Alternative titles; symbols
HGNC Approved Gene Symbol: KARS1
Cytogenetic location: 16q23.1 Genomic coordinates (GRCh38) : 16:75,627,724-75,647,665 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q23.1 | ?Charcot-Marie-Tooth disease, recessive intermediate, B | 613641 | Autosomal recessive | 3 |
| Deafness, autosomal recessive 89 | 613916 | Autosomal recessive | 3 | |
| Deafness, congenital, and adult-onset progressive leukoencephalopathy | 619196 | Autosomal recessive | 3 | |
| Leukoencephalopathy, progressive, infantile-onset, with or without deafness | 619147 | Autosomal recessive | 3 |
The KARS gene encodes lysyl-tRNA synthetase, which catalyzes the aminoacylation of tRNA-lys in both the cytoplasm and mitochondria. Protein synthesis is initiated by the attachment of amino acids to cognate tRNAs by aminoacyl-tRNA synthetases (ARSs). At least 6 of 20 human ARSs, including KARS, had been identified as targets of autoantibodies in the autoimmune disease polymyositis/dermatomyositis (Targoff et al. (1993)).
Tolkunova et al. (2000) identified 2 full-length sequences for KARS and determined that they represent cytoplasmic and mitochondrial isoforms. The 625-amino acid mitochondrial enzyme and the 597-amino acid cytoplasmic enzyme are identical over the last 576 amino acids, but the mitochondrial enzyme has a different 49-amino acid N terminus containing a mitochondrial targeting sequence. Transfection of both fluorescence-tagged isoforms into an osteosarcoma cell line showed that the cytoplasmic isoform produced a diffuse, cellwide fluorescence, while the mitochondrial isoform resulted in a punctate pattern that colocalized with mitochondrial markers. Ribonuclease protection analysis indicated that the mRNA encoding the cytoplasmic isoform makes up approximately 70%, and the mitochondrial isoform approximately 30%, of mature KARS transcripts.
Using massively parallel sequencing and RT-PCR experiments, Santos-Cortez et al. (2013) demonstrated that KARS is expressed in hair cells of zebrafish, chickens, and mice, as well as in maculae of zebrafish and mice. Immunolabeling experiments using mouse vestibular tissue revealed broad distribution of KARS in hair cells and supporting cells, and organ of Corti sections showed KARS localization to inner and outer hair cells, Dieter cells, and basilar membrane. In addition, the tectorial membrane showed a strong affinity for KARS antibody, and KARS labeling was strongest within the spiral ligament, particularly in the area containing type II and type IV fibrocytes. KARS was also strongly localized to the outer and inner sulcus cells and spiral limbus epithelium.
Lo et al. (2014) reported the discovery of a large number of natural catalytic nulls for each human aminoacyl tRNA synthetase. Splicing events retain noncatalytic domains while ablating the catalytic domain to create catalytic nulls with diverse functions. Each synthetase is converted into several new signaling proteins with biologic activities 'orthogonal' to that of the catalytic parent. The recombinant aminoacyl tRNA synthetase variants had specific biologic activities across a spectrum of cell-based assays: about 46% across all species affect transcriptional regulation, 22% cell differentiation, 10% immunomodulation, 10% cytoprotection, and 4% each for proliferation, adipogenesis/cholesterol transport, and inflammatory response. Lo et al. (2014) identified in-frame splice variants of cytoplasmic aminoacyl tRNA synthetases. They identified 3 catalytic-null splice variants for cytoplasmic LysRS.
The KARS1 gene encodes both the cytosolic and mitochondrial isoforms of KARS1, which are generated by alternative splicing. The cytoplasmic isoform skips exon 2 and splices exon 1 to exon 3, whereas the mitochondrial isoform includes exon 2. The ATG initiation codons are different between the 2 isoforms. The mitochondrial isoform has 28 more residues than the cytosolic isoform. The cytoplasmic isoform represents about 70% and the mitochondrial isoform about 30% of the mature transcript from the KARS1 gene (summary by Scheidecker et al., 2019).
