Full text data of DARS
DARS
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Aspartate--tRNA ligase, cytoplasmic; 6.1.1.12 (Aspartyl-tRNA synthetase; AspRS; Cell proliferation-inducing gene 40 protein)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Aspartate--tRNA ligase, cytoplasmic; 6.1.1.12 (Aspartyl-tRNA synthetase; AspRS; Cell proliferation-inducing gene 40 protein)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00216951
IPI00216951 Aspartyl-tRNA synthetase soluble fraction,aminoacylase activity, aspartate-tRNA ligase activity, aspartyl-tRNA aminoacylation, protein biosynthesis, protein complex assembly soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00216951 Aspartyl-tRNA synthetase soluble fraction,aminoacylase activity, aspartate-tRNA ligase activity, aspartyl-tRNA aminoacylation, protein biosynthesis, protein complex assembly soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
P14868
ID SYDC_HUMAN Reviewed; 501 AA.
AC P14868; A8K3J2; D3DP77; Q2TNI3; Q32Q69; Q53HV4; Q53YC5; Q9BW52;
read moreDT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2002, sequence version 2.
DT 22-JAN-2014, entry version 144.
DE RecName: Full=Aspartate--tRNA ligase, cytoplasmic;
DE EC=6.1.1.12;
DE AltName: Full=Aspartyl-tRNA synthetase;
DE Short=AspRS;
DE AltName: Full=Cell proliferation-inducing gene 40 protein;
GN Name=DARS; ORFNames=PIG40;
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].
RX PubMed=2674137;
RA Jacobo-Molina A., Peterson R., Yang D.C.H.;
RT "cDNA sequence, predicted primary structure, and evolving amphiphilic
RT helix of human aspartyl-tRNA synthetase.";
RL J. Biol. Chem. 264:16608-16612(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kim J.W.;
RT "Identification of a cell proliferation-inducing gene.";
RL Submitted (SEP-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Adipose tissue;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye;
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 [8]
RP INTERACTION WITH KARS.
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 [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-74 AND LYS-374, 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 [11]
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 [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-249, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [14]
RP TISSUE SPECIFICITY, AND VARIANTS HBSL LEU-256; VAL-274; TYR-367;
RP HIS-460; LEU-464; CYS-487; CYS-494 AND GLY-494.
RX PubMed=23643384; DOI=10.1016/j.ajhg.2013.04.006;
RA Taft R.J., Vanderver A., Leventer R.J., Damiani S.A., Simons C.,
RA Grimmond S.M., Miller D., Schmidt J., Lockhart P.J., Pope K., Ru K.,
RA Crawford J., Rosser T., de Coo I.F., Juneja M., Verma I.C.,
RA Prabhakar P., Blaser S., Raiman J., Pouwels P.J., Bevova M.R.,
RA Abbink T.E., van der Knaap M.S., Wolf N.I.;
RT "Mutations in DARS cause hypomyelination with brain stem and spinal
RT cord involvement and leg spasticity.";
RL Am. J. Hum. Genet. 92:774-780(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.
CC -!- CATALYTIC ACTIVITY: ATP + L-aspartate + tRNA(Asp) = AMP +
CC diphosphate + L-aspartyl-tRNA(Asp).
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.
CC -!- INTERACTION:
CC P62993:GRB2; NbExp=2; IntAct=EBI-358730, EBI-401755;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Expression in the developing and adult brain
CC shows similar patterns. Highly expressed in the ventricular and
CC subventricular zones, including hippocampal subfields, the
CC midlateral temporaal cortex and the frontal polar cortex. The
CC cerebellum, cereral cortex, hippocampus, and lateral ventricle
CC show preferential neuronal expression. Expression in the
CC peripheral neurons is evident in the colon.
CC -!- DISEASE: Hypomyelination with brainstem and spinal cord
CC involvement and leg spasticity (HBSL) [MIM:615281]: An autosomal
CC recessive leukoencephalopathy characterized by onset in the first
CC year of life of severe spasticity, mainly affecting the lower
CC limbs and resulting in an inability to achieve independent
CC ambulation. Affected individuals show delayed motor development
CC and nystagmus; some may have mild mental retardation. Brain MRI
CC shows hypomyelination and white matter lesions in the cerebrum,
CC brainstem, cerebellum, and spinal cord. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the class-II aminoacyl-tRNA synthetase
CC family.
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DR EMBL; J05032; AAA35567.1; -; mRNA.
DR EMBL; AY762100; AAX07827.1; -; mRNA.
DR EMBL; BT006710; AAP35356.1; -; mRNA.
DR EMBL; AK222476; BAD96196.1; -; mRNA.
DR EMBL; AK290607; BAF83296.1; -; mRNA.
DR EMBL; CH471058; EAX11617.1; -; Genomic_DNA.
DR EMBL; CH471058; EAX11620.1; -; Genomic_DNA.
DR EMBL; BC000629; AAH00629.1; -; mRNA.
DR EMBL; BC107749; AAI07750.1; -; mRNA.
DR PIR; A34393; SYHUDT.
DR RefSeq; NP_001340.2; NM_001349.2.
DR UniGene; Hs.503787; -.
DR PDB; 4J15; X-ray; 2.24 A; A/B=1-501.
DR PDBsum; 4J15; -.
DR ProteinModelPortal; P14868; -.
DR SMR; P14868; 21-495.
DR IntAct; P14868; 12.
DR MINT; MINT-141082; -.
DR STRING; 9606.ENSP00000264161; -.
DR DrugBank; DB00128; L-Aspartic Acid.
DR PhosphoSite; P14868; -.
DR DMDM; 20178330; -.
DR OGP; P14868; -.
DR REPRODUCTION-2DPAGE; IPI00216951; -.
DR PaxDb; P14868; -.
DR PeptideAtlas; P14868; -.
DR PRIDE; P14868; -.
DR DNASU; 1615; -.
DR Ensembl; ENST00000264161; ENSP00000264161; ENSG00000115866.
DR GeneID; 1615; -.
