Affinage

KARS1

Lysine--tRNA ligase · UniProt Q15046

Length
597 aa
Mass
68.0 kDa
Annotated
2026-06-10
27 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KARS1 encodes a dual-localized lysyl-tRNA synthetase (LysRS) that charges both cytosolic and mitochondrial tRNALys with lysine, the committed first step of protein translation, and pathogenic variants converge on loss of this aminoacylation activity as a core disease mechanism (PMID:30737337, PMID:32189241). The cytosolic isoform is incorporated into the multiple aminoacyl-tRNA synthetase complex (MSC), and disease variants act through distinct routes: some (p.R477H) release LysRS from the MSC and reduce charging without altering oligomerization or distribution (PMID:28887846), while others (p.Pro228Leu, p.Phe291Val) lower cytosolic protein levels and weaken MSC interaction (PMID:31116475). Variants can selectively cripple the mitochondrial isoform, impairing mitochondrial translation and producing combined oxidative phosphorylation deficiency, as shown by isoform-specific rescue with the mitochondrial but not cytosolic protein (PMID:30252186, PMID:32189241). In an in vivo knock-in mouse model, compound LysRS deficiency arrests oligodendrocyte differentiation, reduces mitochondrial tRNALys aminoacylation, lowers Complex IV activity and ATP, raises ROS, and impairs myelination (PMID:39087379). Beyond its canonical role, a constitutively active LysRS conformation arising from the P542R variant mislocalizes to the cytoplasm and drives MITF-dependent mast cell hyperactivation and proinflammatory mediator release (PMID:33385443). These canonical translational and non-canonical signaling functions underlie a phenotypic spectrum spanning hearing impairment, leukodystrophy, and immune defects (PMID:23768514, PMID:37770806).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2013 Medium

    Established that KARS1 is expressed in inner-ear sensory and supporting structures, providing the anatomical rationale for its link to hearing impairment.

    Evidence Immunolocalization/expression analysis in cochlear tissues of zebrafish, chicken, and mouse

    PMID:23768514

    Open questions at the time
    • Functional consequence of cochlear localization not directly demonstrated
    • Does not establish which isoform mediates the ear-specific requirement
  2. 2017 High

    Resolved that some pathogenic variants act not only by lowering catalysis but by structurally releasing LysRS from the MSC, distinguishing complex-assembly defects from purely enzymatic ones.

    Evidence Aminoacylation assays, circular dichroism, gel filtration, and immunofluorescence on p.R477H and p.P505S mutants

    PMID:28887846

    Open questions at the time
    • Did not test mitochondrial isoform consequences
    • In vivo phenotype of MSC release not assessed in this study
  3. 2018 High

    Demonstrated isoform specificity: a variant can selectively disable the mitochondrial LysRS and cause OXPHOS deficiency, settling that the two isoforms are functionally separable in disease.

    Evidence Patient fibroblast characterization with isoform-specific wild-type rescue and OXPHOS assay (p.Pro228Leu)

    PMID:30252186

    Open questions at the time
    • Tissue-specific basis of mitochondrial vulnerability not addressed
    • Did not test cytosolic translation in same cells
  4. 2019 High

    Confirmed reduced aminoacylation as the shared core mechanism across pathogenic variants, quantifying ~50% activity loss in patient cells.

    Evidence Aminoacylation assays on purified recombinant protein and patient lymphoblasts/fibroblasts

    PMID:30737337

    Open questions at the time
    • Does not connect residual activity level to phenotype severity
    • Cytosolic vs mitochondrial contribution not separated
  5. 2019 High

    Linked variant pathogenicity to both reduced cytosolic protein levels and weakened MSC interaction, and connected enzyme loss to abnormal CNS development in vivo.

    Evidence Western blot, Co-IP for MSC interaction, in vitro aminoacylation (patient cells); Xenopus loss-of-function embryo model

    PMID:30715177 PMID:31116475

    Open questions at the time
    • Non-canonical transcriptional/immune role of LysRS noted but not mechanistically dissected here
    • Causal chain from MSC loss to neurodevelopmental defect not established
  6. 2020 High

    Showed that hearing-impairment variants spare MSC incorporation but differentially impair cytosolic versus mitochondrial tRNALys charging, mapping genotype to isoform-level deficits.

