Full text data of KARS
KARS
(KIAA0070)
[Confidence: low (only semi-automatic identification from reviews)]
Lysine--tRNA ligase; 6.1.1.6 (Lysyl-tRNA synthetase; LysRS)
Lysine--tRNA ligase; 6.1.1.6 (Lysyl-tRNA synthetase; LysRS)
UniProt
Q15046
ID SYK_HUMAN Reviewed; 597 AA.
AC Q15046; A8MSK1; D3DUK4; O14946; Q96J25; Q9HB23;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-APR-2002, sequence version 3.
DT 22-JAN-2014, entry version 129.
DE RecName: Full=Lysine--tRNA ligase;
DE EC=6.1.1.6;
DE AltName: Full=Lysyl-tRNA synthetase;
DE Short=LysRS;
GN Name=KARS; Synonyms=KIAA0070;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM CYTOPLASMIC).
RC TISSUE=Brain;
RX PubMed=9278442; DOI=10.1074/jbc.272.36.22809;
RA Shiba K., Stello T., Motegi H., Noda T., Musier-Forsyth K.,
RA Schimmel P.;
RT "Human lysyl-tRNA synthetase accepts nucleotide 73 variants and
RT rescues Escherichia coli double-defective mutant.";
RL J. Biol. Chem. 272:22809-22816(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM MITOCHONDRIAL), SUBCELLULAR
RP LOCATION, AND VARIANT SER-595.
RX PubMed=10952987; DOI=10.1074/jbc.M006265200;
RA Tolkunova E., Park H., Xia J., King M.P., Davidson E.;
RT "The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and
RT mitochondrial enzymes by means of an unusual alternative splicing of
RT the primary transcript.";
RL J. Biol. Chem. 275:35063-35069(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM CYTOPLASMIC), AND
RP VARIANT SER-595.
RC TISSUE=Bone marrow;
RX PubMed=7584044; DOI=10.1093/dnares/1.5.223;
RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S.,
RA Seki N., Kawarabayasi Y., Ishikawa K., Tabata S.;
RT "Prediction of the coding sequences of unidentified human genes. II.
RT The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by
RT analysis of cDNA clones from human cell line KG-1.";
RL DNA Res. 1:223-229(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM CYTOPLASMIC).
RC TISSUE=Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 2-10; 112-127; 142-148; 231-241; 306-314 AND
RP 486-492, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND
RP MASS SPECTROMETRY (ISOFORM CYTOPLASMIC).
RC TISSUE=Hepatoma;
RA Bienvenut W.V., Boldt K., von Kriegsheim A.F., Kolch W.;
RL Submitted (JUL-2007) to UniProtKB.
RN [8]
RP FUNCTION.
RX PubMed=5338216; DOI=10.1016/0006-291X(66)90415-3;
RA Zamecnik P.C., Stephenson M.L., Janeway C.M., Randerath K.;
RT "Enzymatic synthesis of diadenosine tetraphosphate and diadenosine
RT triphosphate with a purified lysyl-tRNA synthetase.";
RL Biochem. Biophys. Res. Commun. 24:91-97(1966).
RN [9]
RP INTERACTION WITH AIMP2.
RX PubMed=9878398; DOI=10.1006/jmbi.1998.2316;
RA Quevillon S., Robinson J.-C., Berthonneau E., Siatecka M., Mirande M.;
RT "Macromolecular assemblage of aminoacyl-tRNA synthetases:
RT identification of protein-protein interactions and characterization of
RT a core protein.";
RL J. Mol. Biol. 285:183-195(1999).
RN [10]
RP BIDIRECTIONAL PROMOTER WITH TERF2IP.
RX PubMed=14659874; DOI=10.1016/j.gene.2003.08.026;
RA Tan M., Wei C., Price C.M.;
RT "The telomeric protein Rap1 is conserved in vertebrates and is
RT expressed from a bidirectional promoter positioned between the Rap1
RT and KARS genes.";
RL Gene 323:1-10(2003).
RN [11]
RP INTERACTION WITH MIFT.
RX PubMed=14975237; DOI=10.1016/S1074-7613(04)00020-2;
RA Lee Y.N., Nechushtan H., Figov N., Razin E.;
RT "The function of lysyl-tRNA synthetase and Ap4A as signaling
RT regulators of MITF activity in FcepsilonRI-activated mast cells.";
RL Immunity 20:145-151(2004).
RN [12]
RP SUBUNIT, AND INTERACTION WITH HIV-1 GAG.
RX PubMed=12756246; DOI=10.1074/jbc.M301840200;
RA Javanbakht H., Halwani R., Cen S., Saadatmand J., Musier-Forsyth K.,
RA Gottlinger H., Kleiman L.;
RT "The interaction between HIV-1 Gag and human lysyl-tRNA synthetase
RT during viral assembly.";
RL J. Biol. Chem. 278:27644-27651(2003).
RN [13]
RP SUBCELLULAR LOCATION, MUTAGENESIS OF 1-MET--GLY-65, AND INTERACTION
RP WITH AIMP2 AND HIV-1 GAG.
RX PubMed=15220430; DOI=10.1128/JVI.78.14.7553-7564.2004;
RA Halwani R., Cen S., Javanbakht H., Saadatmand J., Kim S., Shiba K.,
RA Kleiman L.;
RT "Cellular distribution of Lysyl-tRNA synthetase and its interaction
RT with Gag during human immunodeficiency virus type 1 assembly.";
RL J. Virol. 78:7553-7564(2004).
RN [14]
RP SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=15851690; DOI=10.1073/pnas.0500226102;
RA Park S.G., Kim H.J., Min Y.H., Choi E.-C., Shin Y.K., Park B.-J.,
RA Lee S.W., Kim S.;
RT "Human lysyl-tRNA synthetase is secreted to trigger proinflammatory
RT response.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:6356-6361(2005).
RN [15]
RP INTERACTION WITH EEF1A1; AIMP2 AND DARS.
RX PubMed=18029264; DOI=10.1016/j.bbrc.2007.11.028;
RA Guzzo C.M., Yang D.C.H.;
RT "Lysyl-tRNA synthetase interacts with EF1alpha, aspartyl-tRNA
RT synthetase and p38 in vitro.";
RL Biochem. Biophys. Res. Commun. 365:718-723(2008).
RN [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-88 AND LYS-141, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.31 ANGSTROMS) OF 70-581 IN COMPLEX WITH
RP SUBSTRATE AND ATP.
RX PubMed=18272479; DOI=10.1073/pnas.0712072105;
RA Guo M., Ignatov M., Musier-Forsyth K., Schimmel P., Yang X.-L.;
RT "Crystal structure of tetrameric form of human lysyl-tRNA synthetase:
RT Implications for multisynthetase complex formation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:2331-2336(2008).
RN [21]
RP VARIANTS CMTRIB HIS-105 AND MET-274, AND VARIANT SER-595.
RX PubMed=20920668; DOI=10.1016/j.ajhg.2010.09.008;
RA McLaughlin H.M., Sakaguchi R., Liu C., Igarashi T., Pehlivan D.,
RA Chu K., Iyer R., Cruz P., Cherukuri P.F., Hansen N.F., Mullikin J.C.,
RA Biesecker L.G., Wilson T.E., Ionasescu V., Nicholson G., Searby C.,
RA Talbot K., Vance J.M., Zuchner S., Szigeti K., Lupski J.R., Hou Y.M.,
RA Green E.D., Antonellis A.;
RT "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase
RT mutations in a patient with peripheral neuropathy.";
RL Am. J. Hum. Genet. 87:560-566(2010).