DR KEGG; hsa:1615; -.
DR UCSC; uc002tux.1; human.
DR CTD; 1615; -.
DR GeneCards; GC02M136686; -.
DR HGNC; HGNC:2678; DARS.
DR HPA; HPA020451; -.
DR HPA; HPA029804; -.
DR HPA; HPA029805; -.
DR MIM; 603084; gene.
DR MIM; 615281; phenotype.
DR neXtProt; NX_P14868; -.
DR PharmGKB; PA27146; -.
DR eggNOG; COG0017; -.
DR HOVERGEN; HBG001028; -.
DR InParanoid; P14868; -.
DR KO; K01876; -.
DR OMA; TNQAIFK; -.
DR OrthoDB; EOG7P5T0X; -.
DR PhylomeDB; P14868; -.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; DARS; human.
DR GeneWiki; DARS_(gene); -.
DR GenomeRNAi; 1615; -.
DR NextBio; 6634; -.
DR PRO; PR:P14868; -.
DR ArrayExpress; P14868; -.
DR Bgee; P14868; -.
DR CleanEx; HS_DARS; -.
DR Genevestigator; P14868; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004046; F:aminoacylase activity; TAS:ProtInc.
DR GO; GO:0004815; F:aspartate-tRNA ligase activity; TAS:ProtInc.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003676; F:nucleic acid binding; IEA:InterPro.
DR GO; GO:0006422; P:aspartyl-tRNA aminoacylation; TAS:ProtInc.
DR GO; GO:0006461; P:protein complex assembly; TAS:ProtInc.
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; IPR004523; Asp-tRNA_synthase.
DR InterPro; IPR002312; Asp/Asn-tRNA-synth_IIb.
DR InterPro; IPR012340; NA-bd_OB-fold.
DR InterPro; IPR004365; NA-bd_OB_tRNA.
DR PANTHER; PTHR22594; PTHR22594; 1.
DR PANTHER; PTHR22594:SF10; PTHR22594:SF10; 1.
DR Pfam; PF00152; tRNA-synt_2; 1.
DR Pfam; PF01336; tRNA_anti-codon; 1.
DR PRINTS; PR01042; TRNASYNTHASP.
DR SUPFAM; SSF50249; SSF50249; 1.
DR TIGRFAMs; TIGR00458; aspS_nondisc; 1.
DR PROSITE; PS50862; AA_TRNA_LIGASE_II; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Aminoacyl-tRNA synthetase; ATP-binding;
KW Complete proteome; Cytoplasm; Disease mutation; Ligase;
KW Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Protein biosynthesis; Reference proteome.
FT CHAIN 1 501 Aspartate--tRNA ligase, cytoplasmic.
FT /FTId=PRO_0000111010.
FT REGION 411 415 Binding site for the 3'-end of tRNA
FT (Potential).
FT MOD_RES 74 74 N6-acetyllysine.
FT MOD_RES 249 249 Phosphoserine.
FT MOD_RES 374 374 N6-acetyllysine.
FT MOD_RES 500 500 Phosphothreonine; by PKA (Potential).
FT VARIANT 256 256 M -> L (in HBSL).
FT /FTId=VAR_070038.
FT VARIANT 274 274 A -> V (in HBSL).
FT /FTId=VAR_070039.
FT VARIANT 367 367 D -> Y (in HBSL).
FT /FTId=VAR_070040.
FT VARIANT 426 426 L -> F (in dbSNP:rs1803165).
FT /FTId=VAR_027611.
FT VARIANT 460 460 R -> H (in HBSL).
FT /FTId=VAR_070041.
FT VARIANT 464 464 P -> L (in HBSL).
FT /FTId=VAR_070042.
FT VARIANT 487 487 R -> C (in HBSL).
FT /FTId=VAR_070043.
FT VARIANT 494 494 R -> C (in HBSL).
FT /FTId=VAR_070044.
FT VARIANT 494 494 R -> G (in HBSL).
FT /FTId=VAR_070045.
FT CONFLICT 5 7 SAS -> TQ (in Ref. 1; AAA35567).
FT CONFLICT 31 31 I -> T (in Ref. 7; AAI07750).
FT CONFLICT 38 38 Q -> H (in Ref. 5; BAD96196).
FT CONFLICT 164 164 A -> Q (in Ref. 1; AAA35567).
FT CONFLICT 312 312 Q -> H (in Ref. 2; AAX07827).
FT CONFLICT 414 414 N -> K (in Ref. 1; AAA35567).
FT CONFLICT 447 447 I -> N (in Ref. 1; AAA35567).
FT HELIX 26 28
FT STRAND 29 31
FT HELIX 48 50
FT HELIX 53 55
FT STRAND 59 72
FT STRAND 75 82
FT STRAND 85 93
FT TURN 94 96
FT HELIX 99 107
FT STRAND 113 122
FT STRAND 134 146
FT HELIX 156 160
FT HELIX 176 181
FT HELIX 183 186
FT HELIX 190 212
FT HELIX 250 259
FT STRAND 264 271
FT STRAND 286 294
FT HELIX 300 320
FT HELIX 322 331
FT STRAND 344 347
FT HELIX 348 357
FT HELIX 370 384
FT STRAND 387 392
FT HELIX 396 398
FT STRAND 407 409
FT STRAND 412 420
FT STRAND 423 431
FT HELIX 435 444
FT HELIX 450 452
FT HELIX 453 457
FT TURN 458 461
FT STRAND 466 472
FT HELIX 473 481
FT HELIX 486 489
SQ SEQUENCE 501 AA; 57136 MW; B181572DF0AF5F94 CRC64;
MPSASASRKS QEKPREIMDA AEDYAKERYG ISSMIQSQEK PDRVLVRVRD LTIQKADEVV
WVRARVHTSR AKGKQCFLVL RQQQFNVQAL VAVGDHASKQ MVKFAANINK ESIVDVEGVV
RKVNQKIGSC TQQDVELHVQ KIYVISLAEP RLPLQLDDAV RPEAEGEEEG RATVNQDTRL
DNRVIDLRTS TSQAVFRLQS GICHLFRETL INKGFVEIQT PKIISAASEG GANVFTVSYF
KNNAYLAQSP QLYKQMCICA DFEKVFSIGP VFRAEDSNTH RHLTEFVGLD IEMAFNYHYH
EVMEEIADTM VQIFKGLQER FQTEIQTVNK QFPCEPFKFL EPTLRLEYCE ALAMLREAGV
EMGDEDDLST PNEKLLGHLV KEKYDTDFYI LDKYPLAVRP FYTMPDPRNP KQSNSYDMFM
RGEEILSGAQ RIHDPQLLTE RALHHGIDLE KIKAYIDSFR FGAPPHAGGG IGLERVTMLF
LGLHNVRQTS MFPRDPKRLT P
//
ID SYDC_HUMAN Reviewed; 501 AA.
