption rates with Agilent Seahorse XF24 Analyzer Mitostress Test, (Agilent, Santa Clara, CA, USA). We report two siblings with two novel compound heterozygous pathogenic variants in YARS2 gene: a single nucleotide deletion in exon 1, c.314delG (p.(Gly105Alafs*4)), which creates a premature stop codon in the amino acid 109, and a single nucleotide change in exon 5 c.1391T>C (p.(Ile464Thr)), that cause a missense variant in amino acid 464. We demonstrate the pathogenicity of these new variants associated with reduced YARS2 mRNA transcript, reduced mitochondrial protein translation and dysfunctional organelle function. These pathogenic variants are responsible for late onset MLASA, herein accompanied by pancreatic insufficiency, observed in both brothers, clinically considered as Pearson’s syndrome. Molecular study of YARS2 gene should be considered in patients presenting Pearson’s syndrome characteristics and MLASA related phenotypes.
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spelling pubmed-83971072021-08-28 Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency Carreño-Gago, Lidia Juárez-Flores, Diana Luz Grau, Josep Maria Ramón, Javier Lozano, Ester Vila-Julià, Ferran Martí, Ramon Garrabou, Glòria Garcia-Arumí, Elena J Clin Med Article Pathogenic variants in the mitochondrial tyrosyl-tRNA synthetase gene (YARS2) were associated with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). However, patients can present mitochondrial myopathy, with exercise intolerance and muscle weakness, leading from mild to lethal phenotypes. Genes implicated in mtDNA replication were studied by Next Generation Sequencing (NGS) and whole exome sequence with the TruSeq Rapid Exome kit (Illumina, San Diego, CA, USA). Mitochondrial protein translation was studied following the Sasarman and Shoubridge protocol and oxygen consumption rates with Agilent Seahorse XF24 Analyzer Mitostress Test, (Agilent, Santa Clara, CA, USA). We report two siblings with two novel compound heterozygous pathogenic variants in YARS2 gene: a single nucleotide deletion in exon 1, c.314delG (p.(Gly105Alafs*4)), which creates a premature stop codon in the amino acid 109, and a single nucleotide change in exon 5 c.1391T>C (p.(Ile464Thr)), that cause a missense variant in amino acid 464. We demonstrate the pathogenicity of these new variants associated with reduced YARS2 mRNA transcript, reduced mitochondrial protein translation and dysfunctional organelle function. These pathogenic variants are responsible for late onset MLASA, herein accompanied by pancreatic insufficiency, observed in both brothers, clinically considered as Pearson’s syndrome. Molecular study of YARS2 gene should be considered in patients presenting Pearson’s syndrome characteristics and MLASA related phenotypes. MDPI 2021-08-05 /pmc/articles/PMC8397107/ /pubmed/34441767 http://dx.doi.org/10.3390/jcm10163471 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Carreño-Gago, Lidia
Juárez-Flores, Diana Luz
Grau, Josep Maria
Ramón, Javier
Lozano, Ester
Vila-Julià, Ferran
Martí, Ramon
Garrabou, Glòria
Garcia-Arumí, Elena
Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency
title Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency
title_full Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency
title_fullStr Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency
title_full_unstemmed Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency
title_short Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency
title_sort two novel variants in yars2 gene are responsible for an extended mlasa phenotype with pancreatic insufficiency
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397107/
https://www.ncbi.nlm.nih.gov/pubmed/34441767
http://dx.doi.org/10.3390/jcm10163471
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