RN [22]
RP VARIANTS DFNB89 HIS-145 AND ASN-349.
RX PubMed=23768514; DOI=10.1016/j.ajhg.2013.05.018;
RG University of Washington Center for Mendelian Genomics;
RA Santos-Cortez R.L., Lee K., Azeem Z., Antonellis P.J., Pollock L.M.,
RA Khan S., Ullah I., Andrade-Elizondo P.B., Chiu I., Adams M.D.,
RA Basit S., Smith J.D., Nickerson D.A., McDermott B.M. Jr., Ahmad W.,
RA Leal S.M.;
RT "Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-
RT recessive nonsyndromic hearing impairment DFNB89.";
RL Am. J. Hum. Genet. 93:132-140(2013).
CC -!- FUNCTION: Catalyzes the specific attachment of an amino acid to
CC its cognate tRNA in a 2 step reaction: the amino acid (AA) is
CC first activated by ATP to form AA-AMP and then transferred to the
CC acceptor end of the tRNA. When secreted, acts as a signaling
CC molecule that induces immune response through the activation of
CC monocyte/macrophages. Catalyzes the synthesis of diadenosine
CC oligophosphate (Ap4A), a signaling molecule involved in the
CC activation of MITF transcriptional activity. Interacts with HIV-1
CC virus GAG protein, facilitating the selective packaging of
CC tRNA(3)(Lys), the primer for reverse transcription initiation.
CC -!- CATALYTIC ACTIVITY: ATP + L-lysine + tRNA(Lys) = AMP + diphosphate
CC + L-lysyl-tRNA(Lys).
CC -!- ENZYME REGULATION: Up-regulated by DARS and EEF1A1, but not by
CC AIMP2.
CC -!- SUBUNIT: Homodimer; also part of a multisubunit complex that
CC groups AIMP1, AIMP2, EEF1A1 and tRNA ligases for Arg, Asp, Glu,
CC Gln, Ile, Leu, Lys, Met and Pro. Interacts with AIMP2 (via N-
CC terminus) and MITF. Interacts directly with HIV-1 virus GAG
CC protein.
CC -!- INTERACTION:
CC Q13155:AIMP2; NbExp=3; IntAct=EBI-356367, EBI-745226;
CC -!- SUBCELLULAR LOCATION: Isoform Cytoplasmic: Cytoplasm. Nucleus.
CC Cell membrane; Peripheral membrane protein. Secreted.
CC Note=Secretion is induced by TNF-alpha.
CC -!- SUBCELLULAR LOCATION: Isoform Mitochondrial: Mitochondrion.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Cytoplasmic;
CC IsoId=Q15046-1; Sequence=Displayed;
CC Name=Mitochondrial;
CC IsoId=Q15046-2; Sequence=VSP_038481;
CC Note=Mitochondrial precursor. Contains a mitochondrial transit
CC peptide at positions 1-16. Ref.2 (AAG30114) sequence is in
CC conflict in position: 48:R->G;
CC -!- DOMAIN: The N-terminal domain (1-65) of the cytoplasmic isoform is
CC a functional tRNA-binding domain (By similarity), is required for
CC nuclear localization, is involved in the interaction with DARS,
CC but has a repulsive role in the binding to EEF1A1. A central
CC domain (208-259) is involved in homodimerization and is required
CC for interaction with HIV-1 GAG and incorporation into virions. The
CC C-terminal domain (452-597) is not required for interaction with
CC AIMP2.
CC -!- DISEASE: Charcot-Marie-Tooth disease, recessive, intermediate
CC type, B (CMTRIB) [MIM:613641]: A form of Charcot-Marie-Tooth
CC disease, a disorder of the peripheral nervous system,
CC characterized by progressive weakness and atrophy, initially of
CC the peroneal muscles and later of the distal muscles of the arms.
CC Recessive intermediate forms of Charcot-Marie-Tooth disease are
CC characterized by clinical and pathologic features intermediate
CC between demyelinating and axonal peripheral neuropathies, and
CC motor median nerve conduction velocities ranging from 25 to 45
CC m/sec. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Deafness, autosomal recessive, 89 (DFNB89) [MIM:613916]:
CC A form of non-syndromic deafness characterized by bilateral,
CC prelingual, moderate to severe hearing loss affecting all
CC frequencies. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- MISCELLANEOUS: Shares a bidirectional promoter with TERF2IP/RAP1
CC (PubMed:14659874).
CC -!- SIMILARITY: Belongs to the class-II aminoacyl-tRNA synthetase
CC family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA06688.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; D32053; BAA22084.1; -; mRNA.
DR EMBL; AF285758; AAG30114.1; -; mRNA.
DR EMBL; D31890; BAA06688.1; ALT_INIT; mRNA.
DR EMBL; AC025287; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471114; EAW95622.1; -; Genomic_DNA.
DR EMBL; CH471114; EAW95624.1; -; Genomic_DNA.
DR EMBL; BC004132; AAH04132.1; -; mRNA.
DR RefSeq; NP_001123561.1; NM_001130089.1.
DR RefSeq; NP_005539.1; NM_005548.2.
DR UniGene; Hs.3100; -.
DR PDB; 3BJU; X-ray; 2.31 A; A/B/C/D=70-581.
DR PDB; 4DPG; X-ray; 2.84 A; A/B/C/D/E/F/G/H=70-581.
DR PDBsum; 3BJU; -.
DR PDBsum; 4DPG; -.
DR ProteinModelPortal; Q15046; -.
DR SMR; Q15046; 71-576.
DR DIP; DIP-29725N; -.
DR IntAct; Q15046; 19.
DR MINT; MINT-1154971; -.
DR STRING; 9606.ENSP00000325448; -.
DR BindingDB; Q15046; -.
DR ChEMBL; CHEMBL5575; -.
DR DrugBank; DB00123; L-Lysine.
DR PhosphoSite; Q15046; -.
DR DMDM; 20178333; -.
DR PaxDb; Q15046; -.
DR PRIDE; Q15046; -.
DR DNASU; 3735; -.
DR Ensembl; ENST00000302445; ENSP00000303043; ENSG00000065427.
DR Ensembl; ENST00000319410; ENSP00000325448; ENSG00000065427.
DR GeneID; 3735; -.
DR KEGG; hsa:3735; -.
DR UCSC; uc002feq.3; human.
DR CTD; 3735; -.
DR GeneCards; GC16M075661; -.
DR HGNC; HGNC:6215; KARS.
DR HPA; HPA041345; -.
DR HPA; HPA041550; -.
DR MIM; 601421; gene.
DR MIM; 613641; phenotype.
DR MIM; 613916; phenotype.
DR neXtProt; NX_Q15046; -.
DR Orphanet; 254334; Autosomal recessive intermediate Charcot-Marie-Tooth disease type B.
DR Orphanet; 90636; Autosomal recessive nonsyndromic sensorineural deafness type DFNB.
DR PharmGKB; PA30016; -.
DR eggNOG; COG1190; -.
DR HOGENOM; HOG000236577; -.
DR HOVERGEN; HBG002562; -.
DR KO; K04567; -.
DR OMA; DLMDFTE; -.
DR OrthoDB; EOG7XSTD7; -.
DR BRENDA; 6.1.1.6; 2681.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; KARS; human.
DR EvolutionaryTrace; Q15046; -.
DR GeneWiki; KARS_(gene); -.
DR GenomeRNAi; 3735; -.
DR NextBio; 14617; -.
DR PRO; PR:Q15046; -.
DR ArrayExpress; Q15046; -.
DR Bgee; Q15046; -.
DR CleanEx; HS_KARS; -.