AC P14868; A8K3J2; D3DP77; Q2TNI3; Q32Q69; Q53HV4; Q53YC5; Q9BW52;
read moreDT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2002, sequence version 2.
DT 22-JAN-2014, entry version 144.
DE RecName: Full=Aspartate--tRNA ligase, cytoplasmic;
DE EC=6.1.1.12;
DE AltName: Full=Aspartyl-tRNA synthetase;
DE Short=AspRS;
DE AltName: Full=Cell proliferation-inducing gene 40 protein;
GN Name=DARS; ORFNames=PIG40;
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].
RX PubMed=2674137;
RA Jacobo-Molina A., Peterson R., Yang D.C.H.;
RT "cDNA sequence, predicted primary structure, and evolving amphiphilic
RT helix of human aspartyl-tRNA synthetase.";
RL J. Biol. Chem. 264:16608-16612(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kim J.W.;
RT "Identification of a cell proliferation-inducing gene.";
RL Submitted (SEP-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Adipose tissue;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye;
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 [8]
RP INTERACTION WITH KARS.
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 [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-74 AND LYS-374, 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 [11]
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 [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-249, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [14]
RP TISSUE SPECIFICITY, AND VARIANTS HBSL LEU-256; VAL-274; TYR-367;
RP HIS-460; LEU-464; CYS-487; CYS-494 AND GLY-494.
RX PubMed=23643384; DOI=10.1016/j.ajhg.2013.04.006;
RA Taft R.J., Vanderver A., Leventer R.J., Damiani S.A., Simons C.,
RA Grimmond S.M., Miller D., Schmidt J., Lockhart P.J., Pope K., Ru K.,
RA Crawford J., Rosser T., de Coo I.F., Juneja M., Verma I.C.,
RA Prabhakar P., Blaser S., Raiman J., Pouwels P.J., Bevova M.R.,
RA Abbink T.E., van der Knaap M.S., Wolf N.I.;
RT "Mutations in DARS cause hypomyelination with brain stem and spinal
RT cord involvement and leg spasticity.";
RL Am. J. Hum. Genet. 92:774-780(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.
CC -!- CATALYTIC ACTIVITY: ATP + L-aspartate + tRNA(Asp) = AMP +
CC diphosphate + L-aspartyl-tRNA(Asp).
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.
CC -!- INTERACTION:
CC P62993:GRB2; NbExp=2; IntAct=EBI-358730, EBI-401755;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Expression in the developing and adult brain
CC shows similar patterns. Highly expressed in the ventricular and
CC subventricular zones, including hippocampal subfields, the
CC midlateral temporaal cortex and the frontal polar cortex. The
CC cerebellum, cereral cortex, hippocampus, and lateral ventricle
CC show preferential neuronal expression. Expression in the
CC peripheral neurons is evident in the colon.
CC -!- DISEASE: Hypomyelination with brainstem and spinal cord
CC involvement and leg spasticity (HBSL) [MIM:615281]: An autosomal
CC recessive leukoencephalopathy characterized by onset in the first
CC year of life of severe spasticity, mainly affecting the lower
CC limbs and resulting in an inability to achieve independent
CC ambulation. Affected individuals show delayed motor development
CC and nystagmus; some may have mild mental retardation. Brain MRI
CC shows hypomyelination and white matter lesions in the cerebrum,
CC brainstem, cerebellum, and spinal cord. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the class-II aminoacyl-tRNA synthetase
CC family.
CC -----------------------------------------------------------------------
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DR EMBL; J05032; AAA35567.1; -; mRNA.
DR EMBL; AY762100; AAX07827.1; -; mRNA.
DR EMBL; BT006710; AAP35356.1; -; mRNA.
DR EMBL; AK222476; BAD96196.1; -; mRNA.
DR EMBL; AK290607; BAF83296.1; -; mRNA.
DR EMBL; CH471058; EAX11617.1; -; Genomic_DNA.
DR EMBL; CH471058; EAX11620.1; -; Genomic_DNA.
DR EMBL; BC000629; AAH00629.1; -; mRNA.
DR EMBL; BC107749; AAI07750.1; -; mRNA.
DR PIR; A34393; SYHUDT.
DR RefSeq; NP_001340.2; NM_001349.2.
DR UniGene; Hs.503787; -.
DR PDB; 4J15; X-ray; 2.24 A; A/B=1-501.
DR PDBsum; 4J15; -.
DR ProteinModelPortal; P14868; -.
DR SMR; P14868; 21-495.
DR IntAct; P14868; 12.
DR MINT; MINT-141082; -.
DR STRING; 9606.ENSP00000264161; -.
DR DrugBank; DB00128; L-Aspartic Acid.
DR PhosphoSite; P14868; -.
DR DMDM; 20178330; -.
DR OGP; P14868; -.
DR REPRODUCTION-2DPAGE; IPI00216951; -.
DR PaxDb; P14868; -.
DR PeptideAtlas; P14868; -.
DR PRIDE; P14868; -.
DR DNASU; 1615; -.
DR Ensembl; ENST00000264161; ENSP00000264161; ENSG00000115866.
DR GeneID; 1615; -.
DR KEGG; hsa:1615; -.
