Full text data of AARS
AARS
[Confidence: low (only semi-automatic identification from reviews)]
Alanine--tRNA ligase, cytoplasmic; 6.1.1.7 (Alanyl-tRNA synthetase; AlaRS; Renal carcinoma antigen NY-REN-42)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Alanine--tRNA ligase, cytoplasmic; 6.1.1.7 (Alanyl-tRNA synthetase; AlaRS; Renal carcinoma antigen NY-REN-42)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P49588
ID SYAC_HUMAN Reviewed; 968 AA.
AC P49588; A6NF14; Q53GV7; Q96FA0;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 03-OCT-2006, sequence version 2.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=Alanine--tRNA ligase, cytoplasmic;
DE EC=6.1.1.7;
DE AltName: Full=Alanyl-tRNA synthetase;
DE Short=AlaRS;
DE AltName: Full=Renal carcinoma antigen NY-REN-42;
GN Name=AARS;
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=7654687; DOI=10.1021/bi00033a004;
RA Shiba K., Ripmaster T.L., Suzuki N., Nichols R., Plotz P., Noda T.,
RA Schimmel P.;
RT "Human alanyl-tRNA synthetase: conservation in evolution of catalytic
RT core and microhelix recognition.";
RL Biochemistry 34:10340-10349(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 [3]
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 [4]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [6]
RP PROTEIN SEQUENCE OF 1-11; 304-320 AND 684-695, ACETYLATION AT MET-1,
RP AND MASS SPECTROMETRY.
RC TISSUE=Osteosarcoma;
RA Bienvenut W.V., Glen H., Brunton V.G., Frame M.C.;
RL Submitted (JUL-2007) to UniProtKB.
RN [7]
RP IDENTIFICATION AS A RENAL CANCER ANTIGEN.
RC TISSUE=Renal cell carcinoma;
RX PubMed=10508479;
RX DOI=10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5;
RA Scanlan M.J., Gordan J.D., Williamson B., Stockert E., Bander N.H.,
RA Jongeneel C.V., Gure A.O., Jaeger D., Jaeger E., Knuth A., Chen Y.-T.,
RA Old L.J.;
RT "Antigens recognized by autologous antibody in patients with renal-
RT cell carcinoma.";
RL Int. J. Cancer 83:456-464(1999).
RN [8]
RP ISGYLATION.
RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132;
RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J.,
RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.;
RT "Proteomic identification of proteins conjugated to ISG15 in mouse and
RT human cells.";
RL Biochem. Biophys. Res. Commun. 336:496-506(2005).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-555, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, 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 [11]
RP DOMAIN EXCHANGE EXPERIMENTS.
RX PubMed=19661429; DOI=10.1126/science.1174343;
RA Guo M., Chong Y.E., Beebe K., Shapiro R., Yang X.-L., Schimmel P.;
RT "The C-Ala domain brings together editing and aminoacylation functions
RT on one tRNA.";
RL Science 325:744-747(2009).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-19 AND LYS-876, 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 [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-399, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [14]
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 [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, 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 [16]
RP VARIANT CMT2N HIS-329.
RX PubMed=20045102; DOI=10.1016/j.ajhg.2009.12.005;
RA Latour P., Thauvin-Robinet C., Baudelet-Mery C., Soichot P., Cusin V.,
RA Faivre L., Locatelli M.C., Mayencon M., Sarcey A., Broussolle E.,
RA Camu W., David A., Rousson R.;
RT "A major determinant for binding and aminoacylation of tRNA(Ala) in
RT cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal
RT Charcot-Marie-Tooth disease.";
RL Am. J. Hum. Genet. 86:77-82(2010).
RN [17]
RP VARIANT CMT2N TYR-71.
RX PubMed=22206013; DOI=10.1371/journal.pone.0029393;
RA Lin K.P., Soong B.W., Yang C.C., Huang L.W., Chang M.H., Lee I.H.,
RA Antonellis A., Lee Y.C.;
RT "The mutational spectrum in a cohort of Charcot-Marie-Tooth disease
RT type 2 among the Han Chinese in Taiwan.";
RL PLoS ONE 6:E29393-E29393(2011).
RN [18]
RP VARIANT CMT2N HIS-329, AND CHARACTERIZATION OF VARIANT CMT2N HIS-329.
RX PubMed=22009580; DOI=10.1002/humu.21635;
RA McLaughlin H.M., Sakaguchi R., Giblin W., Wilson T.E., Biesecker L.,
RA Lupski J.R., Talbot K., Vance J.M., Zuchner S., Lee Y.C.,
RA Kennerson M., Hou Y.M., Nicholson G., Antonellis A.;
RT "A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation
RT in patients with Charcot-Marie-Tooth disease type 2N (CMT2N).";
RL Hum. Mutat. 33:244-253(2012).
CC -!- FUNCTION: Catalyzes the attachment of alanine to tRNA(Ala) in a
CC two-step reaction: alanine is first activated by ATP to form Ala-
CC AMP and then transferred to the acceptor end of tRNA(Ala). Also
CC edits incorrectly charged tRNA(Ala) via its editing domain (By
CC similarity).
CC -!- CATALYTIC ACTIVITY: ATP + L-alanine + tRNA(Ala) = AMP +
CC diphosphate + L-alanyl-tRNA(Ala).
CC -!- COFACTOR: Binds 1 zinc ion per subunit (Potential).
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity).
CC -!- DOMAIN: Consists of three domains; the N-terminal catalytic
CC domain, the editing domain and the C-terminal C-Ala domain. The
CC editing domain removes incorrectly charged amino acids, while the
CC C-Ala domain, along with tRNA(Ala), serves as a bridge to
CC cooperatively bring together the editing and aminoacylation
CC centers thus stimulating deacylation of misacylated tRNAs (By
CC similarity).
CC -!- DOMAIN: The C-terminal C-Ala domain (residues 756 to 968), along
CC with tRNA(Ala), serves as a bridge to cooperatively bring together
CC the editing and aminoacylation centers thus stimulating
CC deacylation of misacylated tRNAs. The human domain can be used in
CC vitro to replace the corresponding domain in E.coli.
CC -!- PTM: ISGylated.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2N (CMT2N) [MIM:613287]: An
CC axonal form of Charcot-Marie-Tooth disease, a disorder of the
CC peripheral nervous system, characterized by progressive weakness
CC and atrophy, initially of the peroneal muscles and later of the
CC distal muscles of the arms. Charcot-Marie-Tooth disease is
CC classified in two main groups on the basis of electrophysiologic
CC properties and histopathology: primary peripheral demyelinating
CC neuropathies (designated CMT1 when they are dominantly inherited)
CC and primary peripheral axonal neuropathies (CMT2). Neuropathies of
CC the CMT2 group are characterized by signs of axonal degeneration
CC in the absence of obvious myelin alterations, normal or slightly
CC reduced nerve conduction velocities, and progressive distal muscle
CC weakness and atrophy. Nerve conduction velocities are normal or
CC slightly reduced. Note=The disease is caused by mutations
CC 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; D32050; BAA06808.1; -; mRNA.
DR EMBL; AK222824; BAD96544.1; -; mRNA.
DR EMBL; AC012184; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471241; EAW51839.1; -; Genomic_DNA.
DR EMBL; BC011451; AAH11451.1; -; mRNA.
DR PIR; I60107; I60107.
DR RefSeq; NP_001596.2; NM_001605.2.
DR RefSeq; XP_005255870.1; XM_005255813.1.
DR UniGene; Hs.315137; -.
DR ProteinModelPortal; P49588; -.
DR SMR; P49588; 6-757.
DR IntAct; P49588; 4.
DR MINT; MINT-1490092; -.
DR STRING; 9606.ENSP00000261772; -.
DR BindingDB; P49588; -.
DR ChEMBL; CHEMBL3574; -.
DR DrugBank; DB00160; L-Alanine.
DR PhosphoSite; P49588; -.
DR DMDM; 115502460; -.
DR PaxDb; P49588; -.
DR PRIDE; P49588; -.
DR DNASU; 16; -.
DR Ensembl; ENST00000261772; ENSP00000261772; ENSG00000090861.
DR GeneID; 16; -.
DR KEGG; hsa:16; -.
DR UCSC; uc002eyn.1; human.
DR CTD; 16; -.
DR GeneCards; GC16M070286; -.
DR HGNC; HGNC:20; AARS.
DR HPA; CAB034261; -.
DR HPA; HPA040870; -.
DR MIM; 601065; gene.
DR MIM; 613287; phenotype.
DR neXtProt; NX_P49588; -.
DR Orphanet; 228174; Autosomal dominant Charcot-Marie-Tooth disease type 2N.
DR PharmGKB; PA24367; -.
DR eggNOG; COG0013; -.
DR HOGENOM; HOG000156964; -.