DR Genevestigator; Q15046; -.
DR GO; GO:0017101; C:aminoacyl-tRNA synthetase multienzyme complex; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0015630; C:microtubule cytoskeleton; IDA:HPA.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016597; F:amino acid binding; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004824; F:lysine-tRNA ligase activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000049; F:tRNA binding; NAS:UniProtKB.
DR GO; GO:0015966; P:diadenosine tetraphosphate biosynthetic process; IEA:Ensembl.
DR GO; GO:0006430; P:lysyl-tRNA aminoacylation; IDA:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0008033; P:tRNA processing; NAS:UniProtKB.
DR Gene3D; 2.40.50.140; -; 1.
DR InterPro; IPR004364; aa-tRNA-synt_II.
DR InterPro; IPR018150; aa-tRNA-synt_II-like.
DR InterPro; IPR006195; aa-tRNA-synth_II.
DR InterPro; IPR002313; Lys-tRNA-ligase_II.
DR InterPro; IPR018149; Lys-tRNA-synth_II_C.
DR InterPro; IPR012340; NA-bd_OB-fold.
DR InterPro; IPR004365; NA-bd_OB_tRNA.
DR PANTHER; PTHR22594; PTHR22594; 1.
DR PANTHER; PTHR22594:SF4; PTHR22594:SF4; 1.
DR Pfam; PF00152; tRNA-synt_2; 1.
DR Pfam; PF01336; tRNA_anti-codon; 1.
DR PRINTS; PR00982; TRNASYNTHLYS.
DR SUPFAM; SSF50249; SSF50249; 1.
DR TIGRFAMs; TIGR00499; lysS_bact; 1.
DR PROSITE; PS50862; AA_TRNA_LIGASE_II; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing;
KW Aminoacyl-tRNA synthetase; ATP-binding; Cell membrane;
KW Charcot-Marie-Tooth disease; Complete proteome; Cytoplasm; Deafness;
KW Direct protein sequencing; Disease mutation; Host-virus interaction;
KW Ligase; Membrane; Metal-binding; Mitochondrion; Neuropathy;
KW Non-syndromic deafness; Nucleotide-binding; Nucleus; Polymorphism;
KW Protein biosynthesis; Reference proteome; Secreted.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 597 Lysine--tRNA ligase.
FT /FTId=PRO_0000152765.
FT NP_BIND 323 325 ATP.
FT NP_BIND 331 332 ATP.
FT NP_BIND 494 495 ATP.
FT NP_BIND 550 553 ATP.
FT METAL 487 487 Calcium.
FT METAL 494 494 Calcium.
FT BINDING 277 277 Substrate; via carbonyl oxygen.
FT BINDING 301 301 Substrate.
FT BINDING 339 339 Substrate.
FT BINDING 341 341 Substrate.
FT BINDING 497 497 Substrate.
FT BINDING 501 501 Substrate.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 88 88 N6-acetyllysine.
FT MOD_RES 141 141 N6-acetyllysine.
FT VAR_SEQ 1 21 MAAVQAAEVKVDGSEPKLSKN -> MLTQAAVRLVRGSLRK
FT TSWAEWGHRELRLGQLAPFTAPHKDKSFSDQRS (in
FT isoform Mitochondrial).
FT /FTId=VSP_038481.
FT VARIANT 105 105 L -> H (in CMTRIB; severely affects
FT enzyme activity).
FT /FTId=VAR_064911.
FT VARIANT 145 145 Y -> H (in DFNB89).
FT /FTId=VAR_070233.
FT VARIANT 179 179 G -> A (in dbSNP:rs11557665).
FT /FTId=VAR_052640.
FT VARIANT 274 274 I -> M (in CMTRIB).
FT /FTId=VAR_064912.
FT VARIANT 349 349 D -> N (in DFNB89).
FT /FTId=VAR_070234.
FT VARIANT 595 595 T -> S (in dbSNP:rs6834).
FT /FTId=VAR_016105.
FT MUTAGEN 1 65 Missing: Loss of nuclear localization,
FT but no effect on packaging into HIV-1.
FT HELIX 73 89
FT HELIX 105 112
FT STRAND 126 149
FT STRAND 152 159
FT HELIX 160 162
FT HELIX 166 175
FT STRAND 181 190
FT STRAND 196 207
FT HELIX 223 228
FT HELIX 230 236
FT HELIX 238 260
FT STRAND 270 274
FT STRAND 277 279
FT STRAND 284 287
FT TURN 288 291
FT STRAND 292 296
FT HELIX 301 309
FT STRAND 314 322
FT STRAND 328 330
FT STRAND 333 343
FT HELIX 347 366
FT STRAND 367 373
FT STRAND 383 386
FT STRAND 392 395
FT HELIX 396 404
FT HELIX 411 413
FT HELIX 417 429
FT HELIX 440 451
FT HELIX 453 455
FT STRAND 460 463
FT HELIX 467 469
FT STRAND 477 479
FT STRAND 482 490
FT STRAND 493 501
FT HELIX 505 521
FT HELIX 531 537
FT TURN 538 540
FT STRAND 543 550
FT HELIX 551 558
FT HELIX 564 566
FT STRAND 568 570
SQ SEQUENCE 597 AA; 68048 MW; E7770953332D905D CRC64;
MAAVQAAEVK VDGSEPKLSK NELKRRLKAE KKVAEKEAKQ KELSEKQLSQ ATAAATNHTT
DNGVGPEEES VDPNQYYKIR SQAIHQLKVN GEDPYPHKFH VDISLTDFIQ KYSHLQPGDH
LTDITLKVAG RIHAKRASGG KLIFYDLRGE GVKLQVMANS RNYKSEEEFI HINNKLRRGD
IIGVQGNPGK TKKGELSIIP YEITLLSPCL HMLPHLHFGL KDKETRYRQR YLDLILNDFV
RQKFIIRSKI ITYIRSFLDE LGFLEIETPM MNIIPGGAVA KPFITYHNEL DMNLYMRIAP
ELYHKMLVVG GIDRVYEIGR QFRNEGIDLT HNPEFTTCEF YMAYADYHDL MEITEKMVSG
MVKHITGSYK VTYHPDGPEG QAYDVDFTPP FRRINMVEEL EKALGMKLPE TNLFETEETR
KILDDICVAK AVECPPPRTT ARLLDKLVGE FLEVTCINPT FICDHPQIMS PLAKWHRSKE
GLTERFELFV MKKEICNAYT ELNDPMRQRQ LFEEQAKAKA AGDDEAMFID ENFCTALEYG
LPPTAGWGMG IDRVAMFLTD SNNIKEVLLF PAMKPEDKKE NVATTDTLES TTVGTSV
//
ID SYK_HUMAN Reviewed; 597 AA.
AC Q15046; A8MSK1; D3DUK4; O14946; Q96J25; Q9HB23;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-APR-2002, sequence version 3.
DT 22-JAN-2014, entry version 129.
DE RecName: Full=Lysine--tRNA ligase;
DE EC=6.1.1.6;
DE AltName: Full=Lysyl-tRNA synthetase;
DE Short=LysRS;
GN Name=KARS; Synonyms=KIAA0070;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM CYTOPLASMIC).
RC TISSUE=Brain;
RX PubMed=9278442; DOI=10.1074/jbc.272.36.22809;
RA Shiba K., Stello T., Motegi H., Noda T., Musier-Forsyth K.,
RA Schimmel P.;
RT "Human lysyl-tRNA synthetase accepts nucleotide 73 variants and
RT rescues Escherichia coli double-defective mutant.";
RL J. Biol. Chem. 272:22809-22816(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM MITOCHONDRIAL), SUBCELLULAR
RP LOCATION, AND VARIANT SER-595.