    Evidence In vitro aminoacylation of cytosolic and mitochondrial tRNALys, gel filtration, and yeast complementation (p.Asp377Asn, p.Tyr173His)

    PMID:32189241

    Open questions at the time
    • Cochlear cell-type basis of deafness not resolved
    • Relationship between charging deficit magnitude and clinical severity unclear
  7. 2020 Medium

    Uncovered a non-canonical mechanism whereby a variant locks LysRS in an active conformation, driving cytoplasmic mislocalization, MITF activation, and mast cell hyperactivation.

    Evidence Biochemical assays, confocal microscopy, degranulation and PGD2 secretion assays, and molecular dynamics simulations (P542R)

    PMID:33385443

    Open questions at the time
    • Single lab; in vivo immune phenotype not validated in patients
    • Molecular link between LysRS and MITF not biochemically defined
  8. 2021 Medium

    Established that biallelic variants commonly affect both isoforms and that lysine substrate availability modulates pathogenicity, implicating substrate provision in mechanism.

    Evidence Yeast complementation for cytosolic and mitochondrial isoforms with lysine supplementation rescue

    PMID:33942428

    Open questions at the time
    • Lysine rescue only partial and not validated in human cells or in vivo
    • Single lab
  9. 2024 High

    Provided in vivo mechanistic integration: LysRS deficiency impairs mitochondrial tRNALys charging and bioenergetics in oligodendrocytes, arresting myelination, with melatonin rescuing the deficits.

    Evidence CRISPR knock-in mouse (R477H/P505S equivalent), aminoacylation, Complex IV/ATP/ROS assays, electron microscopy, immunohistochemistry, melatonin rescue

    PMID:39087379

    Open questions at the time
    • Melatonin mechanism of rescue not fully defined
    • Generalizability to other cell types and variants untested
  10. 2025 Medium

    Mapped the proteome-wide consequences of kars loss in vivo, identifying ribosome and aminoacyl-tRNA biosynthesis pathways as most affected.

    Evidence iTRAQ proteomics with PRM validation on kars knockout zebrafish larvae

    PMID:40032059

    Open questions at the time
    • Links to individual proteins are correlative
    • Causal role of identified proteins in phenotype untested
  11. 2023 Low

    Extended the mitochondrial mechanism to the immune system, linking impaired B cell mitochondrial function to hypogammaglobulinemia in KARS1 disease.