DR HOVERGEN; HBG017874; -.
DR InParanoid; P49588; -.
DR KO; K01872; -.
DR OMA; KIMDDLD; -.
DR OrthoDB; EOG7M3HZH; -.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; AARS; human.
DR GenomeRNAi; 16; -.
DR NextBio; 39; -.
DR PRO; PR:P49588; -.
DR Bgee; P49588; -.
DR CleanEx; HS_AARS; -.
DR Genevestigator; P49588; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004813; F:alanine-tRNA ligase activity; IEA:UniProtKB-EC.
DR GO; GO:0016597; F:amino acid binding; IEA:Ensembl.
DR GO; GO:0002161; F:aminoacyl-tRNA editing activity; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000049; F:tRNA binding; TAS:ProtInc.
DR GO; GO:0006419; P:alanyl-tRNA aminoacylation; TAS:ProtInc.
DR GO; GO:0021680; P:cerebellar Purkinje cell layer development; IEA:Ensembl.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IEA:Ensembl.
DR GO; GO:0001942; P:hair follicle development; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0050885; P:neuromuscular process controlling balance; IEA:Ensembl.
DR GO; GO:0006457; P:protein folding; IEA:Ensembl.
DR GO; GO:0043200; P:response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0006400; P:tRNA modification; IEA:Ensembl.
DR GO; GO:0008033; P:tRNA processing; TAS:ProtInc.
DR HAMAP; MF_00036_B; Ala_tRNA_synth_B; 1; -.
DR InterPro; IPR002318; Ala-tRNA-lgiase_IIc.
DR InterPro; IPR018162; Ala-tRNA-ligase_IIc_anticod-bd.
DR InterPro; IPR018165; Ala-tRNA-synth_IIc_core.
DR InterPro; IPR018164; Ala-tRNA-synth_IIc_N.
DR InterPro; IPR023033; Ala_tRNA_ligase_euk/bac.
DR InterPro; IPR003156; Pesterase_DHHA1.
DR InterPro; IPR018163; Thr/Ala-tRNA-synth_IIc_edit.
DR InterPro; IPR009000; Transl_B-barrel.
DR InterPro; IPR012947; tRNA_SAD.
DR PANTHER; PTHR11777:SF6; PTHR11777:SF6; 1.
DR Pfam; PF02272; DHHA1; 1.
DR Pfam; PF01411; tRNA-synt_2c; 1.
DR Pfam; PF07973; tRNA_SAD; 1.
DR PRINTS; PR00980; TRNASYNTHALA.
DR SMART; SM00863; tRNA_SAD; 1.
DR SUPFAM; SSF101353; SSF101353; 1.
DR SUPFAM; SSF50447; SSF50447; 1.
DR SUPFAM; SSF55186; SSF55186; 1.
DR TIGRFAMs; TIGR00344; alaS; 1.
DR PROSITE; PS50860; AA_TRNA_LIGASE_II_ALA; 1.
PE 1: Evidence at protein level;
KW Acetylation; Aminoacyl-tRNA synthetase; ATP-binding;
KW Charcot-Marie-Tooth disease; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Ligase; Metal-binding;
KW Neuropathy; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Protein biosynthesis; Reference proteome; RNA-binding; tRNA-binding;
KW Ubl conjugation; Zinc.
FT CHAIN 1 968 Alanine--tRNA ligase, cytoplasmic.
FT /FTId=PRO_0000075281.
FT METAL 605 605 Zinc (Potential).
FT METAL 609 609 Zinc (Potential).
FT METAL 723 723 Zinc (Potential).
FT METAL 727 727 Zinc (Potential).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 19 19 N6-acetyllysine.
FT MOD_RES 399 399 Phosphoserine.
FT MOD_RES 555 555 Phosphoserine.
FT MOD_RES 876 876 N6-acetyllysine.
FT VARIANT 71 71 N -> Y (in CMT2N).
FT /FTId=VAR_067084.
FT VARIANT 275 275 G -> D (in dbSNP:rs11537667).
FT /FTId=VAR_028204.
FT VARIANT 329 329 R -> H (in CMT2N; severely reduces enzyme
FT activity).
FT /FTId=VAR_063527.
FT CONFLICT 82 82 H -> Q (in Ref. 1; BAA06808).
FT CONFLICT 867 867 S -> T (in Ref. 2; BAD96544).
SQ SEQUENCE 968 AA; 106810 MW; 8683F111CEE42506 CRC64;
MDSTLTASEI RQRFIDFFKR NEHTYVHSSA TIPLDDPTLL FANAGMNQFK PIFLNTIDPS
HPMAKLSRAA NTQKCIRAGG KHNDLDDVGK DVYHHTFFEM LGSWSFGDYF KELACKMALE
LLTQEFGIPI ERLYVTYFGG DEAAGLEADL ECKQIWQNLG LDDTKILPGN MKDNFWEMGD
TGPCGPCSEI HYDRIGGRDA AHLVNQDDPN VLEIWNLVFI QYNREADGIL KPLPKKSIDT
GMGLERLVSV LQNKMSNYDT DLFVPYFEAI QKGTGARPYT GKVGAEDADG IDMAYRVLAD
HARTITVALA DGGRPDNTGR GYVLRRILRR AVRYAHEKLN ASRGFFATLV DVVVQSLGDA
FPELKKDPDM VKDIINEEEV QFLKTLSRGR RILDRKIQSL GDSKTIPGDT AWLLYDTYGF
PVDLTGLIAE EKGLVVDMDG FEEERKLAQL KSQGKGAGGE DLIMLDIYAI EELRARGLEV
TDDSPKYNYH LDSSGSYVFE NTVATVMALR REKMFVEEVS TGQECGVVLD KTCFYAEQGG
QIYDEGYLVK VDDSSEDKTE FTVKNAQVRG GYVLHIGTIY GDLKVGDQVW LFIDEPRRRP
IMSNHTATHI LNFALRSVLG EADQKGSLVA PDRLRFDFTA KGAMSTQQIK KAEEIANEMI
EAAKAVYTQD CPLAAAKAIQ GLRAVFDETY PDPVRVVSIG VPVSELLDDP SGPAGSLTSV
EFCGGTHLRN SSHAGAFVIV TEEAIAKGIR RIVAVTGAEA QKALRKAESL KKCLSVMEAK
VKAQTAPNKD VQREIADLGE ALATAVIPQW QKDELRETLK SLKKVMDDLD RASKADVQKR
VLEKTKQFID SNPNQPLVIL EMESGASAKA LNEALKLFKM HSPQTSAMLF TVDNEAGKIT
CLCQVPQNAA NRGLKASEWV QQVSGLMDGK GGGKDVSAQA TGKNVGCLQE ALQLATSFAQ
LRLGDVKN
//
ID SYAC_HUMAN Reviewed; 968 AA.
AC P49588; A6NF14; Q53GV7; Q96FA0;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 03-OCT-2006, sequence version 2.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=Alanine--tRNA ligase, cytoplasmic;
DE EC=6.1.1.7;
DE AltName: Full=Alanyl-tRNA synthetase;
DE Short=AlaRS;
DE AltName: Full=Renal carcinoma antigen NY-REN-42;
GN Name=AARS;
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=7654687; DOI=10.1021/bi00033a004;
RA Shiba K., Ripmaster T.L., Suzuki N., Nichols R., Plotz P., Noda T.,
RA Schimmel P.;
RT "Human alanyl-tRNA synthetase: conservation in evolution of catalytic
RT core and microhelix recognition.";
RL Biochemistry 34:10340-10349(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 [3]
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 [4]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [6]
RP PROTEIN SEQUENCE OF 1-11; 304-320 AND 684-695, ACETYLATION AT MET-1,
RP AND MASS SPECTROMETRY.
RC TISSUE=Osteosarcoma;
RA Bienvenut W.V., Glen H., Brunton V.G., Frame M.C.;
RL Submitted (JUL-2007) to UniProtKB.
RN [7]
RP IDENTIFICATION AS A RENAL CANCER ANTIGEN.
RC TISSUE=Renal cell carcinoma;
RX PubMed=10508479;
RX DOI=10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5;
RA Scanlan M.J., Gordan J.D., Williamson B., Stockert E., Bander N.H.,
RA Jongeneel C.V., Gure A.O., Jaeger D., Jaeger E., Knuth A., Chen Y.-T.,
RA Old L.J.;
RT "Antigens recognized by autologous antibody in patients with renal-
RT cell carcinoma.";
RL Int. J. Cancer 83:456-464(1999).
RN [8]
RP ISGYLATION.
RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132;
RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J.,
RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.;
RT "Proteomic identification of proteins conjugated to ISG15 in mouse and
RT human cells.";
RL Biochem. Biophys. Res. Commun. 336:496-506(2005).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-555, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, 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 [11]
RP DOMAIN EXCHANGE EXPERIMENTS.
