Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, YARS2, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome

Abstract

Mitochondrial respiratory chain disorders are a heterogeneous group of disorders in which the underlying genetic defect is often unknown. We have identified a pathogenic mutation (c.156C>G [p.F52L]) in YARS2, located at chromosome 12p11.21, by using genome-wide SNP-based homozygosity analysis of a family with affected members displaying myopathy, lactic acidosis, and sideroblastic anemia (MLASA). We subsequently identified the same mutation in another unrelated MLASA patient. The YARS2 gene product, mitochondrial tyrosyl-tRNA synthetase (YARS2), was present at lower levels in skeletal muscle whereas fibroblasts were relatively normal. Complex I, III, and IV were dysfunctional as indicated by enzyme analysis, immunoblotting, and immunohistochemistry. A mitochondrial protein-synthesis assay showed reduced levels of respiratory chain subunits in myotubes generated from patient cell lines. A tRNA aminoacylation assay revealed that mutant YARS2 was still active; however, enzyme kinetics were abnormal compared to the wild-type protein. We propose that the reduced aminoacylation activity of mutant YARS2 enzyme leads to decreased mitochondrial protein synthesis, resulting in mitochondrial respiratory chain dysfunction. MLASA has previously been associated with PUS1 mutations; hence, the YARS2 mutation reported here is an alternative cause of MLASA.

RMND1 deficiency associated with neonatal lactic acidosis, infantile onset renal failure, deafness, and multiorgan involvement

“…As the first report of mutations in a mitochondrial translation elongation factor, 1 investigation of patients with defects in mitochondrial protein synthesis have identified mutations in many known translation factors, 2 and some accessory proteins that were not known to be a part of the core translation machinery. [3][4][5] In some instances, mutations in specific genes have been linked to particular clinical phenotypes, [6][7][8] but the molecular basis for these patterns remains an enduring mystery, and there is generally a great deal of unexplained clinical heterogeneity in patients with defects in mitochondrial protein synthesis.…”

Unusual clinical expression and long survival of a pseudouridylate synthase (PUS1) mutation into adulthood

“…2 Recently, nuclear-encoded disorders of mitochondrial translation have emerged as a novel cause of syndromic sideroblastic anemia with myopathy and lactic acidosis. Indeed, two disease genes affecting mitochondrial translation have been shown to cause syndromic sideroblastic anemia, namely the mitochondrial tyrosyl-tRNA synthetase 2 gene (YARS2) 3 and the pseudouridylate synthase gene (PUS1). 4 On the other hand, the myopathy, lactic acidosis and sideroblastic anemia syndrome (MLASA) is a rare condition that combines early-onset myopathy with lactic acidosis and sideroblastic anemia.…”

Radioactive Labeling of Mitochondrial Translation Products in Cultured Cells

“…Changes in the normal pattern of mitochondrial protein synthesis, as revealed through radioactive labeling, have served to identify and confi rm causal mutations, and to analyze the pathogenic mechanism of mitochondrial diseases caused by mutations in components of the mitochondrial translation system that are encoded by either the mitochondrial ( 5-10 ) or the nuclear genome (11)(12)(13)(14)(15)(16)(17)(18)(19)(20) …”