RX PubMed=10952987; DOI=10.1074/jbc.M006265200;
RA Tolkunova E., Park H., Xia J., King M.P., Davidson E.;
RT "The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and
RT mitochondrial enzymes by means of an unusual alternative splicing of
RT the primary transcript.";
RL J. Biol. Chem. 275:35063-35069(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM CYTOPLASMIC), AND
RP VARIANT SER-595.
RC TISSUE=Bone marrow;
RX PubMed=7584044; DOI=10.1093/dnares/1.5.223;
RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S.,
RA Seki N., Kawarabayasi Y., Ishikawa K., Tabata S.;
RT "Prediction of the coding sequences of unidentified human genes. II.
RT The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by
RT analysis of cDNA clones from human cell line KG-1.";
RL DNA Res. 1:223-229(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM CYTOPLASMIC).
RC TISSUE=Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 2-10; 112-127; 142-148; 231-241; 306-314 AND
RP 486-492, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND
RP MASS SPECTROMETRY (ISOFORM CYTOPLASMIC).
RC TISSUE=Hepatoma;
RA Bienvenut W.V., Boldt K., von Kriegsheim A.F., Kolch W.;
RL Submitted (JUL-2007) to UniProtKB.
RN [8]
RP FUNCTION.
RX PubMed=5338216; DOI=10.1016/0006-291X(66)90415-3;
RA Zamecnik P.C., Stephenson M.L., Janeway C.M., Randerath K.;
RT "Enzymatic synthesis of diadenosine tetraphosphate and diadenosine
RT triphosphate with a purified lysyl-tRNA synthetase.";
RL Biochem. Biophys. Res. Commun. 24:91-97(1966).
RN [9]
RP INTERACTION WITH AIMP2.
RX PubMed=9878398; DOI=10.1006/jmbi.1998.2316;
RA Quevillon S., Robinson J.-C., Berthonneau E., Siatecka M., Mirande M.;
RT "Macromolecular assemblage of aminoacyl-tRNA synthetases:
RT identification of protein-protein interactions and characterization of
RT a core protein.";
RL J. Mol. Biol. 285:183-195(1999).
RN [10]
RP BIDIRECTIONAL PROMOTER WITH TERF2IP.
RX PubMed=14659874; DOI=10.1016/j.gene.2003.08.026;
RA Tan M., Wei C., Price C.M.;
RT "The telomeric protein Rap1 is conserved in vertebrates and is
RT expressed from a bidirectional promoter positioned between the Rap1
RT and KARS genes.";
RL Gene 323:1-10(2003).
RN [11]
RP INTERACTION WITH MIFT.
RX PubMed=14975237; DOI=10.1016/S1074-7613(04)00020-2;
RA Lee Y.N., Nechushtan H., Figov N., Razin E.;
RT "The function of lysyl-tRNA synthetase and Ap4A as signaling
RT regulators of MITF activity in FcepsilonRI-activated mast cells.";
RL Immunity 20:145-151(2004).
RN [12]
RP SUBUNIT, AND INTERACTION WITH HIV-1 GAG.
RX PubMed=12756246; DOI=10.1074/jbc.M301840200;
RA Javanbakht H., Halwani R., Cen S., Saadatmand J., Musier-Forsyth K.,
RA Gottlinger H., Kleiman L.;
RT "The interaction between HIV-1 Gag and human lysyl-tRNA synthetase
RT during viral assembly.";
RL J. Biol. Chem. 278:27644-27651(2003).
RN [13]
RP SUBCELLULAR LOCATION, MUTAGENESIS OF 1-MET--GLY-65, AND INTERACTION
RP WITH AIMP2 AND HIV-1 GAG.
RX PubMed=15220430; DOI=10.1128/JVI.78.14.7553-7564.2004;
RA Halwani R., Cen S., Javanbakht H., Saadatmand J., Kim S., Shiba K.,
RA Kleiman L.;
RT "Cellular distribution of Lysyl-tRNA synthetase and its interaction
RT with Gag during human immunodeficiency virus type 1 assembly.";
RL J. Virol. 78:7553-7564(2004).
RN [14]
RP SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=15851690; DOI=10.1073/pnas.0500226102;
RA Park S.G., Kim H.J., Min Y.H., Choi E.-C., Shin Y.K., Park B.-J.,
RA Lee S.W., Kim S.;
RT "Human lysyl-tRNA synthetase is secreted to trigger proinflammatory
RT response.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:6356-6361(2005).
RN [15]
RP INTERACTION WITH EEF1A1; AIMP2 AND DARS.
RX PubMed=18029264; DOI=10.1016/j.bbrc.2007.11.028;
RA Guzzo C.M., Yang D.C.H.;
RT "Lysyl-tRNA synthetase interacts with EF1alpha, aspartyl-tRNA
RT synthetase and p38 in vitro.";
RL Biochem. Biophys. Res. Commun. 365:718-723(2008).
RN [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-88 AND LYS-141, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.31 ANGSTROMS) OF 70-581 IN COMPLEX WITH
RP SUBSTRATE AND ATP.
RX PubMed=18272479; DOI=10.1073/pnas.0712072105;
RA Guo M., Ignatov M., Musier-Forsyth K., Schimmel P., Yang X.-L.;
RT "Crystal structure of tetrameric form of human lysyl-tRNA synthetase:
RT Implications for multisynthetase complex formation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:2331-2336(2008).
RN [21]
RP VARIANTS CMTRIB HIS-105 AND MET-274, AND VARIANT SER-595.
RX PubMed=20920668; DOI=10.1016/j.ajhg.2010.09.008;
RA McLaughlin H.M., Sakaguchi R., Liu C., Igarashi T., Pehlivan D.,
RA Chu K., Iyer R., Cruz P., Cherukuri P.F., Hansen N.F., Mullikin J.C.,
RA Biesecker L.G., Wilson T.E., Ionasescu V., Nicholson G., Searby C.,
RA Talbot K., Vance J.M., Zuchner S., Szigeti K., Lupski J.R., Hou Y.M.,
RA Green E.D., Antonellis A.;
RT "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase
RT mutations in a patient with peripheral neuropathy.";
RL Am. J. Hum. Genet. 87:560-566(2010).
RN [22]
RP VARIANTS DFNB89 HIS-145 AND ASN-349.
RX PubMed=23768514; DOI=10.1016/j.ajhg.2013.05.018;
RG University of Washington Center for Mendelian Genomics;
RA Santos-Cortez R.L., Lee K., Azeem Z., Antonellis P.J., Pollock L.M.,
RA Khan S., Ullah I., Andrade-Elizondo P.B., Chiu I., Adams M.D.,
RA Basit S., Smith J.D., Nickerson D.A., McDermott B.M. Jr., Ahmad W.,
RA Leal S.M.;
RT "Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-
RT recessive nonsyndromic hearing impairment DFNB89.";
RL Am. J. Hum. Genet. 93:132-140(2013).
CC -!- FUNCTION: Catalyzes the specific attachment of an amino acid to
CC its cognate tRNA in a 2 step reaction: the amino acid (AA) is
CC first activated by ATP to form AA-AMP and then transferred to the
CC acceptor end of the tRNA. When secreted, acts as a signaling
CC molecule that induces immune response through the activation of
CC monocyte/macrophages. Catalyzes the synthesis of diadenosine
CC oligophosphate (Ap4A), a signaling molecule involved in the
CC activation of MITF transcriptional activity. Interacts with HIV-1
CC virus GAG protein, facilitating the selective packaging of
CC tRNA(3)(Lys), the primer for reverse transcription initiation.