Tolkunova et al. (2000) determined that the KARS gene contains 15 exons and spans about 20 kb. The cytoplasmic and mitochondrial KARS isoforms result from alternative splicing of the first 3 exons. Tolkunova et al. (2000) found that the initiation codons for KARS and RAP1 (605061) are separated by 243 bp. This region lacks a conventional TATA sequence but contains several SP1 (189906)-binding domains oriented in both directions.
Nichols et al. (1996) used Southern hybridization of human/rodent somatic cell hybrids to localize the KARS gene to chromosome 16. By fluorescence in situ hybridization analysis, they assigned the gene to 16q23-q24. By radiation hybrid panel analysis, Maas et al. (2001) mapped KARS and the gene for tRNA-specific adenosine deaminase (ADAT1; 604230) to 16q22.2-q22.3, with alanyl-tRNA synthetase (AARS; 601065) positioned centromeric to these 2 genes.
Tolkunova et al. (2000) found that both full-length mitochondrial and cytoplasmic KARS, purified after expression in E. coli, aminoacylated in vitro transcripts corresponding to both the cytoplasmic and mitochondrial tRNA-lys.
Park et al. (2005) stated that, in addition to their essential role in protein synthesis, ARSs function as regulators and signaling molecules. KARS can synthesize diadenosine polyphosphates, and this activity plays a role in transcriptional control through MITF (156845). Park et al. (2005) found that KARS was secreted from multiple human cell lines in response to TNF-alpha (TNF; 191160). Secreted KARS bound macrophages and peripheral blood mononuclear cells and enhanced TNF-alpha production and cell migration. The signaling pathways triggered by KARS involved ERK (see MAPK3; 601795), p38 MAPK (MAPK14; 600289), and an inhibitory G protein (see GNAI1, 139310).
Charcot-Marie-Tooth Disease, Recessive Intermediate B
McLaughlin et al. (2010) noted that mutations in 3 genes encoding aminoacyl-tRNA synthetases, GARS (600287), YARS (603623), and AARS (601065), had been implicated in Charcot-Marie-Tooth (CMT) disease primarily associated with an axonal pathology (CMT2D, 601472; CMTDIC, 608323; and CMT2N, 613287, respectively). They performed a large-scale mutation screen of 37 human ARS genes in a cohort of 355 patients with a phenotype consistent with CMT. One patient was found to be compound heterozygous for 2 mutations in the KARS gene (601421.0001 and 601421.0002). The phenotype was consistent with a recessive intermediate form of CMT (CMTRIB; 613641), but the patient had additional features, including developmental delay, dysmorphic features, and vestibular Schwannoma. Because the patient was adopted, parental studies were not possible. Thus, KARS was the fourth ARS gene associated with CMT disease, indicating that this family of enzymes is specifically critical for axon function.
Autosomal Recessive Deafness 89
In affected individuals from 3 consanguineous Pakistani families with nonsyndromic deafness mapping to chromosome 16q21-q23.2, (DFNB89; 613916), Santos-Cortez et al. (2013) identified homozygosity for 2 missense mutations in the KARS gene, Y173H (601421.0003) and D377N (601421.0004), that segregated with disease in the respective families and were not found in ethnically matched controls or in variant databases. Additional testing for evaluation of CMT disease and acoustic neuroma in 3 affected members from 2 of the DFNB89 families showed no evidence of auditory or limb neuropathy.
Infantile-Onset Progressive Leukoencephalopathy with or without Deafness
In 2 sibs, born of unrelated parents, with infantile-onset progressive leukoencephalopathy without deafness (LEPID; 619147), McMillan et al. (2015) identified compound heterozygous missense in the KARS1 gene (R438W, 601421.0005 and E525K, 601421.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but both mutations occurred in a highly conserved region of the catalytic domain.