RX PubMed=19661429; DOI=10.1126/science.1174343;
RA Guo M., Chong Y.E., Beebe K., Shapiro R., Yang X.-L., Schimmel P.;
RT "The C-Ala domain brings together editing and aminoacylation functions
RT on one tRNA.";
RL Science 325:744-747(2009).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-19 AND LYS-876, 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 [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-399, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [14]
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 [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, 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 [16]
RP VARIANT CMT2N HIS-329.
RX PubMed=20045102; DOI=10.1016/j.ajhg.2009.12.005;
RA Latour P., Thauvin-Robinet C., Baudelet-Mery C., Soichot P., Cusin V.,
RA Faivre L., Locatelli M.C., Mayencon M., Sarcey A., Broussolle E.,
RA Camu W., David A., Rousson R.;
RT "A major determinant for binding and aminoacylation of tRNA(Ala) in
RT cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal
RT Charcot-Marie-Tooth disease.";
RL Am. J. Hum. Genet. 86:77-82(2010).
RN [17]
RP VARIANT CMT2N TYR-71.
RX PubMed=22206013; DOI=10.1371/journal.pone.0029393;
RA Lin K.P., Soong B.W., Yang C.C., Huang L.W., Chang M.H., Lee I.H.,
RA Antonellis A., Lee Y.C.;
RT "The mutational spectrum in a cohort of Charcot-Marie-Tooth disease
RT type 2 among the Han Chinese in Taiwan.";
RL PLoS ONE 6:E29393-E29393(2011).
RN [18]
RP VARIANT CMT2N HIS-329, AND CHARACTERIZATION OF VARIANT CMT2N HIS-329.
RX PubMed=22009580; DOI=10.1002/humu.21635;
RA McLaughlin H.M., Sakaguchi R., Giblin W., Wilson T.E., Biesecker L.,
RA Lupski J.R., Talbot K., Vance J.M., Zuchner S., Lee Y.C.,
RA Kennerson M., Hou Y.M., Nicholson G., Antonellis A.;
RT "A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation
RT in patients with Charcot-Marie-Tooth disease type 2N (CMT2N).";
RL Hum. Mutat. 33:244-253(2012).
CC -!- FUNCTION: Catalyzes the attachment of alanine to tRNA(Ala) in a
CC two-step reaction: alanine is first activated by ATP to form Ala-
CC AMP and then transferred to the acceptor end of tRNA(Ala). Also
CC edits incorrectly charged tRNA(Ala) via its editing domain (By
CC similarity).
CC -!- CATALYTIC ACTIVITY: ATP + L-alanine + tRNA(Ala) = AMP +
CC diphosphate + L-alanyl-tRNA(Ala).
CC -!- COFACTOR: Binds 1 zinc ion per subunit (Potential).
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity).
CC -!- DOMAIN: Consists of three domains; the N-terminal catalytic
CC domain, the editing domain and the C-terminal C-Ala domain. The
CC editing domain removes incorrectly charged amino acids, while the
CC C-Ala domain, along with tRNA(Ala), serves as a bridge to
CC cooperatively bring together the editing and aminoacylation
CC centers thus stimulating deacylation of misacylated tRNAs (By
CC similarity).
CC -!- DOMAIN: The C-terminal C-Ala domain (residues 756 to 968), along
CC with tRNA(Ala), serves as a bridge to cooperatively bring together
CC the editing and aminoacylation centers thus stimulating
CC deacylation of misacylated tRNAs. The human domain can be used in
CC vitro to replace the corresponding domain in E.coli.
CC -!- PTM: ISGylated.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2N (CMT2N) [MIM:613287]: An
CC axonal form of Charcot-Marie-Tooth disease, a disorder of the
CC peripheral nervous system, characterized by progressive weakness
CC and atrophy, initially of the peroneal muscles and later of the
CC distal muscles of the arms. Charcot-Marie-Tooth disease is
CC classified in two main groups on the basis of electrophysiologic
CC properties and histopathology: primary peripheral demyelinating
CC neuropathies (designated CMT1 when they are dominantly inherited)
CC and primary peripheral axonal neuropathies (CMT2). Neuropathies of
CC the CMT2 group are characterized by signs of axonal degeneration
CC in the absence of obvious myelin alterations, normal or slightly
CC reduced nerve conduction velocities, and progressive distal muscle
CC weakness and atrophy. Nerve conduction velocities are normal or
CC slightly reduced. Note=The disease is caused by mutations
CC 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; D32050; BAA06808.1; -; mRNA.
DR EMBL; AK222824; BAD96544.1; -; mRNA.
DR EMBL; AC012184; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471241; EAW51839.1; -; Genomic_DNA.
DR EMBL; BC011451; AAH11451.1; -; mRNA.
DR PIR; I60107; I60107.
DR RefSeq; NP_001596.2; NM_001605.2.
DR RefSeq; XP_005255870.1; XM_005255813.1.
DR UniGene; Hs.315137; -.
DR ProteinModelPortal; P49588; -.
DR SMR; P49588; 6-757.
DR IntAct; P49588; 4.
DR MINT; MINT-1490092; -.
DR STRING; 9606.ENSP00000261772; -.
DR BindingDB; P49588; -.
DR ChEMBL; CHEMBL3574; -.
DR DrugBank; DB00160; L-Alanine.
DR PhosphoSite; P49588; -.
DR DMDM; 115502460; -.
DR PaxDb; P49588; -.
DR PRIDE; P49588; -.
DR DNASU; 16; -.
DR Ensembl; ENST00000261772; ENSP00000261772; ENSG00000090861.
DR GeneID; 16; -.
DR KEGG; hsa:16; -.
DR UCSC; uc002eyn.1; human.
DR CTD; 16; -.
DR GeneCards; GC16M070286; -.
DR HGNC; HGNC:20; AARS.
DR HPA; CAB034261; -.
DR HPA; HPA040870; -.
DR MIM; 601065; gene.
DR MIM; 613287; phenotype.
DR neXtProt; NX_P49588; -.
DR Orphanet; 228174; Autosomal dominant Charcot-Marie-Tooth disease type 2N.
DR PharmGKB; PA24367; -.
DR eggNOG; COG0013; -.
DR HOGENOM; HOG000156964; -.
DR HOVERGEN; HBG017874; -.
DR InParanoid; P49588; -.
DR KO; K01872; -.
DR OMA; KIMDDLD; -.
DR OrthoDB; EOG7M3HZH; -.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; AARS; human.
DR GenomeRNAi; 16; -.
DR NextBio; 39; -.
DR PRO; PR:P49588; -.
DR Bgee; P49588; -.
DR CleanEx; HS_AARS; -.
DR Genevestigator; P49588; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004813; F:alanine-tRNA ligase activity; IEA:UniProtKB-EC.
DR GO; GO:0016597; F:amino acid binding; IEA:Ensembl.
DR GO; GO:0002161; F:aminoacyl-tRNA editing activity; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000049; F:tRNA binding; TAS:ProtInc.
DR GO; GO:0006419; P:alanyl-tRNA aminoacylation; TAS:ProtInc.
DR GO; GO:0021680; P:cerebellar Purkinje cell layer development; IEA:Ensembl.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IEA:Ensembl.
DR GO; GO:0001942; P:hair follicle development; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0050885; P:neuromuscular process controlling balance; IEA:Ensembl.
DR GO; GO:0006457; P:protein folding; IEA:Ensembl.
DR GO; GO:0043200; P:response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0006400; P:tRNA modification; IEA:Ensembl.
DR GO; GO:0008033; P:tRNA processing; TAS:ProtInc.
DR HAMAP; MF_00036_B; Ala_tRNA_synth_B; 1; -.
DR InterPro; IPR002318; Ala-tRNA-lgiase_IIc.
DR InterPro; IPR018162; Ala-tRNA-ligase_IIc_anticod-bd.
DR InterPro; IPR018165; Ala-tRNA-synth_IIc_core.
DR InterPro; IPR018164; Ala-tRNA-synth_IIc_N.
DR InterPro; IPR023033; Ala_tRNA_ligase_euk/bac.
DR InterPro; IPR003156; Pesterase_DHHA1.
DR InterPro; IPR018163; Thr/Ala-tRNA-synth_IIc_edit.
DR InterPro; IPR009000; Transl_B-barrel.
DR InterPro; IPR012947; tRNA_SAD.
DR PANTHER; PTHR11777:SF6; PTHR11777:SF6; 1.
DR Pfam; PF02272; DHHA1; 1.
DR Pfam; PF01411; tRNA-synt_2c; 1.
DR Pfam; PF07973; tRNA_SAD; 1.
DR PRINTS; PR00980; TRNASYNTHALA.
DR SMART; SM00863; tRNA_SAD; 1.