CC -!- CATALYTIC ACTIVITY: ATP + L-lysine + tRNA(Lys) = AMP + diphosphate
CC + L-lysyl-tRNA(Lys).
CC -!- ENZYME REGULATION: Up-regulated by DARS and EEF1A1, but not by
CC AIMP2.
CC -!- SUBUNIT: Homodimer; also part of a multisubunit complex that
CC groups AIMP1, AIMP2, EEF1A1 and tRNA ligases for Arg, Asp, Glu,
CC Gln, Ile, Leu, Lys, Met and Pro. Interacts with AIMP2 (via N-
CC terminus) and MITF. Interacts directly with HIV-1 virus GAG
CC protein.
CC -!- INTERACTION:
CC Q13155:AIMP2; NbExp=3; IntAct=EBI-356367, EBI-745226;
CC -!- SUBCELLULAR LOCATION: Isoform Cytoplasmic: Cytoplasm. Nucleus.
CC Cell membrane; Peripheral membrane protein. Secreted.
CC Note=Secretion is induced by TNF-alpha.
CC -!- SUBCELLULAR LOCATION: Isoform Mitochondrial: Mitochondrion.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Cytoplasmic;
CC IsoId=Q15046-1; Sequence=Displayed;
CC Name=Mitochondrial;
CC IsoId=Q15046-2; Sequence=VSP_038481;
CC Note=Mitochondrial precursor. Contains a mitochondrial transit
CC peptide at positions 1-16. Ref.2 (AAG30114) sequence is in
CC conflict in position: 48:R->G;
CC -!- DOMAIN: The N-terminal domain (1-65) of the cytoplasmic isoform is
CC a functional tRNA-binding domain (By similarity), is required for
CC nuclear localization, is involved in the interaction with DARS,
CC but has a repulsive role in the binding to EEF1A1. A central
CC domain (208-259) is involved in homodimerization and is required
CC for interaction with HIV-1 GAG and incorporation into virions. The
CC C-terminal domain (452-597) is not required for interaction with
CC AIMP2.
CC -!- DISEASE: Charcot-Marie-Tooth disease, recessive, intermediate
CC type, B (CMTRIB) [MIM:613641]: A form of Charcot-Marie-Tooth
CC disease, a disorder of the peripheral nervous system,
CC characterized by progressive weakness and atrophy, initially of
CC the peroneal muscles and later of the distal muscles of the arms.
CC Recessive intermediate forms of Charcot-Marie-Tooth disease are
CC characterized by clinical and pathologic features intermediate
CC between demyelinating and axonal peripheral neuropathies, and
CC motor median nerve conduction velocities ranging from 25 to 45
CC m/sec. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Deafness, autosomal recessive, 89 (DFNB89) [MIM:613916]:
CC A form of non-syndromic deafness characterized by bilateral,
CC prelingual, moderate to severe hearing loss affecting all
CC frequencies. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- MISCELLANEOUS: Shares a bidirectional promoter with TERF2IP/RAP1
CC (PubMed:14659874).
CC -!- SIMILARITY: Belongs to the class-II aminoacyl-tRNA synthetase
CC family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA06688.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; D32053; BAA22084.1; -; mRNA.
DR EMBL; AF285758; AAG30114.1; -; mRNA.
DR EMBL; D31890; BAA06688.1; ALT_INIT; mRNA.
DR EMBL; AC025287; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471114; EAW95622.1; -; Genomic_DNA.
DR EMBL; CH471114; EAW95624.1; -; Genomic_DNA.
DR EMBL; BC004132; AAH04132.1; -; mRNA.
DR RefSeq; NP_001123561.1; NM_001130089.1.
DR RefSeq; NP_005539.1; NM_005548.2.
DR UniGene; Hs.3100; -.
DR PDB; 3BJU; X-ray; 2.31 A; A/B/C/D=70-581.
DR PDB; 4DPG; X-ray; 2.84 A; A/B/C/D/E/F/G/H=70-581.
DR PDBsum; 3BJU; -.
DR PDBsum; 4DPG; -.
DR ProteinModelPortal; Q15046; -.
DR SMR; Q15046; 71-576.
DR DIP; DIP-29725N; -.
DR IntAct; Q15046; 19.
DR MINT; MINT-1154971; -.
DR STRING; 9606.ENSP00000325448; -.
DR BindingDB; Q15046; -.
DR ChEMBL; CHEMBL5575; -.
DR DrugBank; DB00123; L-Lysine.
DR PhosphoSite; Q15046; -.
DR DMDM; 20178333; -.
DR PaxDb; Q15046; -.
DR PRIDE; Q15046; -.
DR DNASU; 3735; -.
DR Ensembl; ENST00000302445; ENSP00000303043; ENSG00000065427.
DR Ensembl; ENST00000319410; ENSP00000325448; ENSG00000065427.
DR GeneID; 3735; -.
DR KEGG; hsa:3735; -.
DR UCSC; uc002feq.3; human.
DR CTD; 3735; -.
DR GeneCards; GC16M075661; -.
DR HGNC; HGNC:6215; KARS.
DR HPA; HPA041345; -.
DR HPA; HPA041550; -.
DR MIM; 601421; gene.
DR MIM; 613641; phenotype.
DR MIM; 613916; phenotype.
DR neXtProt; NX_Q15046; -.
DR Orphanet; 254334; Autosomal recessive intermediate Charcot-Marie-Tooth disease type B.
DR Orphanet; 90636; Autosomal recessive nonsyndromic sensorineural deafness type DFNB.
DR PharmGKB; PA30016; -.
DR eggNOG; COG1190; -.
DR HOGENOM; HOG000236577; -.
DR HOVERGEN; HBG002562; -.
DR KO; K04567; -.
DR OMA; DLMDFTE; -.
DR OrthoDB; EOG7XSTD7; -.
DR BRENDA; 6.1.1.6; 2681.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; KARS; human.
DR EvolutionaryTrace; Q15046; -.
DR GeneWiki; KARS_(gene); -.
DR GenomeRNAi; 3735; -.
DR NextBio; 14617; -.
DR PRO; PR:Q15046; -.
DR ArrayExpress; Q15046; -.
DR Bgee; Q15046; -.
DR CleanEx; HS_KARS; -.
DR Genevestigator; Q15046; -.
DR GO; GO:0017101; C:aminoacyl-tRNA synthetase multienzyme complex; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0015630; C:microtubule cytoskeleton; IDA:HPA.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016597; F:amino acid binding; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004824; F:lysine-tRNA ligase activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000049; F:tRNA binding; NAS:UniProtKB.
DR GO; GO:0015966; P:diadenosine tetraphosphate biosynthetic process; IEA:Ensembl.
DR GO; GO:0006430; P:lysyl-tRNA aminoacylation; IDA:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0008033; P:tRNA processing; NAS:UniProtKB.
DR Gene3D; 2.40.50.140; -; 1.
DR InterPro; IPR004364; aa-tRNA-synt_II.
DR InterPro; IPR018150; aa-tRNA-synt_II-like.
DR InterPro; IPR006195; aa-tRNA-synth_II.
DR InterPro; IPR002313; Lys-tRNA-ligase_II.
DR InterPro; IPR018149; Lys-tRNA-synth_II_C.
DR InterPro; IPR012340; NA-bd_OB-fold.
DR InterPro; IPR004365; NA-bd_OB_tRNA.
DR PANTHER; PTHR22594; PTHR22594; 1.