DR UCSC; uc002tux.1; human.
DR CTD; 1615; -.
DR GeneCards; GC02M136686; -.
DR HGNC; HGNC:2678; DARS.
DR HPA; HPA020451; -.
DR HPA; HPA029804; -.
DR HPA; HPA029805; -.
DR MIM; 603084; gene.
DR MIM; 615281; phenotype.
DR neXtProt; NX_P14868; -.
DR PharmGKB; PA27146; -.
DR eggNOG; COG0017; -.
DR HOVERGEN; HBG001028; -.
DR InParanoid; P14868; -.
DR KO; K01876; -.
DR OMA; TNQAIFK; -.
DR OrthoDB; EOG7P5T0X; -.
DR PhylomeDB; P14868; -.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; DARS; human.
DR GeneWiki; DARS_(gene); -.
DR GenomeRNAi; 1615; -.
DR NextBio; 6634; -.
DR PRO; PR:P14868; -.
DR ArrayExpress; P14868; -.
DR Bgee; P14868; -.
DR CleanEx; HS_DARS; -.
DR Genevestigator; P14868; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004046; F:aminoacylase activity; TAS:ProtInc.
DR GO; GO:0004815; F:aspartate-tRNA ligase activity; TAS:ProtInc.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003676; F:nucleic acid binding; IEA:InterPro.
DR GO; GO:0006422; P:aspartyl-tRNA aminoacylation; TAS:ProtInc.
DR GO; GO:0006461; P:protein complex assembly; TAS:ProtInc.
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; IPR004523; Asp-tRNA_synthase.
DR InterPro; IPR002312; Asp/Asn-tRNA-synth_IIb.
DR InterPro; IPR012340; NA-bd_OB-fold.
DR InterPro; IPR004365; NA-bd_OB_tRNA.
DR PANTHER; PTHR22594; PTHR22594; 1.
DR PANTHER; PTHR22594:SF10; PTHR22594:SF10; 1.
DR Pfam; PF00152; tRNA-synt_2; 1.
DR Pfam; PF01336; tRNA_anti-codon; 1.
DR PRINTS; PR01042; TRNASYNTHASP.
DR SUPFAM; SSF50249; SSF50249; 1.
DR TIGRFAMs; TIGR00458; aspS_nondisc; 1.
DR PROSITE; PS50862; AA_TRNA_LIGASE_II; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Aminoacyl-tRNA synthetase; ATP-binding;
KW Complete proteome; Cytoplasm; Disease mutation; Ligase;
KW Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Protein biosynthesis; Reference proteome.
FT CHAIN 1 501 Aspartate--tRNA ligase, cytoplasmic.
FT /FTId=PRO_0000111010.
FT REGION 411 415 Binding site for the 3'-end of tRNA
FT (Potential).
FT MOD_RES 74 74 N6-acetyllysine.
FT MOD_RES 249 249 Phosphoserine.
FT MOD_RES 374 374 N6-acetyllysine.
FT MOD_RES 500 500 Phosphothreonine; by PKA (Potential).
FT VARIANT 256 256 M -> L (in HBSL).
FT /FTId=VAR_070038.
FT VARIANT 274 274 A -> V (in HBSL).
FT /FTId=VAR_070039.
FT VARIANT 367 367 D -> Y (in HBSL).
FT /FTId=VAR_070040.
FT VARIANT 426 426 L -> F (in dbSNP:rs1803165).
FT /FTId=VAR_027611.
FT VARIANT 460 460 R -> H (in HBSL).
FT /FTId=VAR_070041.
FT VARIANT 464 464 P -> L (in HBSL).
FT /FTId=VAR_070042.
FT VARIANT 487 487 R -> C (in HBSL).
FT /FTId=VAR_070043.
FT VARIANT 494 494 R -> C (in HBSL).
FT /FTId=VAR_070044.
FT VARIANT 494 494 R -> G (in HBSL).
FT /FTId=VAR_070045.
FT CONFLICT 5 7 SAS -> TQ (in Ref. 1; AAA35567).
FT CONFLICT 31 31 I -> T (in Ref. 7; AAI07750).
FT CONFLICT 38 38 Q -> H (in Ref. 5; BAD96196).
FT CONFLICT 164 164 A -> Q (in Ref. 1; AAA35567).
FT CONFLICT 312 312 Q -> H (in Ref. 2; AAX07827).
FT CONFLICT 414 414 N -> K (in Ref. 1; AAA35567).
FT CONFLICT 447 447 I -> N (in Ref. 1; AAA35567).
FT HELIX 26 28
FT STRAND 29 31
FT HELIX 48 50
FT HELIX 53 55
FT STRAND 59 72
FT STRAND 75 82
FT STRAND 85 93
FT TURN 94 96
FT HELIX 99 107
FT STRAND 113 122
FT STRAND 134 146
FT HELIX 156 160
FT HELIX 176 181
FT HELIX 183 186
FT HELIX 190 212
FT HELIX 250 259
FT STRAND 264 271
FT STRAND 286 294
FT HELIX 300 320
FT HELIX 322 331
FT STRAND 344 347
FT HELIX 348 357
FT HELIX 370 384
FT STRAND 387 392
FT HELIX 396 398
FT STRAND 407 409
FT STRAND 412 420
FT STRAND 423 431
FT HELIX 435 444
FT HELIX 450 452
FT HELIX 453 457
FT TURN 458 461
FT STRAND 466 472
FT HELIX 473 481
FT HELIX 486 489
SQ SEQUENCE 501 AA; 57136 MW; B181572DF0AF5F94 CRC64;
MPSASASRKS QEKPREIMDA AEDYAKERYG ISSMIQSQEK PDRVLVRVRD LTIQKADEVV
WVRARVHTSR AKGKQCFLVL RQQQFNVQAL VAVGDHASKQ MVKFAANINK ESIVDVEGVV
RKVNQKIGSC TQQDVELHVQ KIYVISLAEP RLPLQLDDAV RPEAEGEEEG RATVNQDTRL
DNRVIDLRTS TSQAVFRLQS GICHLFRETL INKGFVEIQT PKIISAASEG GANVFTVSYF
KNNAYLAQSP QLYKQMCICA DFEKVFSIGP VFRAEDSNTH RHLTEFVGLD IEMAFNYHYH
EVMEEIADTM VQIFKGLQER FQTEIQTVNK QFPCEPFKFL EPTLRLEYCE ALAMLREAGV
EMGDEDDLST PNEKLLGHLV KEKYDTDFYI LDKYPLAVRP FYTMPDPRNP KQSNSYDMFM
RGEEILSGAQ RIHDPQLLTE RALHHGIDLE KIKAYIDSFR FGAPPHAGGG IGLERVTMLF
LGLHNVRQTS MFPRDPKRLT P
//
MIM
603084
*RECORD*
*FIELD* NO
603084
*FIELD* TI
*603084 ASPARTYL-tRNA SYNTHETASE; DARS
*FIELD* TX
DESCRIPTION
The DARS gene encodes cytoplasmic aspartyl-tRNA synthetase.