In a male infant (patient 459) with deficiencies of mitochondrial complexes I and IV, Kohda et al. (2016) identified compound heterozygous missense mutations in the KARS1 gene: a c.1343T-A transversion (NM_005548), resulting in a val448-to-asp (V448D) substitution, and a c.953T-C transition, resulting in an ile318-to-thr (I318T) substitution. The mutations, which were found by high-throughput exome sequencing of 142 unrelated patients with childhood-onset mitochondrial respiratory chain complex deficiencies, segregated with the disorder in the family. A cDNA complementation assay revealed that mitochondrial KARS, but not the cytosolic form, successfully rescued the enzyme defects and assembly of complexes I and IV. Clinical details of the patient were limited, but he was noted to have developmental delay, seizures, nystagmus, lactic acidosis, and hypertrophic cardiomyopathy, suggestive of LEPID.
In 3 unrelated patients with LEPID, Ardissone et al. (2018) identified homozygous or compound heterozygous missense mutations in the KARS1 gene (see, e.g., 601421.0007). The mutations, which were found by whole-exome or next-generation sequencing of a panel, were confirmed by Sanger sequencing and demonstrated to segregate with the disorder in at least 1 family. Functional studies of the variants and studies of patient cells were not performed.
In a French girl with LEPID, Ruzzenente et al. (2018) identified compound heterozygous mutations in the KARS1 gene (P228L, 601421.0009 and c.1438delC, 601421.0010). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Detailed in vitro functional expression studies of patient fibroblasts showed that cytoplasmic translation was intact, but mitochondrial translation was specifically decreased. There were assembly defects of multiple OXPHOS complexes, which could be rescued by expression of mitochondrial KARS1, but not cytoplasmic KARS1. Ruzzenente et al. (2018) concluded that inhibition of mitochondrial translation underlies the disease mechanism.
In 7 children from 5 unrelated Japanese families with LEPID, Itoh et al. (2019) identified homozygous or compound heterozygous mutations in the KARS1 gene (see, e.g., 601421.0012 and 601421.0013). The mutations were found by exome sequencing and confirmed by Sanger sequencing; segregation was consistent with autosomal recessive inheritance in the 2 families from whom parental DNA was available. KARS1 expression levels were decreased in patient tissue, including liver and brain, and enzymatic activity of both the mitochondrial and cytosolic isoforms was decreased compared to controls. Kars-depleted Xenopus embryos showed developmental defects of the head and eyes, which could be rescued with wildtype KARS, but not by the mutant KARS variants found in the patients.
Congenital Deafness and Adult-Onset Progressive Leukoencephalopathy
In 2 adult sibs, born of unrelated Chinese Han parents, with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196), Zhou et al. (2017) identified compound heterozygous missense mutations in the KARS1 gene (R477H, 601421.0007 and P505S, 601421.0008). These mutations correspond to R505H and P533S, respectively, in the mitochondrial isoform (see Scheidecker et al., 2019). The mutations, which were found by next-generation sequencing of candidate genes and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations affected highly conserved residues in the catalytic domain. In vitro functional expression studies showed that the R477H mutation impaired KARS incorporation into the multiple-synthetase complex (MSC). In addition, both mutations caused abnormal protein aggregation and resulted in decreased KARS aminoacylation activity (5.7% that of wildtype for the combined mutations).
In a 36-year-old man (patient 5) with DEAPLE, van der Knaap et al. (2019) identified compound heterozygous missense mutations in the KARS gene (R108H and V476F). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient-derived fibroblasts showed about a 50% decrease in cytosolic KARS aminoacylation activity compared to controls.