DR SUPFAM; SSF101353; SSF101353; 1.
DR SUPFAM; SSF50447; SSF50447; 1.
DR SUPFAM; SSF55186; SSF55186; 1.
DR TIGRFAMs; TIGR00344; alaS; 1.
DR PROSITE; PS50860; AA_TRNA_LIGASE_II_ALA; 1.
PE 1: Evidence at protein level;
KW Acetylation; Aminoacyl-tRNA synthetase; ATP-binding;
KW Charcot-Marie-Tooth disease; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Ligase; Metal-binding;
KW Neuropathy; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Protein biosynthesis; Reference proteome; RNA-binding; tRNA-binding;
KW Ubl conjugation; Zinc.
FT CHAIN 1 968 Alanine--tRNA ligase, cytoplasmic.
FT /FTId=PRO_0000075281.
FT METAL 605 605 Zinc (Potential).
FT METAL 609 609 Zinc (Potential).
FT METAL 723 723 Zinc (Potential).
FT METAL 727 727 Zinc (Potential).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 19 19 N6-acetyllysine.
FT MOD_RES 399 399 Phosphoserine.
FT MOD_RES 555 555 Phosphoserine.
FT MOD_RES 876 876 N6-acetyllysine.
FT VARIANT 71 71 N -> Y (in CMT2N).
FT /FTId=VAR_067084.
FT VARIANT 275 275 G -> D (in dbSNP:rs11537667).
FT /FTId=VAR_028204.
FT VARIANT 329 329 R -> H (in CMT2N; severely reduces enzyme
FT activity).
FT /FTId=VAR_063527.
FT CONFLICT 82 82 H -> Q (in Ref. 1; BAA06808).
FT CONFLICT 867 867 S -> T (in Ref. 2; BAD96544).
SQ SEQUENCE 968 AA; 106810 MW; 8683F111CEE42506 CRC64;
MDSTLTASEI RQRFIDFFKR NEHTYVHSSA TIPLDDPTLL FANAGMNQFK PIFLNTIDPS
HPMAKLSRAA NTQKCIRAGG KHNDLDDVGK DVYHHTFFEM LGSWSFGDYF KELACKMALE
LLTQEFGIPI ERLYVTYFGG DEAAGLEADL ECKQIWQNLG LDDTKILPGN MKDNFWEMGD
TGPCGPCSEI HYDRIGGRDA AHLVNQDDPN VLEIWNLVFI QYNREADGIL KPLPKKSIDT
GMGLERLVSV LQNKMSNYDT DLFVPYFEAI QKGTGARPYT GKVGAEDADG IDMAYRVLAD
HARTITVALA DGGRPDNTGR GYVLRRILRR AVRYAHEKLN ASRGFFATLV DVVVQSLGDA
FPELKKDPDM VKDIINEEEV QFLKTLSRGR RILDRKIQSL GDSKTIPGDT AWLLYDTYGF
PVDLTGLIAE EKGLVVDMDG FEEERKLAQL KSQGKGAGGE DLIMLDIYAI EELRARGLEV
TDDSPKYNYH LDSSGSYVFE NTVATVMALR REKMFVEEVS TGQECGVVLD KTCFYAEQGG
QIYDEGYLVK VDDSSEDKTE FTVKNAQVRG GYVLHIGTIY GDLKVGDQVW LFIDEPRRRP
IMSNHTATHI LNFALRSVLG EADQKGSLVA PDRLRFDFTA KGAMSTQQIK KAEEIANEMI
EAAKAVYTQD CPLAAAKAIQ GLRAVFDETY PDPVRVVSIG VPVSELLDDP SGPAGSLTSV
EFCGGTHLRN SSHAGAFVIV TEEAIAKGIR RIVAVTGAEA QKALRKAESL KKCLSVMEAK
VKAQTAPNKD VQREIADLGE ALATAVIPQW QKDELRETLK SLKKVMDDLD RASKADVQKR
VLEKTKQFID SNPNQPLVIL EMESGASAKA LNEALKLFKM HSPQTSAMLF TVDNEAGKIT
CLCQVPQNAA NRGLKASEWV QQVSGLMDGK GGGKDVSAQA TGKNVGCLQE ALQLATSFAQ
LRLGDVKN
//
MIM
601065
*RECORD*
*FIELD* NO
601065
*FIELD* TI
*601065 ALANYL-tRNA SYNTHETASE; AARS
*FIELD* TX
DESCRIPTION
The AARS gene encodes alanyl-tRNA synthetase. Each of the amino acid
read moresynthetases catalyzes the attachment of their respective amino acids to
the appropriate tRNA. The class II Escherichia coli and human
alanyl-tRNA synthetases cross-acylate their respective tRNAs and
require, for aminoacylation, an acceptor helix G3:U70 basepair that is
conserved in evolution (Shiba et al., 1995).
Some of the amino acid synthetases are targets for autoantibodies in the
autoimmune disease polymyositis/dermatomyositis (Nichols et al., 1995)
including histidyl-RS (142810), threonyl-RS (187790), isoleucyl-RS
(600709), glycyl-RS (600287) and alanyl-RS.
CLONING
Shiba et al. (1995) reported the primary structure and expression of an
active human alanyl-tRNA synthetase. The N-terminal 498 amino acids of
the 968-residue polypeptide showed 41% identity with the E. coli
protein. The human protein contains the class-defining domain of the E.
coli enzyme, which includes the part needed for recognition of the
acceptor helix G3:U70 basepair as an RNA signal for alanine. The authors
concluded that mutagenesis, modeling, domain organization, and
biochemical characterization of the E. coli protein are valid as a
template for the human protein.
MAPPING
Nichols et al. (1995) mapped the alanyl-RS gene by fluorescence in situ
hybridization to chromosome 16q22. By radiation hybrid panel analysis,
Maas et al. (2001) mapped the AARS gene centromeric to the KARS gene
(601421) and the ADAT1 gene (604230) in region 16q22.2-q22.3.
GENE FUNCTION
The folding of mRNA influences a diverse range of biologic events such
as mRNA splicing and processing, and translational control and
regulation. Because the structure of mRNA is determined by its
nucleotide sequence and its environment, Shen et al. (1999) examined
whether the folding of mRNA could be influenced by the presence of
single-nucleotide polymorphisms (SNPs). They reported marked differences
in mRNA secondary structure associated with SNPs in the coding region of
2 human mRNAs: alanyl-tRNA synthetase and replication protein A, 70-kD
subunit (RPA70; 179835). Enzymatic probing of SNP-containing fragments
of the mRNAs revealed pronounced allelic differences in cleavage pattern
at sites 14 or 18 nucleotides away from the SNP, suggesting that a
single-nucleotide variation can give rise to different mRNA folds. By
using oligodeoxyribonucleotides complementary to the region of different
allelic structures in the RPA70 mRNA, but not extending to the SNP
itself, they found that the SNP exerted an allele-specific effect on the
accessibility of its flanking site in the endogenous human RPA70 mRNA.
The results demonstrated the contribution of common genetic variation
through structural diversity of mRNA and suggested a broader role than
previously thought for the effects of SNPs on mRNA structure and,
ultimately, biologic function.
MOLECULAR GENETICS
In affected members of a large French family with axonal
Charcot-Marie-Tooth disease type 2N (CMT2N; 613287), Latour et al.
(2010) identified a heterozygous mutation in the AARS gene (R329H;
601065.0001). Affected members of an unrelated affected French family
were found to carry the same mutation. Haplotype analysis excluded a
founder effect in these families.
In affected members of a Taiwanese family with CMT2N, Lin et al. (2011)
identified a heterozygous mutation in the AARS gene (N71Y; 601065.0002).
McLaughlin et al. (2012) identified a heterozygous R329H mutation in an
Australian family with CMT2N.
EVOLUTION
Chihade et al. (2000) presented data on AARS from an early eukaryote and
other sources that were consistent with the notion that mitochondrial
genesis did not significantly precede nucleus formation.
Guo et al. (2009) demonstrated that the C-Ala domain is universally
tethered to the editing domain both in alanyl-tRNA synthetase and in
many homologous free-standing editing proteins. Crystal structure and
functional analyses showed that C-Ala forms an ancient single-stranded
nucleic acid binding motif that promotes cooperative binding of both
aminoacylation and editing domains to tRNA(Ala). In addition, C-Ala may
have played an essential role in the evolution of alanyl-tRNA
synthetases by coupling aminoacylation to editing to prevent
mistranslation.
Mistranslation arising from confusion of serine for alanine by
alanyl-tRNA synthetases (AlaRSs) has profound functional consequences.