read moreAminoacyl-tRNA synthetases constitute a family of enzymes catalyzing the
specific aminoacylation of cognate tRNA in the initial step of
ribosome-dependent protein biosynthesis. Mammalian synthetases differ
from those of prokaryotes and lower eukaryotes in that they associate as
multienzyme complexes (summary by Jacobo-Molina et al., 1989).
CLONING
By screening a HeLa cell cDNA library with a rat Dars cDNA cloned by
them, Jacobo-Molina et al. (1989) isolated a cDNA encoding DARS. The
predicted DARS protein has 500 amino acids and a calculated molecular
mass of 57,000 Da. The human DARS protein has 95% amino acid identity
with rat Dars and shares unevenly distributed identity with yeast
aspartyl-tRNA synthetase, with 69% identity at the C-terminal half and
46% identity at the N-terminal half. The authors discussed several
potential functional domains in the DAR protein, including a region of
conserved lysine residues which is also found in bacterial and yeast
synthetases and is likely to be the binding site for the 3-prime end of
tRNA, a nucleotide triphosphate-binding motif, an ATP-binding motif with
strong similarity to that present in E. coli alanyl-tRNA synthetase, and
a cyclic AMP-dependent protein kinase phosphorylation site.
Jacobo-Molina et al. (1989) predicted a neutral amphiphilic helix at the
N-terminal end of the DARS protein and stated that this structure does
not occur in other known synthetases from bacteria, yeast, and higher
organisms.
Based on a curated set of publicly available data, Taft et al. (2013)
found that Dars is diffusely localized in the cytoplasm and broadly
expressed across tissue types, including the central nervous system. In
mice, Dars showed specific expression in neurons of the hippocampus, the
dentate gyrus, and the molecular layer of the cerebellum. DARS
expression in the developing and adult human brain showed a similar
pattern, with preferential immunostaining of neurons in the cerebellum,
cerebral cortex, hippocampus, and lateral ventricle. In addition,
staining of peripheral neurons was evident in the colon.
MAPPING
Gross (2012) mapped the DARS gene to chromosome 2q21.3 based on an
alignment of the DARS sequence (GenBank GENBANK BC000629) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
In 10 patients from 7 unrelated families of various origins with
hypomyelination with brainstem and spinal cord involvement and
spasticity (HBSL; 615281), Taft et al. (2013) identified homozygous or
compound heterozygous mutations in the DARS gene (see, e.g.,
603084.0001-603084.0006). The mutations, which were found by exome
sequencing, occurred in the 3-prime third of DARS, which corresponds to
the C-terminal active-site domain of the enzyme. The phenotype was
characterized by onset in the first year of life of severe spasticity,
mainly affecting the lower limbs and resulting in an inability to
achieve independent ambulation. Affected individuals showed delayed
motor development and nystagmus; 4 patients had mild mental retardation.
Brain MRI showed hypomyelination and white matter lesions in the
cerebrum, brainstem, cerebellum, and spinal cord. Taft et al. (2013)
noted the phenotypic similarities to leukoencephalopathy with brainstem
and spinal cord involvement and lactate elevation (LBSL; 611105), which
is caused by mutation in the DARS2 gene (610956).
*FIELD* AV
.0001
HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY
DARS, ASP367TYR
In an Australian boy with hypomyelination with brainstem and spinal cord
involvement and leg spasticity (HBSL; 615281), Taft et al. (2013)
identified compound heterozygous mutations in the DARS gene: a c.1099G-T
transversion in exon 11, resulting in an asp367-to-tyr (D367Y)
substitution, and a c.821C-T transition in exon 10, resulting in an
ala274-to-val (A274V; dbSNP rs112205661; 603084.0002) substitution. Both
mutations occurred at conserved residues in the active-site pocket. The
mutations, which were identified by whole-genome sequencing and
confirmed by Sanger sequencing, segregated with the disorder in the
family. The D367Y mutation was not found in several large control
databases, while the A274V mutation was found at a frequency of 0.001%.
.0002
HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY
DARS, ALA274VAL (dbSNP rs112205661)
See 603084.0001 and Taft et al. (2013).
.0003
HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY
DARS, MET256LEU
In 2 sibs and 2 additional unrelated patients of Indian or Pakistani
origin with HBSL (615281), Taft et al. (2013) identified a homozygous
c.766A-C transversion in exon 9 of the DARS gene, resulting in a
met256-to-leu (M256L) substitution at a conserved residue. The mutation,
which was initially found by whole-exome sequencing, was not present in
several large databases. Molecular modeling suggested that the mutation
may alter an amino acid likely to be fundamental to chains supporting
the active site.
.0004
HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY
DARS, ARG487CYS
In an Indian boy with HBSL (615281), Taft et al. (2013) identified a
homozygous c.1459C-T transition in exon 16 of the DARS gene, resulting
in an arg487-to-cys (R487C) substitution at a conserved residue. The
mutation, which was found by whole-exome sequencing, was not present in
several large databases. Molecular modeling suggested that the mutation
is likely to destabilize the tRNA-protein interaction.