In a French woman with DEAPLE, Scheidecker et al. (2019) identified compound heterozygous missense mutations in the KARS1 gene (P228L, 601421.0009 and F291V, 601421.0011). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The P228L and F291V mutations correspond to P200L and F263V in the cytoplasmic isoform. Analysis of patient cells showed increased levels of mitochondrial KARS compared to cytoplasmic KARS, the latter of which showed decreased stability. In vitro immunoprecipitation studies in a yeast 2-hybrid assay showed that the cytoplasmic P200L and F263V mutants had reduced binding to p38 (AIMP2; 600859). The authors suggested that these mutations may be pathogenic by impairing the association of cytoplasmic KARS with the MSC complex, thus adversely affecting cytoplasmic protein synthesis. These variants also had decreased aminoacylation activity compared to wildtype KARS. Patient skeletal muscle showed decreased activities of mitochondrial complexes I and IV, and there was an overexpression of KARS in the mitochondria, suggesting mitochondrial dysfunction. Scheidecker et al. (2019) hypothesized that the mitochondrial dysfunction was secondary to defects in cytoplasmic KARS protein synthesis.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human KARS is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a patient with an intermediate form of autosomal recessive Charcot-Marie-Tooth disease (CMTRIB; 613641), McLaughlin et al. (2010) identified compound heterozygosity for 2 mutations in the KARS gene: a 398T-A transversion resulting in a leu133-to-his (L133H) substitution in a highly conserved residue, and a 2-bp insertion (524insTT; 601421.0002) predicted to result in a frameshift, premature termination, and a null allele, as confirmed in yeast complementation studies. The L133H substitution occurred in an N-terminal anticodon-binding domain adjacent to the dimer-dimer interface. In vitro functional expression assays showed that the L133H mutant had severely impaired enzyme activity, with a 94% loss of catalytic activity compared to wildtype. In addition to peripheral neuropathy, the patient also had developmental delay, self-abusive behavior, dysmorphic features, and vestibular Schwannoma, which McLaughlin et al. (2010) postulated was due to severe loss of KARS function in both the cytoplasm and mitochondria.
For discussion of the 2-bp insertion in the KARS gene (524insTT) that was found in compound heterozygous state in a patient with an intermediate form of autosomal recessive Charcot-Marie-Tooth disease (CMTRIB; 613641) by McLaughlin et al. (2010), see 601421.0001.
In affected individuals from 2 consanguineous Pakistani families with nonsyndromic deafness (DFNB89; 613916), 1 of which (family 4406) had previously been studied by Basit et al. (2011), Santos-Cortez et al. (2013) identified homozygosity for a c.517T-C transition in exon 5 of the KARS gene, resulting in a tyr173-to-his (Y173H) substitution at a highly conserved residue within the beta-2 strand. The mutation segregated with disease in both families and was not found in 325 ethnically matched controls or in variant databases.
In an affected individual from a consanguineous Pakistani family with nonsyndromic deafness (DFNB89; 613916), previously studied by Basit et al. (2011) (family 4338), Santos-Cortez et al. (2013) identified homozygosity for a c.1129G-A transition in exon 9 of the KARS gene, resulting in an asp377-to-asn (D377N) substitution at a completely conserved residue within alpha-helix 9, predicted to affect the configuration of the tetramer interface. The mutation segregated with disease in the family and was not found in 325 ethnically matched controls or in variant databases.
In 2 sibs, born of unrelated parents, with infantile-onset progressive leukoencephalopathy without deafness (LEPID; 619147), McMillan et al. (2015) identified compound heterozygous missense mutations in the KARS1 gene: a c.1312C-T transition (c.1312C-T, NM_005548.2), resulting in an arg438-to-trp (R438W) substitution, and a c.1573G-A transition, resulting in a glu525-to-lys (E525K; 601421.0006) substitution. Both mutations occurred at a highly conserved region of the catalytic domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed. The patients presented in infancy with visual impairment, progressive microcephaly, and global developmental delay with poor language acquisition. They also had seizures that could be controlled with medication. Neither was deaf. Brain imaging showed subcortical white matter abnormalities with delayed myelination and thin corpus callosum.
For discussion of the c.1573G-A transition (c.1573G-A, NM_005548.2) in the KARS1 gene, resulting in a glu525-to-lys (E525K) substitution, that was found in compound heterozygous state in 2 sibs with infantile-onset progressive leukoencephalopathy without deafness (LEPID; 619147) by McMillan et al. (2015), see 601421.0005.
