ArticleHuman molecular genetics2019
Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 30 citations in OpenAlex.
- Congenital hyperinsulinism as part of a multisystem disease caused by a compound heterozygous variant in theJCEM case reports · 2026Article
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- Tyrosine Supplementation Rescues a Growth Defect in a HumanizedInternational journal of molecular sciences · 2026Article
- Expanding the phenotype of CARS1 variants to include congenital hyperinsulinism.BMC medical genomics · 2025Article
- Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects.Journal of inherited metabolic disease · 2025Review
- [Expression of YARS1 in hepatocellular carcinoma and its prognostic effect].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2025Article
- Loss-of-Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype.Molecular genetics & genomic medicine · 2025Article
- Interstitial lung disease in the newborn.Journal of perinatology : official journal of the California Perinatal Association · 2025Review
- Case Report: A new case ofFrontiers in pediatrics · 2023Article
- Syndromic forms of congenital hyperinsulinism.Frontiers in endocrinology · 2023Review
- A missense, loss-of-functionCold Spring Harbor molecular case studies · 2022Article
- Precision mouse models of Yars/dominant intermediate Charcot-Marie-Tooth disease type C and Sptlc1/hereditary sensory and autonomic neuropathy type 1.Journal of anatomy · 2022Article
- The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype.Journal of molecular medicine (Berlin, Germany) · 2021Review
- Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation.GeroScience · 2021Article
- A Novel Homozygous Missense Mutation in theJournal of the Endocrine Society · 2021Article
- Alveolar proteinosis of genetic origins.European respiratory review : an official journal of the European Respiratory Society · 2020Article
- Recurrent acute liver failure in alanyl-tRNA synthetase-1 (AARS1) deficiency.Molecular genetics and metabolism reports · 2020Article
- De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.American journal of human genetics · 2020Article
- A Machine Learning Analysis of Prognostic Genes Associated With Allograft Tolerance After Renal Transplantation.Cell transplantationArticle
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Authors and funding
22 authors at 10 institutions in 1 country.
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Abstract
Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly conserved interface required for protein homodimerization, an essential step in YARS catalytic function. Affected children expressed a more severe phenotype than previously reported, including poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Related adults heterozygous for YARS p.Pro167Thr showed no evidence of peripheral neuropathy on electromyography, in contrast to previous reports for other YARS variants. Analysis of YARS p.Pro167Thr in yeast complementation assays revealed a loss-of-function, hypomorphic allele that significantly impaired growth. Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. This work adds to a rapidly growing body of research emphasizing the importance of ARSs in multisystem disease and significantly expands the allelic and clinical heterogeneity of YARS-associated human disease. A deeper understanding of the role of YARS in human disease may inspire innovative therapies and improve care of affected patients.
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