.0005
HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY
DARS, ARG460HIS
In 2 sisters from the U.S. with HBSL (615281), Taft et al. (2013)
identified compound heterozygous mutations in the DARS gene: a c.1379G-A
transition in exon 15, resulting in an arg460-to-his (R460H)
substitution at a conserved residue, and a c.1480C-T transition in exon
16, resulting in an arg494-to-gly (R494G; dbSNP rs147077598;
603084.0006) substitution at a conserved residue. Molecular modeling
suggested that the R460H mutation may alter an amino acid likely to be
fundamental to chains supporting the active site, and that the R494G
mutation is likely to destabilize the tRNA-protein interaction. The
R460H mutation was not found in several large control databases, while
the R494G mutation was found at a frequency of 0.001%.
.0006
HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY
DARS, ARG494GLY (dbSNP rs147077598)
See 603084.0005 and Taft et al. (2013).
*FIELD* RF
1. Gross, M. B.: Personal Communication. Baltimore, Md. 6/19/2012.
2. Jacobo-Molina, A.; Peterson, R.; Yang, D. C. H.: cDNA sequence,
predicted primary structure, and evolving amphiphilic helix of human
aspartyl-tRNA synthetase. J. Biol. Chem. 264: 16608-16612, 1989.
3. Taft, R. J.; Vanderver, A.; Leventer, R. J.; Damiani, S. A.; Simons,
C.; Grimmond, S. M.; Miller, D.; Schmidt, J.; Lockhart, P. J.; Pope,
K.; Ru, K.; Crawford, J.; and 12 others: Mutations in DARS cause
hypomyelination with brain stem and spinal cord involvement and leg
spasticity. Am. J. Hum. Genet. 92: 774-780, 2013.
*FIELD* CN
Cassandra L. Kniffin - updated: 6/18/2013
Matthew B. Gross - updated: 6/19/2012
*FIELD* CD
Sheryl A. Jankowski: 10/2/1998
*FIELD* ED
carol: 06/21/2013
ckniffin: 6/18/2013
mgross: 6/19/2012
carol: 6/18/2012
carol: 6/14/2012
psherman: 10/2/1998
*RECORD*
*FIELD* NO
603084
*FIELD* TI
*603084 ASPARTYL-tRNA SYNTHETASE; DARS
*FIELD* TX
DESCRIPTION
The DARS gene encodes cytoplasmic aspartyl-tRNA synthetase.
read moreAminoacyl-tRNA synthetases constitute a family of enzymes catalyzing the
specific aminoacylation of cognate tRNA in the initial step of
ribosome-dependent protein biosynthesis. Mammalian synthetases differ
from those of prokaryotes and lower eukaryotes in that they associate as
multienzyme complexes (summary by Jacobo-Molina et al., 1989).
CLONING
By screening a HeLa cell cDNA library with a rat Dars cDNA cloned by
them, Jacobo-Molina et al. (1989) isolated a cDNA encoding DARS. The
predicted DARS protein has 500 amino acids and a calculated molecular
mass of 57,000 Da. The human DARS protein has 95% amino acid identity
with rat Dars and shares unevenly distributed identity with yeast
aspartyl-tRNA synthetase, with 69% identity at the C-terminal half and
46% identity at the N-terminal half. The authors discussed several
potential functional domains in the DAR protein, including a region of
conserved lysine residues which is also found in bacterial and yeast
synthetases and is likely to be the binding site for the 3-prime end of
tRNA, a nucleotide triphosphate-binding motif, an ATP-binding motif with
strong similarity to that present in E. coli alanyl-tRNA synthetase, and
a cyclic AMP-dependent protein kinase phosphorylation site.
Jacobo-Molina et al. (1989) predicted a neutral amphiphilic helix at the
N-terminal end of the DARS protein and stated that this structure does
not occur in other known synthetases from bacteria, yeast, and higher
organisms.
Based on a curated set of publicly available data, Taft et al. (2013)
found that Dars is diffusely localized in the cytoplasm and broadly
expressed across tissue types, including the central nervous system. In
mice, Dars showed specific expression in neurons of the hippocampus, the
dentate gyrus, and the molecular layer of the cerebellum. DARS
expression in the developing and adult human brain showed a similar
pattern, with preferential immunostaining of neurons in the cerebellum,
cerebral cortex, hippocampus, and lateral ventricle. In addition,
staining of peripheral neurons was evident in the colon.
MAPPING
Gross (2012) mapped the DARS gene to chromosome 2q21.3 based on an
alignment of the DARS sequence (GenBank GENBANK BC000629) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
In 10 patients from 7 unrelated families of various origins with
hypomyelination with brainstem and spinal cord involvement and
spasticity (HBSL; 615281), Taft et al. (2013) identified homozygous or
compound heterozygous mutations in the DARS gene (see, e.g.,
603084.0001-603084.0006). The mutations, which were found by exome
sequencing, occurred in the 3-prime third of DARS, which corresponds to
the C-terminal active-site domain of the enzyme. The phenotype was
characterized by onset in the first year of life of severe spasticity,
mainly affecting the lower limbs and resulting in an inability to
achieve independent ambulation. Affected individuals showed delayed
motor development and nystagmus; 4 patients had mild mental retardation.
Brain MRI showed hypomyelination and white matter lesions in the
cerebrum, brainstem, cerebellum, and spinal cord. Taft et al. (2013)
noted the phenotypic similarities to leukoencephalopathy with brainstem
and spinal cord involvement and lactate elevation (LBSL; 611105), which
is caused by mutation in the DARS2 gene (610956).