Congenital Deafness and Adult-Onset Progressive Leukoencephalopathy
In 2 adult sibs, born of unrelated Chinese Han parents, with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196), Zhou et al. (2017) identified compound heterozygous missense mutations in the KARS1 gene: a c.1430G-A transition (c.1430G-A, NM_005548.2), resulting in an arg477-to-his (R477H) substitution, and a c.1513C-T transition, resulting in a pro505-to-ser (P505S; 601421.0008) substitution. These mutations correspond to R505H and P533S, respectively, in the mitochondrial isoform (see Scheidecker et al., 2019). The mutations, which were found by next-generation sequencing of candidate genes and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were not present among 1,000 Chinese Han controls. R477H was present at a low frequency (8 x 10(-6)) in the ExAC database, whereas P505S was absent from ExAC. Both mutations affected highly conserved residues in the catalytic domain. In vitro functional expression studies showed that the R477H mutation significantly altered the secondary structure of the protein and impaired the incorporation of KARS into the multiple-synthetase complex (MSC). Expression of both mutations caused abnormal protein aggregation, and both mutations decreased aminoacylation activity (5.7% that of wildtype for the combined mutations). The patients, who were 26 and 21 years of age, had infantile-onset deafness and learning difficulties in childhood, but then presented with progressive cognitive decline later in the second or third decades. Brain imaging showed white matter abnormalities affecting the frontal white matter and corpus callosum. They did not have visual impairment, microcephaly, or seizures; motor abnormalities were not noted.
Infantile-Onset Progressive Leukoencephalopathy with Deafness
In an Italian boy (patient A) with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147) originally reported by Orcesi et al. (2011), Ardissone et al. (2018) identified a homozygous c.1514G-A transition (NM_001130089.1) in the KARS1 gene, resulting in an arg505-to-his (R505H) substitution. These authors stated that this was the same mutation identified by Zhou et al. (2017). The mutation, which was found by whole-exome sequencing, affected a conserved residue. Functional studies of the variant and studies of patient cells were not performed.
In a Colombian boy with LEPID, Vargas et al. (2020) identified compound heterozygous missense mutations in the KARS1 gene: R477H and A526V (A498V). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Both were present at very low frequencies in public databases. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the c.1513C-T transition (c.1513C-T, NM_005548.2) in the KARS1 gene, resulting in a pro505-to-ser (P505S) substitution, that was found in compound heterozygous state in 2 adult sibs with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196) by Zhou et al. (2017), see 601421.0007.
Infantile-Onset Progressive Leukoencephalopathy with Deafness
In a French girl with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147), Ruzzenente et al. (2018) identified compound heterozygous mutations in the KARS1 gene: a c.683C-T transition (c.683C-T, NM_001130089.1), resulting in a pro228-to-leu (P228L) substitution at a highly conserved residue in the anticodon-binding domain, and a 1-bp deletion (c.1438delC; 601421.0010), resulting in a frameshift and premature termination (Leu480TrpfsTer3). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. P228L has a low frequency (0.014%) in the ExAC database. Analysis of patient cells showed only the P228L mutation, suggesting that the frameshift was subject to nonsense-mediated mRNA decay. Detailed in vitro functional expression studies of patient fibroblasts showed that cytoplasmic translation was intact, but that mitochondrial translation was specifically decreased. There were assembly defects of multiple OXPHOS complexes, which could be rescued by expression of mitochondrial KARS1, but not cytoplasmic KARS1. Ruzzenente et al. (2018) concluded that inhibition of mitochondrial translation underlies the disease mechanism.
