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YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, essential for aminoacylation of mitochondrial tRNATyr and proper assembly of respiratory chain complexes I, III, and IV. Biallelic pathogenic variants in YARS2 cause Myopathy, Lactic Acidosis, and Sideroblastic Anemia (MLASA), characterized by exercise intolerance, elevated lactate, and ring sideroblasts. MLASA has an autosomal recessive inheritance pattern with onset typically in infancy or early childhood. Diagnosis relies on genetic testing combined with biochemical assays demonstrating combined respiratory chain deficiency. Functional studies show impaired mitochondrial protein synthesis due to defective aminoacylation and downstream OXPHOS dysfunction.
The initial gene–disease link was established through homozygosity mapping in a consanguineous family, identifying a homozygous c.156C>G (p.Phe52Leu) variant in YARS2 in two unrelated probands (PMID:20598274). Segregation analysis confirmed recessive inheritance across affected siblings. Muscle biopsy showed reduced YARS2 protein levels and deficient complex I, III, and IV activities, while fibroblasts were spared. A mitochondrial protein-synthesis assay in patient myotubes revealed decreased respiratory chain subunit levels, and tRNA aminoacylation kinetics were abnormal in the mutant enzyme.
Subsequent reports expanded the allelic spectrum: a novel c.137G>A (p.Gly46Asp) missense mutation was reported in one MLASA patient (PMID:22504945); a cohort screen identified pathogenic YARS2 variants in 3 of 12 patients with MLASA features (PMID:24344687); and an observational series described 17 individuals with YARS2-related mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (PMID:28395030). Inter- and intra-familial variability has been noted, including a Scottish founder p.Leu392Ser allele.
A broad allelic series has been documented, including recurrent missense mutations (e.g., c.156C>G (p.Phe52Leu), c.572G>T (p.Gly191Val)) and multiple truncating or frameshift alleles. All pathogenic variants are inherited in an autosomal recessive manner. Carrier frequency of the common p.Gly191Val variant reaches ~12.6% in some populations, often in trans with a severe loss-of-function allele, and can manifest as isolated sideroblastic anemia or the full MLASA syndrome (PMID:30026338).
Functional evidence is robust: mitochondrial aminoacylation assays consistently show reduced catalytic efficiency of mutant YARS2; retroviral complementation restores translation defects; biochemical studies in patient fibroblasts and myotubes demonstrate tissue-specific OXPHOS deficiencies; and a zebrafish yars2 knockout model recapitulates retinal and muscle pathology with rescue upon cDNA expression (PMID:33610547). These data firmly establish loss of YARS2 function as the disease mechanism.
Collectively, genetic and experimental data over >10 years provide a definitive association between YARS2 and MLASA. YARS2 sequencing is recommended for patients presenting with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia, even in the absence of anemia, to inform diagnosis, prognosis, and genetic counseling. Key take-home: Biallelic YARS2 variants cause a clinically recognizable, autosomal recessive MLASA syndrome amenable to molecular diagnosis and family planning.
Gene–Disease AssociationDefinitiveOver 30 unrelated MLASA patients reported across multiple families over >10 years with consistent segregation and functional validation Genetic EvidenceStrongBiallelic YARS2 variants including missense and loss-of-function alleles identified in >30 probands with autosomal recessive MLASA, with segregation in multiple families Functional EvidenceStrongConcordant evidence from enzymatic assays, rescue experiments, patient cell OXPHOS studies, and zebrafish KO model demonstrating impaired mitochondrial protein synthesis |