DR PANTHER; PTHR22594:SF4; PTHR22594:SF4; 1.
DR Pfam; PF00152; tRNA-synt_2; 1.
DR Pfam; PF01336; tRNA_anti-codon; 1.
DR PRINTS; PR00982; TRNASYNTHLYS.
DR SUPFAM; SSF50249; SSF50249; 1.
DR TIGRFAMs; TIGR00499; lysS_bact; 1.
DR PROSITE; PS50862; AA_TRNA_LIGASE_II; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing;
KW Aminoacyl-tRNA synthetase; ATP-binding; Cell membrane;
KW Charcot-Marie-Tooth disease; Complete proteome; Cytoplasm; Deafness;
KW Direct protein sequencing; Disease mutation; Host-virus interaction;
KW Ligase; Membrane; Metal-binding; Mitochondrion; Neuropathy;
KW Non-syndromic deafness; Nucleotide-binding; Nucleus; Polymorphism;
KW Protein biosynthesis; Reference proteome; Secreted.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 597 Lysine--tRNA ligase.
FT /FTId=PRO_0000152765.
FT NP_BIND 323 325 ATP.
FT NP_BIND 331 332 ATP.
FT NP_BIND 494 495 ATP.
FT NP_BIND 550 553 ATP.
FT METAL 487 487 Calcium.
FT METAL 494 494 Calcium.
FT BINDING 277 277 Substrate; via carbonyl oxygen.
FT BINDING 301 301 Substrate.
FT BINDING 339 339 Substrate.
FT BINDING 341 341 Substrate.
FT BINDING 497 497 Substrate.
FT BINDING 501 501 Substrate.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 88 88 N6-acetyllysine.
FT MOD_RES 141 141 N6-acetyllysine.
FT VAR_SEQ 1 21 MAAVQAAEVKVDGSEPKLSKN -> MLTQAAVRLVRGSLRK
FT TSWAEWGHRELRLGQLAPFTAPHKDKSFSDQRS (in
FT isoform Mitochondrial).
FT /FTId=VSP_038481.
FT VARIANT 105 105 L -> H (in CMTRIB; severely affects
FT enzyme activity).
FT /FTId=VAR_064911.
FT VARIANT 145 145 Y -> H (in DFNB89).
FT /FTId=VAR_070233.
FT VARIANT 179 179 G -> A (in dbSNP:rs11557665).
FT /FTId=VAR_052640.
FT VARIANT 274 274 I -> M (in CMTRIB).
FT /FTId=VAR_064912.
FT VARIANT 349 349 D -> N (in DFNB89).
FT /FTId=VAR_070234.
FT VARIANT 595 595 T -> S (in dbSNP:rs6834).
FT /FTId=VAR_016105.
FT MUTAGEN 1 65 Missing: Loss of nuclear localization,
FT but no effect on packaging into HIV-1.
FT HELIX 73 89
FT HELIX 105 112
FT STRAND 126 149
FT STRAND 152 159
FT HELIX 160 162
FT HELIX 166 175
FT STRAND 181 190
FT STRAND 196 207
FT HELIX 223 228
FT HELIX 230 236
FT HELIX 238 260
FT STRAND 270 274
FT STRAND 277 279
FT STRAND 284 287
FT TURN 288 291
FT STRAND 292 296
FT HELIX 301 309
FT STRAND 314 322
FT STRAND 328 330
FT STRAND 333 343
FT HELIX 347 366
FT STRAND 367 373
FT STRAND 383 386
FT STRAND 392 395
FT HELIX 396 404
FT HELIX 411 413
FT HELIX 417 429
FT HELIX 440 451
FT HELIX 453 455
FT STRAND 460 463
FT HELIX 467 469
FT STRAND 477 479
FT STRAND 482 490
FT STRAND 493 501
FT HELIX 505 521
FT HELIX 531 537
FT TURN 538 540
FT STRAND 543 550
FT HELIX 551 558
FT HELIX 564 566
FT STRAND 568 570
SQ SEQUENCE 597 AA; 68048 MW; E7770953332D905D CRC64;
MAAVQAAEVK VDGSEPKLSK NELKRRLKAE KKVAEKEAKQ KELSEKQLSQ ATAAATNHTT
DNGVGPEEES VDPNQYYKIR SQAIHQLKVN GEDPYPHKFH VDISLTDFIQ KYSHLQPGDH
LTDITLKVAG RIHAKRASGG KLIFYDLRGE GVKLQVMANS RNYKSEEEFI HINNKLRRGD
IIGVQGNPGK TKKGELSIIP YEITLLSPCL HMLPHLHFGL KDKETRYRQR YLDLILNDFV
RQKFIIRSKI ITYIRSFLDE LGFLEIETPM MNIIPGGAVA KPFITYHNEL DMNLYMRIAP
ELYHKMLVVG GIDRVYEIGR QFRNEGIDLT HNPEFTTCEF YMAYADYHDL MEITEKMVSG
MVKHITGSYK VTYHPDGPEG QAYDVDFTPP FRRINMVEEL EKALGMKLPE TNLFETEETR
KILDDICVAK AVECPPPRTT ARLLDKLVGE FLEVTCINPT FICDHPQIMS PLAKWHRSKE
GLTERFELFV MKKEICNAYT ELNDPMRQRQ LFEEQAKAKA AGDDEAMFID ENFCTALEYG
LPPTAGWGMG IDRVAMFLTD SNNIKEVLLF PAMKPEDKKE NVATTDTLES TTVGTSV
//
MIM
601421
*RECORD*
*FIELD* NO
601421
*FIELD* TI
*601421 LYSYL-tRNA SYNTHETASE; KARS
;;KRS
*FIELD* TX
DESCRIPTION
The KARS gene encodes lysyl-tRNA synthetase, which catalyzes the
read moreaminoacylation of tRNA-lys in 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)).
CLONING
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.
GENE STRUCTURE
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.
MAPPING
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.
GENE FUNCTION
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).
MOLECULAR GENETICS
- 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.
*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE, B
KARS, LEU133HIS
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 transition resulting in a leu133-to-his (L133H) substitution in a
highly conserved residue, and a 2-bp insertion (524insTT; 601421.0001)
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.
.0002
CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE, B
KARS, 2-BP INS, 524TT
See 601421.0001 and McLaughlin et al. (2010).
.0003
DEAFNESS, AUTOSOMAL RECESSIVE 89
KARS, TYR173HIS
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.
.0004
DEAFNESS, AUTOSOMAL RECESSIVE 89
KARS, ASP377ASN
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.
*FIELD* RF
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
*FIELD* CN
Marla J. F. O'Neill - updated: 8/21/2013
Cassandra L. Kniffin - updated: 11/15/2010
Patricia A. Hartz - updated: 5/16/2007
Patricia A. Hartz - updated: 8/6/2002
Victor A. McKusick - updated: 6/4/2001
*FIELD* CD
Victor A. McKusick: 9/12/1996
*FIELD* ED
carol: 09/16/2013
carol: 8/27/2013
ckniffin: 8/26/2013
carol: 8/21/2013
carol: 11/17/2010
ckniffin: 11/15/2010
mgross: 5/22/2007
terry: 5/16/2007
mgross: 8/6/2002
alopez: 6/5/2001
terry: 6/4/2001
mark: 9/13/1996
terry: 9/12/1996
mark: 9/12/1996
*RECORD*
*FIELD* NO
601421
*FIELD* TI
*601421 LYSYL-tRNA SYNTHETASE; KARS
;;KRS
*FIELD* TX
DESCRIPTION
The KARS gene encodes lysyl-tRNA synthetase, which catalyzes the
read moreaminoacylation of tRNA-lys in 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)).