Throughout evolution, 2 editing checkpoints prevent disease-causing
mistranslation from confusing glycine or serine for alanine at the
active site of AlaRS. In both bacteria and mice, serine poses a bigger
challenge than glycine. One checkpoint is the AlaRS editing center, and
the other is from widely distributed AlaXps, free-standing,
genome-encoded editing proteins that clear Ser-tRNA(Ala) (AARSD1;
613212). The paradox of misincorporating both a smaller (glycine) and a
larger (serine) amino acid suggests a deep conflict for nature-designed
AlaRS. Guo et al. (2009) showed the chemical basis for this conflict.
Nine crystal structures, together with kinetic and mutational analysis,
provided snapshots of adenylate formation for each amino acid. An
inherent dilemma is posed by constraints of a structural design that
pins down the alpha-amino group of the bound amino acid by using an
acidic residue. This design, dating back more than 3 billion years,
creates a serendipitous interaction with the serine hydroxide that is
difficult to avoid. Apparently because no better architecture for the
recognition of alanine could be found, the serine misactivation problem
was solved through free-standing AlaXps, which appeared
contemporaneously with early AlaRSs.
ANIMAL MODEL
Lee et al. (2006) demonstrated that low levels of mischarged transfer
RNAs can lead to an intracellular accumulation of misfolded proteins in
neurons. These accumulations are accompanied by upregulation of
cytoplasmic protein chaperones and by induction of the unfolded protein
response. Lee et al. (2006) reported that the mouse 'sticky' (sti)
mutation, which causes cerebellar Purkinje cell loss and ataxia, is a
missense mutation in the editing domain of the alanyl-tRNA synthetase
gene that compromises the proofreading activity of this enzyme during
aminoacylation of tRNAs. Lee et al. (2006) concluded that their findings
demonstrated that disruption of translational fidelity in terminally
differentiated neurons leads to the accumulation of misfolded proteins
and cell death, and provided a novel mechanism underlying
neurodegeneration.
*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2N
AARS, ARG329HIS
In affected members of 2 unrelated French families with autosomal
dominant Charcot-Marie-Tooth disease type 2N (613287), Latour et al.
(2010) identified a heterozygous 986G-A transition in exon 8 of the AARS
gene, resulting in an arg329-to-his (R329H) substitution in the alpha-10
helix. This highly conserved residue is the ortholog of R314 in E. coli,
which is 1 of the major determinants for binding and efficient
aminoacylation of tRNAs. E. coli mutants in this residue showed
significant reduction in enzyme activity due to reduced binding, but the
authors also postulated that the mutation could result in qualitative
errors and the binding of noncognate tRNAs. The R329H mutation was not
found in 1,000 control chromosomes. Haplotype analysis excluded a
founder effect.
McLaughlin et al. (2012) identified a heterozygous R329H mutation in
affected members of an Australian family with CMT2N. The substitution
occurs within a highly conserved residue in the tRNA-binding domain.
Aminoacylation studies showed that the mutation reduced enzyme activity
by about 50% and was unable to complement deletion in yeast viability
studies. There did not appear to be a dominant-negative effect.
Haplotype analysis of this family and the 2 reported by Latour et al.
(2010) showed that the mutation occurred independently. Bisulfite
sequencing indicated that the mutation occurred via methylation-mediated
deamination of a CpG dinucleotide on the noncoding strand. The findings
indicated that R329H is a recurrent loss-of-function mutation.
.0002
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2N
AARS, ASN71TYR
In affected members of a Taiwanese family with CMT2N (613287), Lin et
al. (2011) identified a heterozygous mutation in the AARS gene,
resulting in an asn71-to-tyr (N71Y) substitution in a highly conserved
region in the catalytic domain. In vitro functional expression studies
by McLaughlin et al. (2012) showed that the mutant N71Y protein had
severe loss of enzymatic activity (4,130-fold decrease), and was unable
to complement loss of AARS in yeast viability studies. There was marked
variability in the age of onset (range, 11 to 45 years) and severity.
The proband presented at age 51 years with slowly progressive weakness
and atrophy of the legs that began at age 30 years after normal
development. Physical examination showed marked atrophy and mild
weakness of the muscles in the legs and feet, and milder atrophy and
weakness of the intrinsic hand muscles. He had absent ankle reflexes,
hyporeflexia, and mildly decreased distal sensation. His mother,
brother, and son had a similar disorder. His 2 younger sisters and
niece, who also carried the mutation, denied neurologic symptoms, but
neurologic examination showed distal muscle mild atrophy, weakness in
the intrinsic foot muscles, and generalized hyporeflexia in all of them.
*FIELD* RF
1. Chihade, J. W.; Brown, J. R.; Schimmel, P. R.; Ribas de Pouplana,
L.: Origin of mitochondria in relation to evolutionary history of
eukaryotic alanyl-tRNA synthetase. Proc. Nat. Acad. Sci. 97: 12153-12157,
2000.
2. Guo, M.; Chong, Y. E.; Beebe, K.; Shapiro, R.; Yang, X.-L.; Schimmel,
P.: The C-Ala domain brings together editing and aminoacylation functions
on one tRNA. Science 325: 744-747, 2009. Note: Erratum: Science
326: 46 only, 2009.
3. Guo, M.; Chong, Y. E.; Shapiro, R.; Beebe, K.; Yang, X.-L.; Schimmel,
P.: Paradox of mistranslation of serine for alanine caused by AlaRS
recognition dilemma. Nature 462: 808-812, 2009.
4. Latour, P.; Thauvin-Robinet, C.; Baudelet-Mery, C.; Soichot, P.;
Cusin, V.; Faivre, L.; Locatelli, M.-C.; Mayencon, M.; Sarcey, A.;
Broussolle, E.; Camu, W.; David, A.; Rousson, R.: A major determinant
for binding and aminoacylation of tRNA-Ala in cytoplasmic alanyl-tRNA
synthetase is mutated in dominant axonal Charcot-Marie-Tooth Disease. Am.
J. Hum. Genet. 86: 77-82, 2010.
5. Lee, J. W.; Beebe, K.; Nangle, L. A.; Jang, J.; Longo-Guess, C.
M.; Cook, S. A.; Davisson, M. T.; Sundberg, J. P.; Schimmel, P.; Ackerman,
S. L.: Editing-defective tRNA synthetase causes protein misfolding
and neurodegeneration. Nature 443: 50-55, 2006.
6. Lin, K.-P.; Soong, B.-W.; Yang, C.-C.; Huang, L.-W.; Chang, M.-H.;
Lee, I.-H.; Antonellis, A.; Lee, Y.-C.: The mutational spectrum in
a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese
in Taiwan. PLoS One 6: e29393, 2011. Note: Electronic Article. Note:
Erratum published online.
7. 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.
8. McLaughlin, H. M.; Sakaguchi, R.; Giblin, W.; NISC Comparative
Sequencing Program; Wilson, T. E.; Biesecker, L.; Lupski, J. R.;
Talbot, K.; Vance, J. M.; Zuchner, S.; Lee, Y.-C.; Kennerson, M.;
Hou, Y.-M.; Nicholson, G.; Antonellis, A.: A recurrent loss-of-function
alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth
disease type 2N (CMT2N). Hum. Mutat. 33: 244-253, 2012.
9. Nichols, R. C.; Pai, S. I.; Ge, Q.; Targoff, I. N.; Plotz, P. H.;
Liu, P.: Localization of two human autoantigen genes by PCR screening
and in situ hybridization--Glycyl-tRNA synthetase locates to 7p15
and alanyl-tRNA synthetase locates to 16q22. Genomics 30: 131-132,
1995.
10. Shen, L. X.; Basilion, J. P.; Stanton, V. P., Jr.: Single-nucleotide
polymorphisms can cause different structural folds of mRNA. Proc.
Nat. Acad. Sci. 96: 7871-7876, 1999.
11. Shiba, K.; Ripmaster, T.; Suzuki, N.; Nichols, R.; Plotz, P.;
Noda, T.: Schimmel, P.: Human alanyl-tRNA synthetase: conservation
in evolution of catalytic core and microhelix recognition. Biochemistry 34:
10340-10349, 1995.