Congenital Deafness and Adult-Onset Progressive Leukoencephalopathy
In a French woman with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196), Scheidecker et al. (2019) identified compound heterozygous missense mutations in the KARS1 gene: a c.683C-T transition (c.683C-T, NM_001130089.1), resulting in a pro228-to-leu (P228L) substitution at a moderately conserved residue, and a c.871T-G transversion, resulting in a phe291-to-val (F291V; 601421.0011) substitution at a conserved residue in the catalytic domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The F291V mutation was not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. The P228L and F291V mutations correspond to P200L and F263V in the cytoplasmic isoform. Analysis of patient cells showed increased levels of mitochondrial KARS compared to cytoplasmic KARS, the latter of which showed decreased stability. In vitro immunoprecipitation studies in a yeast 2-hybrid assay showed that the cytoplasmic P200L and F263V mutants had reduced binding to p38 (AIMP2; 600859). The authors suggested that these mutations may be pathogenic by impairing the association of cytoplasmic KARS with the MSC complex, thus adversely affecting cytoplasmic protein synthesis. These variants also had decreased aminoacylation activity compared to wildtype KARS. Patient skeletal muscle showed decreased activities of mitochondrial complexes I and IV, and there was an overexpression of KARS in the mitochondria, suggesting mitochondrial dysfunction. Scheidecker et al. (2019) hypothesized that the mitochondrial dysfunction was secondary to defects in cytoplasmic KARS protein synthesis.
For discussion of the c.1438delC mutation (c.1438delC, NM_001130089.1) in the KARS1 gene, resulting in a frameshift and premature termination (Leu480TrpfsTer3), that was found in compound heterozygous state in a patient with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147) by Ruzzenente et al. (2018), see 601421.0009.
For discussion of the c.871T-G transversion (c.871T-G, NM_001130089.1) in the KARS1 gene, resulting in a phe291-to-val (F291V) substitution, that was found in compound heterozygous state in a patient with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196) by Scheidecker et al. (2019), see 601421.0009.
In 4 patients from 3 unrelated Japanese families (families 1-3) with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147), Itoh et al. (2019) identified a homozygous c.1786C-T transition (c.1786C-T, NM_001130089.1) in the KARS1 gene, resulting in a leu596-to-phe (L596F) substitution in mitochondrial isoform 1 (leu568-to-phe (L568F) in cytosolic isoform 2). Three additional patients from 2 unrelated Japanese families (families 4 and 5) were compound heterozygous for L596F and another mutation in the KARS1 gene (c.879+1G-A, 601421.0013 and G189D). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families from whom parental DNA was available. The c.879+1G-A mutation resulted in a splicing defect and an in-frame deletion of exon 7 (Glu252_Glu293del). None of the mutations were present in the dbSNP, 1000 Genomes Project, or Japanese control databases. Liver and brain tissue derived from some of the deceased patients showed decreased KARS1 expression levels and decreased aminoacylation activity of both the mitochondrial and cytosolic forms compared to controls. Kars-depleted Xenopus embryos showed developmental defects of the head and eyes, which could be rescued with wildtype KARS, but not by mutant KARS variants found in the patients. Three of the patients, including 2 sibs and an unrelated boy, had previously been reported by Yoshimura et al. (1997) and Kuki et al. (2011).
For discussion of the G-to-A transition (c.879+1G-A, NM_001130089.1) in the KARS1 gene, resulting in a splicing defect and in-frame deletion (Glu252_Glu293del), that was found in compound heterozygous state in 2 sibs with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147) by Itoh et al. (2019), see 601421.0013.