    Evidence Functional analysis of patient B cell mitochondrial number and activity

    PMID:37770806

    Open questions at the time
    • Single patient cell-based observation with limited mechanistic follow-up
    • Direct causal link to antibody deficiency not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How specific variant-driven balances of cytosolic-MSC, mitochondrial-translation, and non-canonical MITF dysfunction map onto distinct clinical phenotypes remains unresolved.
  • No unifying genotype-phenotype model across deafness, leukodystrophy, neuropathy, and immune defects
  • Molecular basis of the LysRS-MITF signaling axis not defined
  • Tissue-specific vulnerability mechanisms unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0003723 RNA binding 2 GO:0140098 catalytic activity, acting on RNA 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005739 mitochondrion 3 GO:0005829 cytosol 3
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-392499 Metabolism of proteins 2
Partners
MITFTERF2IP
Complex memberships
multiple aminoacyl-tRNA synthetase complex (MSC)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 KARS1 (lysyl-tRNA synthetase) is expressed in hair cells of zebrafish, chickens, and mice, with strong localization to the spiral ligament region of the cochlea, Deiters' cells, sulcus epithelium, basilar membrane, and spiral limbus surface, consistent with a role in inner-ear aminoacylation. Immunolocalization/expression analysis in cochlear tissues of multiple species American journal of human genetics Medium 23768514
2017 The KARS1 p.R477H mutation alters protein structure (shown by circular dichroism) and releases LysRS from the multiple-synthetase complex (MSC) without affecting dimer-tetramer oligomerization or cellular distribution; p.R477H and p.P505S mutations each reduce tRNALys aminoacylation activity, with a cumulative effect when combined. Enzymatic aminoacylation assays, circular dichroism spectroscopy, gel filtration chromatography, immunofluorescence Human mutation High 28887846
2018 The KARS1 p.Pro228Leu variant impairs mitochondrial translation in patient fibroblasts, causing multiple oxidative phosphorylation deficiency; re-introduction of wild-type mitochondrial KARS (but not the cytosolic isoform) rescued the defect, demonstrating that this variant specifically disrupts the mitochondrial isoform's function. Patient fibroblast molecular characterization, isoform-specific rescue by re-expression, oxidative phosphorylation assay Human mutation High 30252186
2019 Pathogenic KARS1 variants exhibit reduced aminoacylation (tRNA-charging) enzymatic activity in vitro (shown by aminoacylation assays on purified recombinant protein and in patient lymphoblasts/fibroblasts showing ~50% reduction in enzyme activity), establishing loss of catalytic function as a core pathogenic mechanism. Aminoacylation assays on purified recombinant mutant protein and patient-derived lymphoblasts/fibroblasts Neurology High 30737337
2019 KARS1 pathogenic variants (p.Pro228Leu and p.Phe291Val) reduce cytoplasmic KARS protein levels in patient cells and decrease interaction of the cytoplasmic isoform with the multiple aminoacyl-tRNA synthetase complex (MSC); both variants also show decreased aminoacylation activity in vitro. Western blot, Co-immunoprecipitation (interaction with MSC), in vitro aminoacylation assay Human mutation High 31116475
2019 KARS1 missense mutations reduce enzymatic (aminoacylation) activities of LysRS in Xenopus embryo models, and disrupted LysRS causes abnormal CNS development; LysRS is also noted to act as a non-canonical inducer of immune response with transcriptional activity. Enzymatic assays on mutant LysRS proteins; Xenopus embryo loss-of-function model Brain : a journal of neurology Medium 30715177
2020 KARS1 hearing-impairment mutations (c.1129G>A/p.Asp377Asn and c.517T>C/p.Tyr173His) do not affect LysRS incorporation into the multiple-synthetase complex but alter cytosolic LysRS protein level, tertiary structure, and reduce cytosolic tRNA aminoacylation in vitro; the c.517T>C mutant is completely deficient in charging mitochondrial tRNALys both in vitro and in vivo (yeast model), while c.1129G>A shows less severe mitochondrial charging defect. In vitro aminoacylation assays (cytosolic and mitochondrial tRNALys), gel filtration (MSC incorporation), yeast genetic complementation models Science China. Life sciences High 32189241
2020 A KARS1 mutation (P542R) causes constitutive cytoplasmic mislocalization of LysRS and constitutive activation of MITF (microphthalmia transcription factor), leading to mast cell hyperactivation with increased proinflammatory mediator release; structural dynamics simulations indicate the mutant mimics the active LysRS conformation. Biochemical assays, Western blot, confocal microscopy, cell transfection, cell degranulation assays, prostaglandin D2 secretion measurement, molecular dynamics simulations The Journal of allergy and clinical immunology Medium 33385443
2021 KARS1 biallelic variants affect both cytosolic and mitochondrial LysRS isoform function, demonstrated by variable growth defects in yeast complementation models; detrimental effects of two variants were partially rescued by lysine supplementation, suggesting a role for substrate availability in the pathogenic mechanism. Yeast complementation assays for cytosolic and mitochondrial isoforms; lysine supplementation rescue experiment Human mutation Medium 33942428
2024 Kars knock-in mice (p.R477H/p.P505S equivalent) display reduced myelination, oligodendrocyte differentiation arrest, increased caspase-3-mediated apoptosis in oligodendrocytes, reduced aminoacylation and steady-state levels of mitochondrial tRNALys, decreased OXPHOS complex subunit expression, reduced Complex IV activity, decreased ATP production, increased ROS, and abnormal mitochondria in white matter oligodendrocytes; melatonin treatment rescued mitochondrial and oligodendrocyte deficits and restored myelination. CRISPR-Cas9 knock-in mouse model, aminoacylation assays, Complex IV activity assay, ATP/ROS measurement, electron microscopy, immunohistochemistry, melatonin rescue experiment Journal of pineal research High 39087379
2025 Kars knockout zebrafish larvae show differential abundance of 420 proteins versus wildtype; the most enriched pathways affected include ribosome, aminoacyl-tRNA biosynthesis, and hypertrophic cardiomyopathy pathways; specific proteins nars, mybphb, atp2a1l, col6a1, and rps3a are linked to kars deficiency. iTRAQ proteomics on kars knockout zebrafish larvae; parallel reaction monitoring (PRM) validation Gene Medium 40032059
2003 The human KARS1 gene lies immediately adjacent to the RAP1 (TERF2IP) gene in a head-to-head orientation separated by only ~57 nt; both genes share a bidirectional, TATA-less promoter located in the intergenic spacer with downstream promoter elements (DPEs), a conserved arrangement also found in chicken. Genomic locus analysis, promoter activity assays (reporter constructs), EST analysis Gene Medium 14659874
2023 KARS1 mutations impair B cell metabolism, specifically reducing mitochondrial numbers and activity in patient B cells, providing a cellular mechanism for the hypogammaglobulinemia observed in KARS1-related disease. Functional analysis of patient B cells (mitochondrial number and activity measurements) Journal of clinical immunology Low 37770806