*FIELD* CN
Cassandra L. Kniffin - updated: 1/9/2012
Cassandra L. Kniffin - updated: 3/1/2010
Ada Hamosh - updated: 1/8/2010
Ada Hamosh - updated: 11/13/2009
Ada Hamosh - updated: 9/1/2009
Ada Hamosh - updated: 9/20/2006
Victor A. McKusick - updated: 6/4/2001
Victor A. McKusick - updated: 11/27/2000
Victor A. McKusick - updated: 8/10/1999
*FIELD* CD
Alan F. Scott: 2/12/1996
*FIELD* ED
terry: 12/20/2012
carol: 1/19/2012
ckniffin: 1/9/2012
carol: 3/2/2010
ckniffin: 3/1/2010
alopez: 1/11/2010
terry: 1/8/2010
terry: 11/13/2009
alopez: 9/10/2009
terry: 9/1/2009
alopez: 10/3/2006
terry: 9/20/2006
alopez: 6/5/2001
terry: 6/4/2001
mcapotos: 12/11/2000
mcapotos: 12/6/2000
terry: 11/27/2000
alopez: 8/23/1999
terry: 8/10/1999
mark: 2/12/1996
*RECORD*
*FIELD* NO
601065
*FIELD* TI
*601065 ALANYL-tRNA SYNTHETASE; AARS
*FIELD* TX
DESCRIPTION
The AARS gene encodes alanyl-tRNA synthetase. Each of the amino acid
read moresynthetases catalyzes the attachment of their respective amino acids to
the appropriate tRNA. The class II Escherichia coli and human
alanyl-tRNA synthetases cross-acylate their respective tRNAs and
require, for aminoacylation, an acceptor helix G3:U70 basepair that is
conserved in evolution (Shiba et al., 1995).
Some of the amino acid synthetases are targets for autoantibodies in the
autoimmune disease polymyositis/dermatomyositis (Nichols et al., 1995)
including histidyl-RS (142810), threonyl-RS (187790), isoleucyl-RS
(600709), glycyl-RS (600287) and alanyl-RS.
CLONING
Shiba et al. (1995) reported the primary structure and expression of an
active human alanyl-tRNA synthetase. The N-terminal 498 amino acids of
the 968-residue polypeptide showed 41% identity with the E. coli
protein. The human protein contains the class-defining domain of the E.
coli enzyme, which includes the part needed for recognition of the
acceptor helix G3:U70 basepair as an RNA signal for alanine. The authors
concluded that mutagenesis, modeling, domain organization, and
biochemical characterization of the E. coli protein are valid as a
template for the human protein.
MAPPING
Nichols et al. (1995) mapped the alanyl-RS gene by fluorescence in situ
hybridization to chromosome 16q22. By radiation hybrid panel analysis,
Maas et al. (2001) mapped the AARS gene centromeric to the KARS gene
(601421) and the ADAT1 gene (604230) in region 16q22.2-q22.3.
GENE FUNCTION
The folding of mRNA influences a diverse range of biologic events such
as mRNA splicing and processing, and translational control and
regulation. Because the structure of mRNA is determined by its
nucleotide sequence and its environment, Shen et al. (1999) examined
whether the folding of mRNA could be influenced by the presence of
single-nucleotide polymorphisms (SNPs). They reported marked differences
in mRNA secondary structure associated with SNPs in the coding region of
2 human mRNAs: alanyl-tRNA synthetase and replication protein A, 70-kD
subunit (RPA70; 179835). Enzymatic probing of SNP-containing fragments
of the mRNAs revealed pronounced allelic differences in cleavage pattern
at sites 14 or 18 nucleotides away from the SNP, suggesting that a
single-nucleotide variation can give rise to different mRNA folds. By
using oligodeoxyribonucleotides complementary to the region of different
allelic structures in the RPA70 mRNA, but not extending to the SNP
itself, they found that the SNP exerted an allele-specific effect on the
accessibility of its flanking site in the endogenous human RPA70 mRNA.
The results demonstrated the contribution of common genetic variation
through structural diversity of mRNA and suggested a broader role than
previously thought for the effects of SNPs on mRNA structure and,
ultimately, biologic function.
MOLECULAR GENETICS
In affected members of a large French family with axonal
Charcot-Marie-Tooth disease type 2N (CMT2N; 613287), Latour et al.
(2010) identified a heterozygous mutation in the AARS gene (R329H;
601065.0001). Affected members of an unrelated affected French family
were found to carry the same mutation. Haplotype analysis excluded a
founder effect in these families.
In affected members of a Taiwanese family with CMT2N, Lin et al. (2011)
identified a heterozygous mutation in the AARS gene (N71Y; 601065.0002).
McLaughlin et al. (2012) identified a heterozygous R329H mutation in an
Australian family with CMT2N.
EVOLUTION
Chihade et al. (2000) presented data on AARS from an early eukaryote and
other sources that were consistent with the notion that mitochondrial
genesis did not significantly precede nucleus formation.
Guo et al. (2009) demonstrated that the C-Ala domain is universally
tethered to the editing domain both in alanyl-tRNA synthetase and in
many homologous free-standing editing proteins. Crystal structure and
functional analyses showed that C-Ala forms an ancient single-stranded
nucleic acid binding motif that promotes cooperative binding of both
aminoacylation and editing domains to tRNA(Ala). In addition, C-Ala may
have played an essential role in the evolution of alanyl-tRNA
synthetases by coupling aminoacylation to editing to prevent
mistranslation.
Mistranslation arising from confusion of serine for alanine by
alanyl-tRNA synthetases (AlaRSs) has profound functional consequences.
Throughout evolution, 2 editing checkpoints prevent disease-causing
mistranslation from confusing glycine or serine for alanine at the
active site of AlaRS. In both bacteria and mice, serine poses a bigger
challenge than glycine. One checkpoint is the AlaRS editing center, and
the other is from widely distributed AlaXps, free-standing,
genome-encoded editing proteins that clear Ser-tRNA(Ala) (AARSD1;
613212). The paradox of misincorporating both a smaller (glycine) and a
larger (serine) amino acid suggests a deep conflict for nature-designed
AlaRS. Guo et al. (2009) showed the chemical basis for this conflict.
Nine crystal structures, together with kinetic and mutational analysis,
provided snapshots of adenylate formation for each amino acid. An
inherent dilemma is posed by constraints of a structural design that
pins down the alpha-amino group of the bound amino acid by using an
acidic residue. This design, dating back more than 3 billion years,
creates a serendipitous interaction with the serine hydroxide that is
difficult to avoid. Apparently because no better architecture for the
recognition of alanine could be found, the serine misactivation problem
was solved through free-standing AlaXps, which appeared
contemporaneously with early AlaRSs.
ANIMAL MODEL
Lee et al. (2006) demonstrated that low levels of mischarged transfer
RNAs can lead to an intracellular accumulation of misfolded proteins in
neurons. These accumulations are accompanied by upregulation of
cytoplasmic protein chaperones and by induction of the unfolded protein
response. Lee et al. (2006) reported that the mouse 'sticky' (sti)
mutation, which causes cerebellar Purkinje cell loss and ataxia, is a
missense mutation in the editing domain of the alanyl-tRNA synthetase
gene that compromises the proofreading activity of this enzyme during
aminoacylation of tRNAs. Lee et al. (2006) concluded that their findings
demonstrated that disruption of translational fidelity in terminally
differentiated neurons leads to the accumulation of misfolded proteins
and cell death, and provided a novel mechanism underlying
neurodegeneration.
*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2N
AARS, ARG329HIS
In affected members of 2 unrelated French families with autosomal
dominant Charcot-Marie-Tooth disease type 2N (613287), Latour et al.
(2010) identified a heterozygous 986G-A transition in exon 8 of the AARS
gene, resulting in an arg329-to-his (R329H) substitution in the alpha-10
helix. This highly conserved residue is the ortholog of R314 in E. coli,
which is 1 of the major determinants for binding and efficient
aminoacylation of tRNAs. E. coli mutants in this residue showed
significant reduction in enzyme activity due to reduced binding, but the
authors also postulated that the mutation could result in qualitative
errors and the binding of noncognate tRNAs. The R329H mutation was not
found in 1,000 control chromosomes. Haplotype analysis excluded a
founder effect.
McLaughlin et al. (2012) identified a heterozygous R329H mutation in
affected members of an Australian family with CMT2N. The substitution
occurs within a highly conserved residue in the tRNA-binding domain.
Aminoacylation studies showed that the mutation reduced enzyme activity
by about 50% and was unable to complement deletion in yeast viability
studies. There did not appear to be a dominant-negative effect.
Haplotype analysis of this family and the 2 reported by Latour et al.
(2010) showed that the mutation occurred independently. Bisulfite
sequencing indicated that the mutation occurred via methylation-mediated
deamination of a CpG dinucleotide on the noncoding strand. The findings
indicated that R329H is a recurrent loss-of-function mutation.
.0002
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2N
AARS, ASN71TYR
In affected members of a Taiwanese family with CMT2N (613287), Lin et
al. (2011) identified a heterozygous mutation in the AARS gene,
resulting in an asn71-to-tyr (N71Y) substitution in a highly conserved
region in the catalytic domain. In vitro functional expression studies
by McLaughlin et al. (2012) showed that the mutant N71Y protein had
severe loss of enzymatic activity (4,130-fold decrease), and was unable
to complement loss of AARS in yeast viability studies. There was marked
variability in the age of onset (range, 11 to 45 years) and severity.