Ardissone, A., Tonduti, D., Legati, A., Lamantea, E., Barone, R., Dorboz, I., Boespflug-Tanguy, O., Nebbia, G., Maggioni, M., Garavaglia, B., Moroni, I., Farina, L., Pichiecchio, A., Orcesi, S., Chiapparini, L., Ghezzi, D. KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature. Orphanet J. Rare Dis. 13: 45, 2018. Note: Electronic Article. [PubMed: 29615062] [Full Text: https://doi.org/10.1186/s13023-018-0788-4]
Basit, S., Lee, K., Habib, R., Chen, L., Kalsoom, U., Santos-Cortez, R. L. P., Azeem, Z., Andrade, P., Ansar, M., Ahmad, W., Leal, S. M. DFNB89, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 16q21-q23.2. Hum. Genet. 129: 379-285, 2011. [PubMed: 21181198] [Full Text: https://doi.org/10.1007/s00439-010-0934-0]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Itoh, M., Dai, H., Horike, S., Gonzalez, J., Kitami, Y., Meguro-Horike, M., Kuki, I., Shimakawa, S., Yoshinaga, H., Ota, Y., Okazaki, T., Maegaki, Y., Nabatame, S., Okazaki, S., Kawawaki, H., Ueno, N., Goto, Y., Kato, Y. Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy. Brain 142: 560-573, 2019. [PubMed: 30715177] [Full Text: https://doi.org/10.1093/brain/awz001]
Kohda, M., Tokuzawa, Y., Kishita, Y., Nyuzuki, H., Moriyama, Y., Mizuno, Y., Hirata, T., Yatsuka, Y., Yamashita-Sugahara, Y., Nakachi, Y., Kato, H., Okuda, A., and 23 others. A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies. PLoS Genet. 12: e1005679, 2016. Note: Electronic Article. [PubMed: 26741492] [Full Text: https://doi.org/10.1371/journal.pgen.1005679]
Kuki, I., Kawawaki, H., Okazaki, S., Kimura-Ohba, S., Nakano, T., Fukushima, H., Inoue, T., Tomiwa, K., Itoh, M. Progressive leukoencephalopathy with intracranial calcification, congenital deafness, and developmental deterioration. Am. J. Med. Genet. 155A: 2832-2837, 2011. [PubMed: 21964701] [Full Text: https://doi.org/10.1002/ajmg.a.34256]
Lo, W.-S., Gardiner, E., Xu, Z., Lau, C.-F., Wang, F., Zhou, J. J., Mendlein, J. D., Nangle, L. A., Chiang, K. P., Yang, X.-L., Au, K.-F., Wong, W. H., Guo, M., Zhang, M., Schimmel, P. Human tRNA synthetase catalytic nulls with diverse functions. Science 345: 328-332, 2014. [PubMed: 25035493] [Full Text: https://doi.org/10.1126/science.1252943]
Maas, S., Kim, Y.-G., Rich, A. Genomic clustering of tRNA-specific adenosine deaminase ADAT1 and two tRNA synthetases. Mammalian Genome 12: 387-393, 2001. [PubMed: 11331948] [Full Text: https://doi.org/10.1007/s003350020008]
McLaughlin, H. M., Sakaguchi, R., Liu, C., Igarashi, T., Pehlivan, D., Chu, K., Iyer, R., Cruz, P., Cherukuri, P. F., Hansen, N. F., Mullikin, J.C., NISC Comparative Sequencing Program, and 13 others. Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy. Am. J. Hum. Genet. 87: 560-566, 2010. [PubMed: 20920668] [Full Text: https://doi.org/10.1016/j.ajhg.2010.09.008]
McMillan, H. J., Humphreys, P., Smith, A., Schwartzentruber, J., Chakraborty, P., Bulman, D. E., Beaulieu, C. L., FORGE Canada Consortium, Majewski, J., Boycott, K. M., Geraghty, M. T. 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. J. Child Neurol. 30: 1037-1043, 2015. [PubMed: 25330800] [Full Text: https://doi.org/10.1177/0883073814553272]
Nichols, R. C., Blinder, J., Pai, S. I., Ge, Q., Targoff, I. N., Plotz, P. H., Liu, P. Assignment of two human autoantigen genes: isoleucyl-tRNA synthetase locates to 9q21 and lysyl-tRNA synthetase locates to 16q23-q24. Genomics 36: 210-213, 1996. [PubMed: 8812440] [Full Text: https://doi.org/10.1006/geno.1996.0449]