CLONING
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.
GENE STRUCTURE
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.
MAPPING
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.
GENE FUNCTION
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).
MOLECULAR GENETICS
- 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.
*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE, B
KARS, LEU133HIS
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 transition resulting in a leu133-to-his (L133H) substitution in a
highly conserved residue, and a 2-bp insertion (524insTT; 601421.0001)
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.
.0002
CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE, B
KARS, 2-BP INS, 524TT
See 601421.0001 and McLaughlin et al. (2010).
.0003
DEAFNESS, AUTOSOMAL RECESSIVE 89
KARS, TYR173HIS
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.
.0004
DEAFNESS, AUTOSOMAL RECESSIVE 89
KARS, ASP377ASN
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.
*FIELD* RF
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
*FIELD* CN
Marla J. F. O'Neill - updated: 8/21/2013
Cassandra L. Kniffin - updated: 11/15/2010
Patricia A. Hartz - updated: 5/16/2007
Patricia A. Hartz - updated: 8/6/2002
Victor A. McKusick - updated: 6/4/2001
*FIELD* CD
Victor A. McKusick: 9/12/1996
*FIELD* ED
carol: 09/16/2013
carol: 8/27/2013
ckniffin: 8/26/2013
carol: 8/21/2013
carol: 11/17/2010
ckniffin: 11/15/2010
mgross: 5/22/2007
terry: 5/16/2007
mgross: 8/6/2002
alopez: 6/5/2001
terry: 6/4/2001
mark: 9/13/1996
terry: 9/12/1996
mark: 9/12/1996
MIM
613641
*RECORD*
*FIELD* NO
613641
*FIELD* TI
#613641 CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE B; CMTRIB
;;CHARCOT-MARIE-TOOTH NEUROPATHY, RECESSIVE INTERMEDIATE B; RI-CMTB
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
recessive intermediate Charcot-Marie-Tooth disease B (CMTRIB) is caused
by compound heterozygous mutation in the KARS gene (601421) on
chromosome 16q23.
For a discussion of genetic heterogeneity of recessive intermediate
Charcot-marie-Tooth disease, see CMTRIA (608340).
CLINICAL FEATURES
McLaughlin et al. (2010) reported a patient with intermediate
Charcot-Marie-Tooth disease, developmental delay, self-abusive behavior,
dysmorphic features, and vestibular Schwannoma. The patient was
identified from a larger cohort of 355 patients with peripheral
neuropathy. Electrophysiologic studies of this patient showed motor
nerve conduction velocities (NCV) of 39.5 and 30.6 m/s in the median and
ulnar nerves, respectively, consistent with an intermediate phenotype
between that of demyelinating and axonal CMT. There were also decreased
amplitudes of evoked motor responses in these nerves.
MOLECULAR GENETICS
In a patient with recessive intermediate CMT with additional features,
including developmental delay, McLaughlin et al. (2010) identified
compound heterozygous mutations in the KARS gene (601421.0001 and
601421.0002). The patient was adopted, and parental studies were not
possible. McLaughlin et al. (2010) noted that mutations in 3 genes
encoding aminoacyl-tRNA synthetases (ARS), GARS (600287), YARS (603623),
and AARS (601065), had been implicated in Charcot-Marie-Tooth disease
primarily associated with an axonal pathology (CMT2D, 601472; CMTDIC,
608323; and CMT2N, 613287, respectively). Thus, KARS was the fourth ARS
gene associated with CMT disease, indicating that this family of enzymes
is specifically critical for axon function.
*FIELD* RF
1. 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.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Dysmorphic features
SKELETAL:
[Feet];
Pes cavus
NEUROLOGIC:
Delayed development;
[Peripheral nervous system];
Lower limb muscle weakness due to peripheral neuropathy;
Lower limb muscle atrophy due to peripheral neuropathy;
Clumsy gait;
'Steppage' gait;
Foot drop;
Hyporeflexia;
Areflexia;
Distal sensory impairment;
EMG shows neuropathic changes;
Nerve conduction velocities (NCV) vary from normal to decreased;
[Behavioral/psychiatric manifestations];
Self-abusive behavior
NEOPLASIA:
Vestibular Schwannoma
MISCELLANEOUS:
One patient has been reported (last curated November 2010)
MOLECULAR BASIS:
Caused by mutation in the lysyl-tRNA synthetase gene (KARS, 601421.0001)
*FIELD* CD
Cassandra L. Kniffin: 11/15/2010
*FIELD* ED
joanna: 10/22/2013
joanna: 8/1/2012
ckniffin: 11/15/2010
*FIELD* CD
Cassandra L. Kniffin: 11/15/2010
*FIELD* ED
carol: 08/27/2013
ckniffin: 8/26/2013
carol: 11/17/2010
ckniffin: 11/15/2010
*RECORD*
*FIELD* NO
613641
*FIELD* TI
#613641 CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE B; CMTRIB
;;CHARCOT-MARIE-TOOTH NEUROPATHY, RECESSIVE INTERMEDIATE B; RI-CMTB
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
recessive intermediate Charcot-Marie-Tooth disease B (CMTRIB) is caused
by compound heterozygous mutation in the KARS gene (601421) on
chromosome 16q23.
For a discussion of genetic heterogeneity of recessive intermediate
Charcot-marie-Tooth disease, see CMTRIA (608340).
CLINICAL FEATURES
McLaughlin et al. (2010) reported a patient with intermediate
Charcot-Marie-Tooth disease, developmental delay, self-abusive behavior,
dysmorphic features, and vestibular Schwannoma. The patient was
identified from a larger cohort of 355 patients with peripheral
neuropathy. Electrophysiologic studies of this patient showed motor
nerve conduction velocities (NCV) of 39.5 and 30.6 m/s in the median and
ulnar nerves, respectively, consistent with an intermediate phenotype
between that of demyelinating and axonal CMT. There were also decreased
amplitudes of evoked motor responses in these nerves.
MOLECULAR GENETICS
In a patient with recessive intermediate CMT with additional features,
including developmental delay, McLaughlin et al. (2010) identified
compound heterozygous mutations in the KARS gene (601421.0001 and
601421.0002). The patient was adopted, and parental studies were not
possible. McLaughlin et al. (2010) noted that mutations in 3 genes
encoding aminoacyl-tRNA synthetases (ARS), GARS (600287), YARS (603623),
and AARS (601065), had been implicated in Charcot-Marie-Tooth disease
primarily associated with an axonal pathology (CMT2D, 601472; CMTDIC,
608323; and CMT2N, 613287, respectively). Thus, KARS was the fourth ARS
gene associated with CMT disease, indicating that this family of enzymes
is specifically critical for axon function.
*FIELD* RF
1. 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.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Dysmorphic features
SKELETAL:
[Feet];
Pes cavus
NEUROLOGIC:
Delayed development;
[Peripheral nervous system];
Lower limb muscle weakness due to peripheral neuropathy;
Lower limb muscle atrophy due to peripheral neuropathy;
Clumsy gait;
'Steppage' gait;
Foot drop;
Hyporeflexia;
Areflexia;
Distal sensory impairment;
EMG shows neuropathic changes;
Nerve conduction velocities (NCV) vary from normal to decreased;
[Behavioral/psychiatric manifestations];
Self-abusive behavior
NEOPLASIA:
Vestibular Schwannoma
MISCELLANEOUS:
One patient has been reported (last curated November 2010)
MOLECULAR BASIS:
Caused by mutation in the lysyl-tRNA synthetase gene (KARS, 601421.0001)
*FIELD* CD
Cassandra L. Kniffin: 11/15/2010
*FIELD* ED
joanna: 10/22/2013
joanna: 8/1/2012
ckniffin: 11/15/2010
*FIELD* CD
Cassandra L. Kniffin: 11/15/2010
*FIELD* ED
carol: 08/27/2013
ckniffin: 8/26/2013
carol: 11/17/2010
ckniffin: 11/15/2010
MIM
613916
*RECORD*
*FIELD* NO
613916
*FIELD* TI
#613916 DEAFNESS, AUTOSOMAL RECESSIVE 89; DFNB89
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreautosomal recessive deafness-89 (DFNB89) is caused by homozygous
mutation in the KARS gene (601421) on chromosome 16q23.