*FIELD* AV
.0001
HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY
DARS, ASP367TYR
In an Australian boy with hypomyelination with brainstem and spinal cord
involvement and leg spasticity (HBSL; 615281), Taft et al. (2013)
identified compound heterozygous mutations in the DARS gene: a c.1099G-T
transversion in exon 11, resulting in an asp367-to-tyr (D367Y)
substitution, and a c.821C-T transition in exon 10, resulting in an
ala274-to-val (A274V; dbSNP rs112205661; 603084.0002) substitution. Both
mutations occurred at conserved residues in the active-site pocket. The
mutations, which were identified by whole-genome sequencing and
confirmed by Sanger sequencing, segregated with the disorder in the
family. The D367Y mutation was not found in several large control
databases, while the A274V mutation was found at a frequency of 0.001%.
.0002
HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY
DARS, ALA274VAL (dbSNP rs112205661)
See 603084.0001 and Taft et al. (2013).
.0003
HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY
DARS, MET256LEU
In 2 sibs and 2 additional unrelated patients of Indian or Pakistani
origin with HBSL (615281), Taft et al. (2013) identified a homozygous
c.766A-C transversion in exon 9 of the DARS gene, resulting in a
met256-to-leu (M256L) substitution at a conserved residue. The mutation,
which was initially found by whole-exome sequencing, was not present in
several large databases. Molecular modeling suggested that the mutation
may alter an amino acid likely to be fundamental to chains supporting
the active site.
.0004
HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY
DARS, ARG487CYS
In an Indian boy with HBSL (615281), Taft et al. (2013) identified a
homozygous c.1459C-T transition in exon 16 of the DARS gene, resulting
in an arg487-to-cys (R487C) substitution at a conserved residue. The
mutation, which was found by whole-exome sequencing, was not present in
several large databases. Molecular modeling suggested that the mutation
is likely to destabilize the tRNA-protein interaction.
.0005
HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY
DARS, ARG460HIS
In 2 sisters from the U.S. with HBSL (615281), Taft et al. (2013)
identified compound heterozygous mutations in the DARS gene: a c.1379G-A
transition in exon 15, resulting in an arg460-to-his (R460H)
substitution at a conserved residue, and a c.1480C-T transition in exon
16, resulting in an arg494-to-gly (R494G; dbSNP rs147077598;
603084.0006) substitution at a conserved residue. Molecular modeling
suggested that the R460H mutation may alter an amino acid likely to be
fundamental to chains supporting the active site, and that the R494G
mutation is likely to destabilize the tRNA-protein interaction. The
R460H mutation was not found in several large control databases, while
the R494G mutation was found at a frequency of 0.001%.
.0006
HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY
DARS, ARG494GLY (dbSNP rs147077598)
See 603084.0005 and Taft et al. (2013).
*FIELD* RF
1. Gross, M. B.: Personal Communication. Baltimore, Md. 6/19/2012.
2. Jacobo-Molina, A.; Peterson, R.; Yang, D. C. H.: cDNA sequence,
predicted primary structure, and evolving amphiphilic helix of human
aspartyl-tRNA synthetase. J. Biol. Chem. 264: 16608-16612, 1989.
3. Taft, R. J.; Vanderver, A.; Leventer, R. J.; Damiani, S. A.; Simons,
C.; Grimmond, S. M.; Miller, D.; Schmidt, J.; Lockhart, P. J.; Pope,
K.; Ru, K.; Crawford, J.; and 12 others: Mutations in DARS cause
hypomyelination with brain stem and spinal cord involvement and leg
spasticity. Am. J. Hum. Genet. 92: 774-780, 2013.
*FIELD* CN
Cassandra L. Kniffin - updated: 6/18/2013
Matthew B. Gross - updated: 6/19/2012
*FIELD* CD
Sheryl A. Jankowski: 10/2/1998
*FIELD* ED
carol: 06/21/2013
ckniffin: 6/18/2013
mgross: 6/19/2012
carol: 6/18/2012
carol: 6/14/2012
psherman: 10/2/1998
MIM
615281
*RECORD*
*FIELD* NO
615281
*FIELD* TI
#615281 HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY; HBSL
read more;;ASPARTYL-tRNA SYNTHETASE DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because hypomyelination with
brainstem and spinal cord involvement and leg spasticity (HBSL) is
caused by homozygous or compound heterozygous mutation in the DARS gene
(603084) on chromosome 2q21.3.
DESCRIPTION
Hypomyelination with brainstem and spinal cord involvement and leg
spasticity is an autosomal recessive leukoencephalopathy characterized
by onset in the first year of life of severe spasticity, mainly
affecting the lower limbs and resulting in an inability to achieve
independent ambulation. Affected individuals show delayed motor
development and nystagmus; some may have mild mental retardation. Brain
MRI shows hypomyelination and white matter lesions in the cerebrum,
brainstem, cerebellum, and spinal cord (summary by Taft et al., 2013).
CLINICAL FEATURES
Taft et al. (2013) reported 10 patients from 7 unrelated families with
severe lower limb spasticity associated with leukoencephalopathy. The
families were from various countries, including Pakistan, India,
Australia, the U.K., and the U.S., and some were identified from large
biorepositories of patients with white matter disorders. Most patients
had normal early psychomotor development, but 3 had delayed motor
development. Between 4 and 12 months of age, all patients developed
progressive motor dysfunction, mainly spasticity affecting the lower
limbs more than the upper limbs, as well as axial hypotonia and loss of
motor milestones. None achieved independent walking, but some patients
were able to walk with support. Other features included nystagmus,
hyperreflexia, and extensor plantar responses. Four patients showed mild
mental retardation and 3 had pallor of the optic discs. Brain MRI showed
extensive white matter abnormalities involving the supratentorial white
matter, brainstem, cerebellar peduncles, and dorsal columns and lateral
corticospinal tracts of the spinal cord. Taft et al. (2013) noted the
phenotypic similarities to leukoencephalopathy with brainstem and spinal
cord involvement and lactate elevation (LBSL; 611105), which is caused
by mutation in the DARS2 gene (610956).
INHERITANCE
The transmission pattern in the families with HBSL reported by Taft et
al. (2013) was consistent with autosomal recessive inheritance.