The proband presented at age 51 years with slowly progressive weakness
and atrophy of the legs that began at age 30 years after normal
development. Physical examination showed marked atrophy and mild
weakness of the muscles in the legs and feet, and milder atrophy and
weakness of the intrinsic hand muscles. He had absent ankle reflexes,
hyporeflexia, and mildly decreased distal sensation. His mother,
brother, and son had a similar disorder. His 2 younger sisters and
niece, who also carried the mutation, denied neurologic symptoms, but
neurologic examination showed distal muscle mild atrophy, weakness in
the intrinsic foot muscles, and generalized hyporeflexia in all of them.
*FIELD* RF
1. Chihade, J. W.; Brown, J. R.; Schimmel, P. R.; Ribas de Pouplana,
L.: Origin of mitochondria in relation to evolutionary history of
eukaryotic alanyl-tRNA synthetase. Proc. Nat. Acad. Sci. 97: 12153-12157,
2000.
2. Guo, M.; Chong, Y. E.; Beebe, K.; Shapiro, R.; Yang, X.-L.; Schimmel,
P.: The C-Ala domain brings together editing and aminoacylation functions
on one tRNA. Science 325: 744-747, 2009. Note: Erratum: Science
326: 46 only, 2009.
3. Guo, M.; Chong, Y. E.; Shapiro, R.; Beebe, K.; Yang, X.-L.; Schimmel,
P.: Paradox of mistranslation of serine for alanine caused by AlaRS
recognition dilemma. Nature 462: 808-812, 2009.
4. Latour, P.; Thauvin-Robinet, C.; Baudelet-Mery, C.; Soichot, P.;
Cusin, V.; Faivre, L.; Locatelli, M.-C.; Mayencon, M.; Sarcey, A.;
Broussolle, E.; Camu, W.; David, A.; Rousson, R.: A major determinant
for binding and aminoacylation of tRNA-Ala in cytoplasmic alanyl-tRNA
synthetase is mutated in dominant axonal Charcot-Marie-Tooth Disease. Am.
J. Hum. Genet. 86: 77-82, 2010.
5. Lee, J. W.; Beebe, K.; Nangle, L. A.; Jang, J.; Longo-Guess, C.
M.; Cook, S. A.; Davisson, M. T.; Sundberg, J. P.; Schimmel, P.; Ackerman,
S. L.: Editing-defective tRNA synthetase causes protein misfolding
and neurodegeneration. Nature 443: 50-55, 2006.
6. Lin, K.-P.; Soong, B.-W.; Yang, C.-C.; Huang, L.-W.; Chang, M.-H.;
Lee, I.-H.; Antonellis, A.; Lee, Y.-C.: The mutational spectrum in
a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese
in Taiwan. PLoS One 6: e29393, 2011. Note: Electronic Article. Note:
Erratum published online.
7. 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.
8. McLaughlin, H. M.; Sakaguchi, R.; Giblin, W.; NISC Comparative
Sequencing Program; Wilson, T. E.; Biesecker, L.; Lupski, J. R.;
Talbot, K.; Vance, J. M.; Zuchner, S.; Lee, Y.-C.; Kennerson, M.;
Hou, Y.-M.; Nicholson, G.; Antonellis, A.: A recurrent loss-of-function
alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth
disease type 2N (CMT2N). Hum. Mutat. 33: 244-253, 2012.
9. Nichols, R. C.; Pai, S. I.; Ge, Q.; Targoff, I. N.; Plotz, P. H.;
Liu, P.: Localization of two human autoantigen genes by PCR screening
and in situ hybridization--Glycyl-tRNA synthetase locates to 7p15
and alanyl-tRNA synthetase locates to 16q22. Genomics 30: 131-132,
1995.
10. Shen, L. X.; Basilion, J. P.; Stanton, V. P., Jr.: Single-nucleotide
polymorphisms can cause different structural folds of mRNA. Proc.
Nat. Acad. Sci. 96: 7871-7876, 1999.
11. Shiba, K.; Ripmaster, T.; Suzuki, N.; Nichols, R.; Plotz, P.;
Noda, T.: Schimmel, P.: Human alanyl-tRNA synthetase: conservation
in evolution of catalytic core and microhelix recognition. Biochemistry 34:
10340-10349, 1995.
*FIELD* CN
Cassandra L. Kniffin - updated: 1/9/2012
Cassandra L. Kniffin - updated: 3/1/2010
Ada Hamosh - updated: 1/8/2010
Ada Hamosh - updated: 11/13/2009
Ada Hamosh - updated: 9/1/2009
Ada Hamosh - updated: 9/20/2006
Victor A. McKusick - updated: 6/4/2001
Victor A. McKusick - updated: 11/27/2000
Victor A. McKusick - updated: 8/10/1999
*FIELD* CD
Alan F. Scott: 2/12/1996
*FIELD* ED
terry: 12/20/2012
carol: 1/19/2012
ckniffin: 1/9/2012
carol: 3/2/2010
ckniffin: 3/1/2010
alopez: 1/11/2010
terry: 1/8/2010
terry: 11/13/2009
alopez: 9/10/2009
terry: 9/1/2009
alopez: 10/3/2006
terry: 9/20/2006
alopez: 6/5/2001
terry: 6/4/2001
mcapotos: 12/11/2000
mcapotos: 12/6/2000
terry: 11/27/2000
alopez: 8/23/1999
terry: 8/10/1999
mark: 2/12/1996
MIM
613287
*RECORD*
*FIELD* NO
613287
*FIELD* TI
#613287 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2N; CMT2N
;;CHARCOT-MARIE-TOOTH NEUROPATHY, AXONAL, TYPE 2N;;
read moreCHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2N
*FIELD* TX
A number sign (#) is used with this entry because this form of axonal
Charcot-Marie-Tooth disease type 2, here designated CMT2N, is caused by
heterozygous mutation in the AARS gene (601065) on chromosome 16q21.
For a phenotypic description and a discussion of genetic heterogeneity
of axonal CMT, see CMT2A1 (118210).
CLINICAL FEATURES
Latour et al. (2010) reported a large 5-generation French family in
which at least 17 individuals had an axonal form of Charcot-Marie-Tooth
disease with a mean age at onset of 28 years (range, 6-54). One patient
was described in detail. She first noted symptoms at age 25 during her
first pregnancy. She had mild to moderate motor disability of the lower
right limb and occasional motor disability of the right hand. Physical
examination at age 30 showed normal gait, but difficulty standing on the
heels. She had bilateral distal motor weakness in the lower limbs
without amyotrophy or foot deformities, and weak reflexes. Examination
of the upper limbs was normal. All affected family members were
ambulatory, although 1 occasionally used a wheelchair. None had
pyramidal or cerebellar signs. Electromyographic studies showed a motor
and sensory axonal neuropathy with a mean motor nerve conduction
velocity of 41 m/s.
Lin et al. (2011) reported a Taiwanese family with autosomal dominant
CMT2N confirmed by genetic analysis (N71Y; 601065.0002). There was
marked variability in the age of onset (range, 11 to 45 years) and
severity. The proband presented at age 51 years with slowly progressive
weakness and atrophy of the legs that began at age 30 years after normal
development. Physical examination showed marked atrophy and mild
weakness of the muscles in the legs and feet, and milder atrophy and
weakness of the intrinsic hand muscles. He had absent ankle reflexes,
hyporeflexia, and mildly decreased distal sensation. His mother,
brother, and son had a similar disorder. His 2 younger sisters and
niece, who also carried the mutation, denied neurologic symptoms, but
neurologic examination showed distal muscle mild atrophy, weakness in
the intrinsic foot muscles, and generalized hyporeflexia in all of them.
McLaughlin et al. (2012) reported a large unrelated Australian family
with CMT2N confirmed by genetic analysis. Nine individuals showed
early-onset axonal neuropathy with variable sensorineural deafness.
Clinical features included progressive gait difficulty, foot drop, pes
cavus, and hammer toes. Nerve conduction velocities were within the
intermediate range, and audiology showed mild to moderate high frequency
sensorineural loss.
MAPPING
By genomewide scan of a large French family with an axonal form of CMT,
Latour et al. (2010) defined a new locus within a 7.1-cM (10.2-Mb)
region between markers D16S503 and D16S3018 (maximum 2-point parametric
lod score of 4.77 at D16S3050).
MOLECULAR GENETICS
In affected members of a large French family with axonal CMT, Latour et
al. (2010) identified a heterozygous mutation in the AARS gene (R329H;
601065.0001). Affected members of an unrelated affected French family
were found to carry the same mutation. Haplotype analysis excluded a
founder effect in these families.
McLaughlin et al. (2012) identified heterozygosity for the AARS R329H
mutation in affected members of an Australian family with CMT2N.
In affected members of a Taiwanese family with CMT2N, Lin et al. (2011)
identified a heterozygous mutation in the AARS gene (N71Y; 601065.0002).