CLINICAL FEATURES
Basit et al. (2011) reported 2 unrelated consanguineous Pakistani
families with autosomal recessive nonsyndromic moderate to severe
hearing loss affecting all frequencies. The onset of deafness was
prelingual, and there was no apparent vestibular involvement.
Santos-Cortez et al. (2013) provided follow-up on the 2 Pakistani
families with nonsyndromic deafness originally reported by Basit et al.
(2011) (families 4338 and 4406), and described a third consanguineous
Pakistani family (4284) with nonsyndromic deafness showing linkage to
the DFNB89 locus. Santos-Cortez et al. (2013) noted that there were no
other syndromic, vestibular, neurologic, or systemic abnormalities
detected on physical examination of affected individuals in the 3
families. Air-conduction audiometry in 1 affected individual from each
family showed symmetric bilateral severe to profound hearing impairment
in the patients from families 4284 and 4338, and symmetric moderate to
severe hearing impairment across all frequencies tested in the patient
from family 4406.
MAPPING
By genomewide linkage analysis of 2 unrelated consanguineous Pakistani
families with autosomal recessive hearing loss, Basit et al. (2011)
identified a locus, termed DFNB89, on chromosome 16q21-q23.2. Maximum
lod scores of 6.0 and 3.7 were obtained for the respective families; the
maximum multipoint lod for both families was 9.7. The shared region of
homozygosity spanned 16.1 Mb between dbSNP rs717293 and dbSNP rs728929.
Eight candidate genes were sequenced, but no potentially causal variants
were found.
In a third Pakistani family with nonsyndromic deafness, Santos-Cortez et
al. (2013) found suggestive linkage to the DFNB89 locus, with a maximum
multipoint parametric lod score of 1.93.
MOLECULAR GENETICS
Santos-Cortez et al. (2013) performed whole-exome sequencing in 1
affected individual from each of 3 consanguineous Pakistani families
with nonsyndromic deafness mapping to chromosome 16q21-q23.2, 2 of which
had previously been studied by Basit et al. (2011), and identified 2
homozygous missense mutations in the KARS gene: 2 probands were
homozygous for a Y173H substitution (601421.0003), and 1 was homozygous
for a D377N substitution (601421.0004). Sequencing confirmed that both
KARS variants segregated with disease in the respective families, and
neither was found in 325 ethnically matched controls or in variant
databases. Noting that compound heterozygosity for KARS mutations had
previously been identified in a patient with a form of
Charcot-Marie-Tooth disease (613641) and bilateral acoustic neuroma,
Santos-Cortez et al. (2013) performed additional examinations in 3
affected individuals from 2 of the families but found no evidence for
auditory or limb neuropathy in the DFNB89 patients.
*FIELD* RF
1. 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.
2. 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.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Hearing loss (affecting all frequencies), moderate to severe
MISCELLANEOUS:
Prelingual onset
*FIELD* CD
Cassandra L. Kniffin: 4/20/2011
*FIELD* ED
joanna: 02/28/2012
ckniffin: 4/20/2011
*FIELD* CN
Marla J. F. O'Neill - updated: 08/21/2013
*FIELD* CD
Cassandra L. Kniffin: 4/20/2011
*FIELD* ED
carol: 08/21/2013
wwang: 5/11/2011
wwang: 5/2/2011
ckniffin: 4/20/2011
*RECORD*
*FIELD* NO
613916
*FIELD* TI
#613916 DEAFNESS, AUTOSOMAL RECESSIVE 89; DFNB89
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreautosomal recessive deafness-89 (DFNB89) is caused by homozygous
mutation in the KARS gene (601421) on chromosome 16q23.
CLINICAL FEATURES
Basit et al. (2011) reported 2 unrelated consanguineous Pakistani
families with autosomal recessive nonsyndromic moderate to severe
hearing loss affecting all frequencies. The onset of deafness was
prelingual, and there was no apparent vestibular involvement.
Santos-Cortez et al. (2013) provided follow-up on the 2 Pakistani
families with nonsyndromic deafness originally reported by Basit et al.
(2011) (families 4338 and 4406), and described a third consanguineous
Pakistani family (4284) with nonsyndromic deafness showing linkage to
the DFNB89 locus. Santos-Cortez et al. (2013) noted that there were no
other syndromic, vestibular, neurologic, or systemic abnormalities
detected on physical examination of affected individuals in the 3
families. Air-conduction audiometry in 1 affected individual from each
family showed symmetric bilateral severe to profound hearing impairment
in the patients from families 4284 and 4338, and symmetric moderate to
severe hearing impairment across all frequencies tested in the patient
from family 4406.
MAPPING
By genomewide linkage analysis of 2 unrelated consanguineous Pakistani
families with autosomal recessive hearing loss, Basit et al. (2011)
identified a locus, termed DFNB89, on chromosome 16q21-q23.2. Maximum
lod scores of 6.0 and 3.7 were obtained for the respective families; the
maximum multipoint lod for both families was 9.7. The shared region of
homozygosity spanned 16.1 Mb between dbSNP rs717293 and dbSNP rs728929.
Eight candidate genes were sequenced, but no potentially causal variants
were found.
In a third Pakistani family with nonsyndromic deafness, Santos-Cortez et
al. (2013) found suggestive linkage to the DFNB89 locus, with a maximum
multipoint parametric lod score of 1.93.
MOLECULAR GENETICS
Santos-Cortez et al. (2013) performed whole-exome sequencing in 1
affected individual from each of 3 consanguineous Pakistani families
with nonsyndromic deafness mapping to chromosome 16q21-q23.2, 2 of which
had previously been studied by Basit et al. (2011), and identified 2
homozygous missense mutations in the KARS gene: 2 probands were
homozygous for a Y173H substitution (601421.0003), and 1 was homozygous
for a D377N substitution (601421.0004). Sequencing confirmed that both
KARS variants segregated with disease in the respective families, and
neither was found in 325 ethnically matched controls or in variant
databases. Noting that compound heterozygosity for KARS mutations had
previously been identified in a patient with a form of
Charcot-Marie-Tooth disease (613641) and bilateral acoustic neuroma,
Santos-Cortez et al. (2013) performed additional examinations in 3
affected individuals from 2 of the families but found no evidence for
auditory or limb neuropathy in the DFNB89 patients.
*FIELD* RF
1. 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.
2. 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.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Hearing loss (affecting all frequencies), moderate to severe
MISCELLANEOUS:
Prelingual onset
*FIELD* CD
Cassandra L. Kniffin: 4/20/2011
*FIELD* ED
joanna: 02/28/2012
ckniffin: 4/20/2011
*FIELD* CN
Marla J. F. O'Neill - updated: 08/21/2013
*FIELD* CD
Cassandra L. Kniffin: 4/20/2011
*FIELD* ED
carol: 08/21/2013
wwang: 5/11/2011
wwang: 5/2/2011
ckniffin: 4/20/2011