MOLECULAR GENETICS
In 10 patients from 7 unrelated families of various origins with
hypomyelination with brainstem and spinal cord involvement and
spasticity, Taft et al. (2013) identified homozygous or compound
heterozygous mutations in the DARS gene (see, e.g.,
603084.0001-603084.0006). The mutations, which were found by exome
sequencing, occurred in the 3-prime third of DARS, which corresponds to
the C-terminal active-site domain of the enzyme.
*FIELD* RF
1. Taft, R. J.; Vanderver, A.; Leventer, R. J.; Damiani, S. A.; Simons,
C.; Grimmond, S. M.; Miller, D.; Schmidt, J.; Lockhart, P. J.; Pope,
K.; Ru, K.; Crawford, J.; and 12 others: Mutations in DARS cause
hypomyelination with brain stem and spinal cord involvement and leg
spasticity. Am. J. Hum. Genet. 92: 774-780, 2013.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Nystagmus;
Pallor of the optic disks (in some patients)
NEUROLOGIC:
[Central nervous system];
Delayed motor development;
Mental retardation, mild (in some patients);
Spasticity, lower limbs greater than upper limbs;
Hyperreflexia;
Extensor plantar responses;
Independent walking never achieved;
Axial hypotonia;
Leukoencephalopathy;
White matter lesions in the supratentorial white matter, brainstem,
cerebellum, and spinal cord;
Hypomyelination;
Thinning of the corpus callosum
MISCELLANEOUS:
Onset in first year of life;
Progressive disorder
MOLECULAR BASIS:
Caused by mutation in the aspartyl-tRNA synthetase gene (DARS, 603084.0001)
*FIELD* CD
Cassandra L. Kniffin: 6/18/2013
*FIELD* ED
joanna: 07/25/2013
ckniffin: 6/18/2013
*FIELD* CD
Cassandra L. Kniffin: 6/17/2013
*FIELD* ED
carol: 06/21/2013
ckniffin: 6/18/2013
*RECORD*
*FIELD* NO
615281
*FIELD* TI
#615281 HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG
SPASTICITY; HBSL
read more;;ASPARTYL-tRNA SYNTHETASE DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because hypomyelination with
brainstem and spinal cord involvement and leg spasticity (HBSL) is
caused by homozygous or compound heterozygous mutation in the DARS gene
(603084) on chromosome 2q21.3.
DESCRIPTION
Hypomyelination with brainstem and spinal cord involvement and leg
spasticity is an autosomal recessive leukoencephalopathy characterized
by onset in the first year of life of severe spasticity, mainly
affecting the lower limbs and resulting in an inability to achieve
independent ambulation. Affected individuals show delayed motor
development and nystagmus; some may have mild mental retardation. Brain
MRI shows hypomyelination and white matter lesions in the cerebrum,
brainstem, cerebellum, and spinal cord (summary by Taft et al., 2013).
CLINICAL FEATURES
Taft et al. (2013) reported 10 patients from 7 unrelated families with
severe lower limb spasticity associated with leukoencephalopathy. The
families were from various countries, including Pakistan, India,
Australia, the U.K., and the U.S., and some were identified from large
biorepositories of patients with white matter disorders. Most patients
had normal early psychomotor development, but 3 had delayed motor
development. Between 4 and 12 months of age, all patients developed
progressive motor dysfunction, mainly spasticity affecting the lower
limbs more than the upper limbs, as well as axial hypotonia and loss of
motor milestones. None achieved independent walking, but some patients
were able to walk with support. Other features included nystagmus,
hyperreflexia, and extensor plantar responses. Four patients showed mild
mental retardation and 3 had pallor of the optic discs. Brain MRI showed
extensive white matter abnormalities involving the supratentorial white
matter, brainstem, cerebellar peduncles, and dorsal columns and lateral
corticospinal tracts of the spinal cord. Taft et al. (2013) noted the
phenotypic similarities to leukoencephalopathy with brainstem and spinal
cord involvement and lactate elevation (LBSL; 611105), which is caused
by mutation in the DARS2 gene (610956).
INHERITANCE
The transmission pattern in the families with HBSL reported by Taft et
al. (2013) was consistent with autosomal recessive inheritance.
MOLECULAR GENETICS
In 10 patients from 7 unrelated families of various origins with
hypomyelination with brainstem and spinal cord involvement and
spasticity, Taft et al. (2013) identified homozygous or compound
heterozygous mutations in the DARS gene (see, e.g.,
603084.0001-603084.0006). The mutations, which were found by exome
sequencing, occurred in the 3-prime third of DARS, which corresponds to
the C-terminal active-site domain of the enzyme.
*FIELD* RF
1. Taft, R. J.; Vanderver, A.; Leventer, R. J.; Damiani, S. A.; Simons,
C.; Grimmond, S. M.; Miller, D.; Schmidt, J.; Lockhart, P. J.; Pope,
K.; Ru, K.; Crawford, J.; and 12 others: Mutations in DARS cause
hypomyelination with brain stem and spinal cord involvement and leg
spasticity. Am. J. Hum. Genet. 92: 774-780, 2013.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Nystagmus;
Pallor of the optic disks (in some patients)
NEUROLOGIC:
[Central nervous system];
Delayed motor development;
Mental retardation, mild (in some patients);
Spasticity, lower limbs greater than upper limbs;
Hyperreflexia;
Extensor plantar responses;
Independent walking never achieved;
Axial hypotonia;
Leukoencephalopathy;
White matter lesions in the supratentorial white matter, brainstem,
cerebellum, and spinal cord;
Hypomyelination;
Thinning of the corpus callosum
MISCELLANEOUS:
Onset in first year of life;
Progressive disorder
MOLECULAR BASIS:
Caused by mutation in the aspartyl-tRNA synthetase gene (DARS, 603084.0001)
*FIELD* CD
Cassandra L. Kniffin: 6/18/2013
*FIELD* ED
joanna: 07/25/2013
ckniffin: 6/18/2013
*FIELD* CD
Cassandra L. Kniffin: 6/17/2013
*FIELD* ED
carol: 06/21/2013
ckniffin: 6/18/2013