Orcesi, S., La Piana, R., Uggetti, C., Tonduti, D., Pichiecchio, A., Pasin, M., Viselner, G., Comi, G. P., Del Bo, R., Ronchi, D., Bastianello, S., Balottin, U. Spinal cord calcification in an early-onset progressive leukoencephalopathy. J. Child Neurol. 26: 876-880, 2011. [PubMed: 21427441] [Full Text: https://doi.org/10.1177/0883073810390038]
Park, S. G., Kim, H. J., Min, Y. H., Choi, E.-C., Shin, Y. K., Park, B.-J., Lee, S. W., Kim, S. Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response. Proc. Nat. Acad. Sci. 102: 6356-6361, 2005. [PubMed: 15851690] [Full Text: https://doi.org/10.1073/pnas.0500226102]
Ruzzenente, B., Assouline, Z., Barcia, G., Rio, M., Boddaert, N., Munnich, A., Rotig, A., Metodiev, M. D. 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. Hum. Mutat. 39: 2047-2059, 2018. [PubMed: 30252186] [Full Text: https://doi.org/10.1002/humu.23657]
Santos-Cortez, R. L. P., Lee, K., Azeem, Z., Antonellis, P. J., Pollock, L. M., Khan, S., Irfanullah, Andrade-Elizondo, P. B., Chiu, I., Adams, M. D., Basit, S., Smith, J. D., University of Washington Center for Mendelian Genomics, Nickerson, D. A., McDermott, B. M., Jr., Ahmad, W., Leal, S. M. Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89. Am. J. Hum. Genet. 93: 132-140, 2013. [PubMed: 23768514] [Full Text: https://doi.org/10.1016/j.ajhg.2013.05.018]
Scheidecker, S., Bar, S., Stoetzel, C., Geoffroy, V., Lannes, B., Rinaldi, B., Fischer, F., Becker, H. D., Pelletier, V., Pagan, C., Acquaviva-Bourdain, C., Kremer, S., Mirande, M., Tranchant, C., Muller, J., Friant, S., Dollfus, H. Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy. Hum. Mutat. 40: 1826-1840, 2019. [PubMed: 31116475] [Full Text: https://doi.org/10.1002/humu.23799]
Targoff, I. N., Trieu, E. P., Miller, F. W. Reaction of anti-OJ autoantibodies with components of the multi-enzyme complex of aminoacyl-tRNA synthetases in addition to isoleucyl-tRNA synthetase. J. Clin. Invest. 91: 2556-2564, 1993. [PubMed: 8514867] [Full Text: https://doi.org/10.1172/JCI116493]
Tolkunova, E., Park, H., Xia, J., King, M. P., Davidson, E. The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and mitochondrial enzymes by means of an unusual alternative splicing of the primary transcript. J. Biol. Chem. 275: 35063-35069, 2000. [PubMed: 10952987] [Full Text: https://doi.org/10.1074/jbc.M006265200]
van der Knaap, M. S., Bugiani, M., Mendes, M. I., Riley, L. G., Smith, D. E. C., Rudinger-Thirion, J., Frugier, M., Breur, M., Crawford, J., van Gaalen, J., Schouten, M., Willems, M., and 10 others. Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy. Neurology 92: e1225-e1237, 2019. Note: Electronic Article. Erratum: Neurology 93: 982 only, 2019. [PubMed: 30737337] [Full Text: https://doi.org/10.1212/WNL.0000000000007098]
Vargas, A., Rojas, J., Aivasovsky, I., Vergara, S., Castellanos, M., Prieto, C., Celis, L. Progressive early-onset leukodystrophy related to biallelic variants in the KARS gene: the first case described in Latin America. Genes 11: 1437, 2020. Note: Electronic Article. [PubMed: 33260297] [Full Text: https://doi.org/10.3390/genes11121437]
Yoshimura, M., Hara, T., Maegaki, Y., Koeda, T., Okubo, K., Hamasaki, N., Sly, W. S., Takeshita, K. A novel neurological disorder with progressive CNS calcification, deafness, renal tubular acidosis, and microcytic anemia. Dev. Med. Child Neurol. 39: 198-201, 1997. [PubMed: 9112970] [Full Text: https://doi.org/10.1111/j.1469-8749.1997.tb07410.x]
Zhou, X.-L., He, L.-X., Yu, L.-J., Wang, Y., Wang, X.-J., Wang, E.-D., Yang, T. Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: potential pathogenic mechanism. Hum. Mutat. 38: 1740-1750, 2017. [PubMed: 28887846] [Full Text: https://doi.org/10.1002/humu.23335]