A Novel Homozygous YARS2 Mutation in Two Italian Siblings and a Review of Literature

Abstract

YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase that catalyzes the covalent binding of tyrosine to its cognate mt-tRNA. Mutations in YARS2 have been identified in patients with myopathy, lactic acidosis, and sideroblastic anemia type 2 (MLASA2). We report here on two siblings with a novel mutation and a review of literature. The older patient presented at 2 months with marked anemia and lactic acidemia. He required periodic blood transfusions until 14 months of age. Cognitive and motor development was normal. His younger sister was diagnosed at birth, presenting with anemia and lactic acidosis at 1 month of age requiring periodical transfusions. She is now 14 months old and doing well. For both our patients, there was no clinical evidence of muscle involvement. We found a new homozygous mutation in YARS2, located in the α-anticodon-binding (αACB) domain, involved in the interaction with the anticodon of the cognate mt-tRNA^Tyr.

Our study confirms that MLASA must be considered in patients with congenital sideroblastic anemia and underlines the importance of early diagnosis and supportive therapy in order to prevent severe complications. Clinical severity is variable among YARS2-reported patients: our review of the literature suggests a possible phenotype-genotype correlation, although this should be confirmed in a larger population.

Competing interests: None declared

Author contributed equally with all other contributors.

Appendices

Take-Home Message

MLASA must be considered in patients with congenital sideroblastic anemia: early diagnosis and supportive therapy may be important to prevent severe complications.

Compliance with Ethic Guidelines

Conflict of Interest statements

Anna Ardissone, Eleonora Lamantea, Jade Quartararo, Cristina Dallabona, Franco Carrara, Isabella Moroni, Claudia Donnini, Barbara Garavaglia, Massimo Zeviani, and Graziella Uziel declare that they have no conflict of interest.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

Animal Rights

This article does not contain any studies with animal subjects performed by the any of the authors.

Contributions of Individual Authors

AA, IM, and GU evaluated the patients and wrote the case report. FC performed biochemical and molecular analyses. EL monitored biochemical and genetic analyses. JQ and CDa performed experiments in yeast model. CDo coordinated the yeast studies. AA and EL wrote the manuscript; MZ, BG, and GU critically revised the manuscript for important intellectual content. All authors read and approved the manuscript.