16f416a7f07a7a0f339f6b971e9a28ac pmc_34441767.pdf 48394e85132152c3698fece7e44d349f950590e9 pmc_34441767.pdf a901051e26ce2d77417826459d333170f0b34a2a95e8c1b3a43bded8a5607b3f pmc_34441767.pdf Title: Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency Subject: 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. Keywords: mitochondrial aminocyl-tRNA synthetase; novel pathogenic variant; Pearson’s syndrome Author: Lidia Carreño-Gago, Diana Luz Juárez-Flores, Josep Maria Grau, Javier Ramón, Ester Lozano, Ferran Vila-Julià, Ramon Martí, Glòria Garrabou and Elena Garcia-Arumí Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri Aug 6 12:45:40 2021 CEST ModDate: Fri Aug 6 12:56:02 2021 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1592834 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- IHXLPJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 CIQLLF+VnURWPalladioL Type 1 Custom yes yes no 15 0 SFECEF+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 AHNSTB+URWPalladioL-Bold Type 1 Custom yes yes no 24 0 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Panel Destination: subsection.2.3 Item: Title: Whole Mitochondrial mtDNA Sequencing Destination: subsection.2.4 Item: Title: Whole Exome Sequence Destination: subsection.2.5 Item: Title: Expression of YARS2 mRNA by Real Time PCR (qPCR) Destination: subsection.2.6 Item: Title: Mitochondrial Translation Destination: subsection.2.7 Item: Title: SDS Page and Signal Quantification Destination: subsection.2.8 Item: Title: Functional Mitochondrial Characterization Destination: subsection.2.9 Item: Title: Mitochondrial Oxygen Consumption Destination: subsection.2.10 Item: Title: Cell Growth Destination: subsection.2.11 Item: Title: Mitochondrial DNA Deletion Study Destination: subsection.2.12 Item: Title: Statistical Analysis Destination: subsection.2.13 Item: Title: Results Destination: section.3 Children: Item: Title: Clinical Data of Case Reports Destination: subsection.3.1 Item: Title: Genetic and Molecular Findings Revealed Two Potentially Pathogenic Variants in YARS2 Gene Destination: subsection.3.2 Item: Title: YARS2 mRNA Expression in Fibroblasts from Patient P1 Were Consistent with Our Genetic Findings Destination: subsection.3.3 Item: Title: Decreased Mitochondrial Translation in Patient P1 Destination: subsection.3.4 Item: Title: Functional Mitochondrial Characterization Revealed Associated Deficiencies in Mitochondrial Function in Patient P1 Destination: subsection.3.5 Item: Title: Cell Growth Was Significantly Reduced in Fibroblasts from Patient P1 Destination: subsection.3.6 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.5 Info: Title: Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency Author: Lidia Carreño-Gago, Diana Luz Juárez-Flores, Josep Maria Grau, Javier Ramón, Ester Lozano, Ferran Vila-Julià, Ramon Martí, Glòria Garrabou and Elena Garcia-Arumí Subject: 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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