*FIELD* RF
1. Latour, P.; Thauvin-Robinet, C.; Baudelet-Mery, C.; Soichot, P.;
Cusin, V.; Faivre, L.; Locatelli, M.-C.; Mayencon, M.; Sarcey, A.;
Broussolle, E.; Camu, W.; David, A.; Rousson, R.: A major determinant
for binding and aminoacylation of tRNA-Ala in cytoplasmic alanyl-tRNA
synthetase is mutated in dominant axonal Charcot-Marie-Tooth Disease. Am.
J. Hum. Genet. 86: 77-82, 2010.
2. Lin, K.-P.; Soong, B.-W.; Yang, C.-C.; Huang, L.-W.; Chang, M.-H.;
Lee, I.-H.; Antonellis, A.; Lee, Y.-C.: The mutational spectrum in
a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese
in Taiwan. PLoS One 6: e29393, 2011. Note: Electronic Article. Note:
Erratum published online.
3. McLaughlin, H. M.; Sakaguchi, R.; Giblin, W.; NISC Comparative
Sequencing Program; Wilson, T. E.; Biesecker, L.; Lupski, J. R.;
Talbot, K.; Vance, J. M.; Zuchner, S.; Lee, Y.-C.; Kennerson, M.;
Hou, Y.-M.; Nicholson, G.; Antonellis, A.: A recurrent loss-of-function
alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth
disease type 2N (CMT2N). Hum. Mutat. 33: 244-253, 2012.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Sensorineural deafness, variable (in 1 family)
SKELETAL:
[Limbs];
Ankle sprains;
[Feet];
Foot deformities;
Pes cavus;
Hammertoes
NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Lower limbs most affected;
Walking difficulties;
Foot drop;
Hypo- or areflexia;
Distal sensory impairment;
Axonal neuropathy;
Normal or mildly decreased motor nerve conduction velocity (NCV) (greater
than 38 m/s)
MISCELLANEOUS:
Variable age at onset (range 6 to 54 years);
Variable severity
MOLECULAR BASIS:
Caused by mutation in the alanyl-tRNA synthetase gene (AARS, 601065.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 1/9/2012
*FIELD* CD
Cassandra L. Kniffin: 3/1/2010
*FIELD* ED
joanna: 02/28/2012
ckniffin: 1/9/2012
ckniffin: 3/1/2010
*FIELD* CN
Cassandra L. Kniffin - updated: 1/9/2012
*FIELD* CD
Cassandra L. Kniffin: 3/1/2010
*FIELD* ED
carol: 10/25/2013
terry: 12/20/2012
carol: 1/19/2012
ckniffin: 1/9/2012
carol: 3/2/2010
ckniffin: 3/1/2010
*RECORD*
*FIELD* NO
613287
*FIELD* TI
#613287 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2N; CMT2N
;;CHARCOT-MARIE-TOOTH NEUROPATHY, AXONAL, TYPE 2N;;
read moreCHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2N
*FIELD* TX
A number sign (#) is used with this entry because this form of axonal
Charcot-Marie-Tooth disease type 2, here designated CMT2N, is caused by
heterozygous mutation in the AARS gene (601065) on chromosome 16q21.
For a phenotypic description and a discussion of genetic heterogeneity
of axonal CMT, see CMT2A1 (118210).
CLINICAL FEATURES
Latour et al. (2010) reported a large 5-generation French family in
which at least 17 individuals had an axonal form of Charcot-Marie-Tooth
disease with a mean age at onset of 28 years (range, 6-54). One patient
was described in detail. She first noted symptoms at age 25 during her
first pregnancy. She had mild to moderate motor disability of the lower
right limb and occasional motor disability of the right hand. Physical
examination at age 30 showed normal gait, but difficulty standing on the
heels. She had bilateral distal motor weakness in the lower limbs
without amyotrophy or foot deformities, and weak reflexes. Examination
of the upper limbs was normal. All affected family members were
ambulatory, although 1 occasionally used a wheelchair. None had
pyramidal or cerebellar signs. Electromyographic studies showed a motor
and sensory axonal neuropathy with a mean motor nerve conduction
velocity of 41 m/s.
Lin et al. (2011) reported a Taiwanese family with autosomal dominant
CMT2N confirmed by genetic analysis (N71Y; 601065.0002). There was
marked variability in the age of onset (range, 11 to 45 years) and
severity. The proband presented at age 51 years with slowly progressive
weakness and atrophy of the legs that began at age 30 years after normal
development. Physical examination showed marked atrophy and mild
weakness of the muscles in the legs and feet, and milder atrophy and
weakness of the intrinsic hand muscles. He had absent ankle reflexes,
hyporeflexia, and mildly decreased distal sensation. His mother,
brother, and son had a similar disorder. His 2 younger sisters and
niece, who also carried the mutation, denied neurologic symptoms, but
neurologic examination showed distal muscle mild atrophy, weakness in
the intrinsic foot muscles, and generalized hyporeflexia in all of them.
McLaughlin et al. (2012) reported a large unrelated Australian family
with CMT2N confirmed by genetic analysis. Nine individuals showed
early-onset axonal neuropathy with variable sensorineural deafness.
Clinical features included progressive gait difficulty, foot drop, pes
cavus, and hammer toes. Nerve conduction velocities were within the
intermediate range, and audiology showed mild to moderate high frequency
sensorineural loss.
MAPPING
By genomewide scan of a large French family with an axonal form of CMT,
Latour et al. (2010) defined a new locus within a 7.1-cM (10.2-Mb)
region between markers D16S503 and D16S3018 (maximum 2-point parametric
lod score of 4.77 at D16S3050).
MOLECULAR GENETICS
In affected members of a large French family with axonal CMT, Latour et
al. (2010) identified a heterozygous mutation in the AARS gene (R329H;
601065.0001). Affected members of an unrelated affected French family
were found to carry the same mutation. Haplotype analysis excluded a
founder effect in these families.
McLaughlin et al. (2012) identified heterozygosity for the AARS R329H
mutation in affected members of an Australian family with CMT2N.
In affected members of a Taiwanese family with CMT2N, Lin et al. (2011)
identified a heterozygous mutation in the AARS gene (N71Y; 601065.0002).
*FIELD* RF
1. Latour, P.; Thauvin-Robinet, C.; Baudelet-Mery, C.; Soichot, P.;
Cusin, V.; Faivre, L.; Locatelli, M.-C.; Mayencon, M.; Sarcey, A.;
Broussolle, E.; Camu, W.; David, A.; Rousson, R.: A major determinant
for binding and aminoacylation of tRNA-Ala in cytoplasmic alanyl-tRNA
synthetase is mutated in dominant axonal Charcot-Marie-Tooth Disease. Am.
J. Hum. Genet. 86: 77-82, 2010.
2. Lin, K.-P.; Soong, B.-W.; Yang, C.-C.; Huang, L.-W.; Chang, M.-H.;
Lee, I.-H.; Antonellis, A.; Lee, Y.-C.: The mutational spectrum in
a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese
in Taiwan. PLoS One 6: e29393, 2011. Note: Electronic Article. Note:
Erratum published online.
3. McLaughlin, H. M.; Sakaguchi, R.; Giblin, W.; NISC Comparative
Sequencing Program; Wilson, T. E.; Biesecker, L.; Lupski, J. R.;
Talbot, K.; Vance, J. M.; Zuchner, S.; Lee, Y.-C.; Kennerson, M.;
Hou, Y.-M.; Nicholson, G.; Antonellis, A.: A recurrent loss-of-function
alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth
disease type 2N (CMT2N). Hum. Mutat. 33: 244-253, 2012.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Ears];
Sensorineural deafness, variable (in 1 family)
SKELETAL:
[Limbs];
Ankle sprains;
[Feet];
Foot deformities;
Pes cavus;
Hammertoes
NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Lower limbs most affected;
Walking difficulties;
Foot drop;
Hypo- or areflexia;
Distal sensory impairment;
Axonal neuropathy;
Normal or mildly decreased motor nerve conduction velocity (NCV) (greater
than 38 m/s)
MISCELLANEOUS:
Variable age at onset (range 6 to 54 years);
Variable severity
MOLECULAR BASIS:
Caused by mutation in the alanyl-tRNA synthetase gene (AARS, 601065.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 1/9/2012
*FIELD* CD
Cassandra L. Kniffin: 3/1/2010
*FIELD* ED
joanna: 02/28/2012
ckniffin: 1/9/2012
ckniffin: 3/1/2010
*FIELD* CN
Cassandra L. Kniffin - updated: 1/9/2012
*FIELD* CD
Cassandra L. Kniffin: 3/1/2010
*FIELD* ED
carol: 10/25/2013
terry: 12/20/2012
carol: 1/19/2012
ckniffin: 1/9/2012
carol: 3/2/2010
ckniffin: 3/1/2010