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89. American journal of human genetics 94 23768514
2014 Congenital Visual Impairment and Progressive Microcephaly Due to Lysyl-Transfer Ribonucleic Acid (RNA) Synthetase (KARS) Mutations: The Expanding Phenotype of Aminoacyl-Transfer RNA Synthetase Mutations in Human Disease. Journal of child neurology 52 25330800
2019 Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy. Neurology 44 30737337
2017 Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism. Human mutation 38 28887846
2019 Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy. Brain : a journal of neurology 28 30715177
2019 Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy. Human mutation 23 31116475
2020 Hearing impairment-associated KARS mutations lead to defects in aminoacylation of both cytoplasmic and mitochondrial tRNALys. Science China. Life sciences 22 32189241
2018 Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(Pro228Leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis. Human mutation 18 30252186
2003 The telomeric protein Rap1 is conserved in vertebrates and is expressed from a bidirectional promoter positioned between the Rap1 and KARS genes. Gene 18 14659874
2020 Mutation in KARS: A novel mechanism for severe anaphylaxis. The Journal of allergy and clinical immunology 15 33385443
2012 Management of benign ovarian cysts by a novel, gasless, single-incision laparoscopic technique: keyless abdominal rope-lifting surgery (KARS). Surgical endoscopy 15 22733196
2021 Bi-allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem disease. Human mutation 14 33942428
2001 A new bis-indole, KARs, induces selective M arrest with specific spindle aberration in neuroblastoma cell line SH-SY5Y. Molecular pharmacology 13 11723230
2010 DFNB89, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 16q21-q23.2. Human genetics 11 21181198
2023 Antibody Deficiency in Patients with Biallelic KARS1 Mutations. Journal of clinical immunology 9 37770806
2021 Ketogenic Diet for KARS-Related Mitochondrial Dysfunction and Progressive Leukodystrophy. Neuropediatrics 8 34448181
2016 Carriage rate and methicillin resistance of Staphylococcus aureus in food handlers in Kars City, Turkey. SpringerPlus 8 27247904
2021 Leopard-like retinopathy and severe early-onset portal hypertension expand the phenotype of KARS1-related syndrome: a case report. BMC medical genomics 7 33478492
2020 Progressive Early-Onset Leukodystrophy Related to Biallelic Variants in the KARS Gene: The First Case Described in Latin America. Genes 7 33260297
2024 Expansion of the phenotypic spectrum of KARS1-related disorders to include arthrogryposis multiplex congenita and summary of experiences with lysine supplementation. American journal of medical genetics. Part A 4 38980148
2024 KARS Mutations Impair Brain Myelination by Inducing Oligodendrocyte Deficiency: One Potential Mechanism and Improvement by Melatonin. Journal of pineal research 4 39087379
2017 Determining the Prevalence of Cryptosporidium Infections with Acid Fast Staining and ELISA in Calves at the Kars Province of Turkey. Turkiye parazitolojii dergisi 3 28483727
2025 Molecular characterization, identification and enzyme-producing potential of thermophilic bacterial diversity isolated from the Kars sugar factory. BMC microbiology 1 41455928
2007 Genetic diversity of local geese of varying productivity and feather color in Kars. Biochemical genetics 1 17588148
2025 Proteomic profiling of kars knockout zebrafish larvae. Gene 0 40032059
2025 Hyperkinetic Movement Disorder in KARS1-Related Disease: An Illustrative Video-Recorded Case and Narrative Literature Review. Neurology international 0 41002930
2024 Investigating the role of KARS in lung adenocarcinoma via single-cell RNA sequencing. Discover oncology 0 39625565

Missed literature

Know a paper Affinage missed for KARS1? Flag it for the maintainers and the community.

No submissions yet.