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Biallelic pathogenic variants in the mitochondrial tyrosyl-tRNA synthetase gene YARS2 cause an autosomal recessive mitochondrial disorder characterized by myopathy, lactic acidosis, and sideroblastic anemia 2 (myopathy, lactic acidosis, and sideroblastic anemia 2). Initially described in two unrelated MLASA families with a recurrent p.Phe52Leu variant disrupting aminoacylation and respiratory chain function (PMID:20598274), the disease association has been replicated across multiple cohorts and functional models.
Genetic evidence includes a consanguineous Turkish family with two affected siblings harboring a novel homozygous c.1303A>G (p.Ser435Gly) variant in the ribosomal S4-like domain of YARS2 (PMID:24430573). A separate adult case featured compound heterozygosity for a known nonsense allele c.98C>A (p.Ser33Ter) and a novel missense c.948G>T (p.Arg316Ser), manifesting decompensation during pregnancy (PMID:35393742). A case series identified 17 patients from 11 families with 14 distinct YARS2 variants (8 missense, 6 loss-of-function), including a Scottish founder c.1174T>C (p.Leu392Ser) allele (PMID:28395030).
Phenotypic variability ranges from classical MLASA to isolated sideroblastic anemia and mild or asymptomatic presentations. The common p.Gly191Val variant (allele frequency 0.1259) acts as a hypomorphic allele in trans with loss-of-function variants, resulting in milder or isolated sideroblastic anemia phenotypes (PMID:30026338). Symptom onset typically occurs in infancy or childhood but may be delayed; common features include myopathy (HP:0003198), elevated lactate (HP:0003128), anemia (HP:0001903), and episodes of recurrent hypoglycemia (HP:0001988).
Functional studies demonstrate that missense variants such as p.Gly191Asp in the catalytic domain result in a 38-fold loss of aminoacylation efficiency and truncated alleles like p.Arg360Ter produce unstable protein (PMID:24344687). YARS2 knockout HeLa cells and zebrafish models exhibit impaired tRNATyr aminoacylation, destabilization of OXPHOS complexes I and IV, and retinal defects that phenocopy optic neuropathy observed in some patients (PMID:33610547). Rescue of mitochondrial translation and complex assembly by YARS2 cDNA confirms causality.
Mechanistically, pathogenic YARS2 alleles cause loss of mitochondrial tyrosyl-tRNA charging, leading to deficient mitochondrial translation of tyrosine-rich proteins and combined respiratory chain dysfunction. Both loss-of-function and hypomorphic variants contribute to disease severity based on residual enzyme activity.
Collectively, over 17 probands from >11 unrelated families with segregation data, complemented by robust in vitro and in vivo functional assays, establish a Definitive gene–disease association. Genetic testing for YARS2 variants informs diagnosis, guides anticipatory management of cardiomyopathy and anemia, and enables reproductive counseling.
Gene–Disease AssociationDefinitive17 probands from 11 unrelated families, replicated segregation and robust functional concordance Genetic EvidenceStrong14 distinct pathogenic YARS2 variants in AR inheritance across multiple case reports and series Functional EvidenceStrongIn vitro aminoacylation assays, knockout/rescue in cellular and zebrafish models recapitulate MLASA phenotype |