ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 30 citations in OpenAlex.
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- Systematic Engineering of Loss-of-Function Alleles in the Zebrafish Mitochondrial Proteome.bioRxiv : the preprint server for biology · 2026Article
- Clinical and genetic heterogeneity of syndromic hearing loss and its non-syndromic hearing loss mimics.Molecular medicine (Cambridge, Mass.) · 2026Article
- Genetics of Mitochondrial Aminoacyl-tRNA Synthetases Associated with Sensorineural Hearing Loss.Molecular syndromology · 2025Review
- Hyperkinetic Movement Disorder inNeurology international · 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
- Optimizing gRNA selection for high-penetrance F0 CRISPR screening for interrogating disease gene function.Nucleic acids research · 2025Article
- Modeling of Charcot-Marie-Tooth disease in zebrafish.Frontiers in molecular neuroscience · 2025Review
- Aminoacyl-tRNA synthetase defects in neurological diseases.IUBMB life · 2025Review
- Vital Dye Uptake of YO-PRO-1 and DASPEI Depends Upon Mechanoelectrical Transduction Function in Zebrafish Hair Cells.Journal of the Association for Research in Otolaryngology : JARO · 2024Article
- Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.Life science alliance · 2024Article
- Homozygous variants in WDR83OS lead to a neurodevelopmental disorder with hypercholanemia.American journal of human genetics · 2024Article
- Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.Nature communications · 2024Article
- Article
- Loss of symmetric cell division of apical neural progenitors drivesmedRxiv : the preprint server for health sciences · 2024Article
- Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity.Genome medicine · 2023Article
- Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
- Recessive aminoacyl-tRNA synthetase disorders: lessons learned fromFrontiers in neuroscience · 2023Review
- Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing.Nature communications · 2022Article
- A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
Corrections and comments
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Authors and funding
53 authors at 20 institutions in 11 countries.
Funding
Abstract
purposePathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo.
methodsThrough international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish.
resultsWe identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1
conclusionOur work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets.
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