LOCUS       NM_002197               7443 bp    mRNA    linear   PRI 24-OCT-2024
DEFINITION  Homo sapiens aconitase 1 (ACO1), transcript variant 2, mRNA.
ACCESSION   NM_002197
VERSION     NM_002197.3
KEYWORDS    RefSeq; MANE Select.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (bases 1 to 7443)
  AUTHORS   Fahoum,L., Moshe-Belisowski,S., Zaydel,K., Ghatpande,N.,
            Guttmann-Raviv,N., Zhang,W., Li,K., Tong,W.H., Nyska,A.,
            Waterman,M., Weisshof,R., Zuckerman,A. and Meyron-Holtz,E.G.
  TITLE     Iron regulatory protein 1 is required for the propagation of
            inflammation in inflammatory bowel disease
  JOURNAL   J Biol Chem 300 (9), 107639 (2024)
   PUBMED   39122013
  REMARK    GeneRIF: Iron regulatory protein 1 is required for the propagation
            of inflammation in inflammatory bowel disease.
REFERENCE   2  (bases 1 to 7443)
  AUTHORS   Gu,W., Fillebeen,C. and Pantopoulos,K.
  TITLE     Human IRP1 Translocates to the Nucleus in a Cell-Specific and
            Iron-Dependent Manner
  JOURNAL   Int J Mol Sci 23 (18), 10740 (2022)
   PUBMED   36142654
  REMARK    GeneRIF: Human IRP1 Translocates to the Nucleus in a Cell-Specific
            and Iron-Dependent Manner.
            Publication Status: Online-Only
REFERENCE   3  (bases 1 to 7443)
  AUTHORS   Zhang,T., Sun,L., Hao,Y., Suo,C., Shen,S., Wei,H., Ma,W., Zhang,P.,
            Wang,T., Gu,X., Li,S.T., Chen,Z., Yan,R., Zhang,Y., Cai,Y.,
            Zhou,R., Jia,W., Huang,F., Gao,P. and Zhang,H.
  TITLE     ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of
            iron regulatory protein 1
  JOURNAL   Nat Cancer 3 (1), 75-89 (2022)
   PUBMED   35121990
  REMARK    GeneRIF: ENO1 suppresses cancer cell ferroptosis by degrading the
            mRNA of iron regulatory protein 1.
REFERENCE   4  (bases 1 to 7443)
  AUTHORS   Hognon,C., Bignon,E., Harle,G., Touche,N., Grandemange,S. and
            Monari,A.
  TITLE     The Iron Maiden. Cytosolic Aconitase/IRP1 Conformational Transition
            in the Regulation of Ferritin Translation and Iron Hemostasis
  JOURNAL   Biomolecules 11 (9), 1329 (2021)
   PUBMED   34572542
  REMARK    GeneRIF: The Iron Maiden. Cytosolic Aconitase/IRP1 Conformational
            Transition in the Regulation of Ferritin Translation and Iron
            Hemostasis.
            Publication Status: Online-Only
REFERENCE   5  (bases 1 to 7443)
  AUTHORS   Oskarsson,G.R., Oddsson,A., Magnusson,M.K., Kristjansson,R.P.,
            Halldorsson,G.H., Ferkingstad,E., Zink,F., Helgadottir,A.,
            Ivarsdottir,E.V., Arnadottir,G.A., Jensson,B.O., Katrinardottir,H.,
            Sveinbjornsson,G., Kristinsdottir,A.M., Lee,A.L.,
            Saemundsdottir,J., Stefansdottir,L., Sigurdsson,J.K.,
            Davidsson,O.B., Benonisdottir,S., Jonasdottir,A., Jonasdottir,A.,
            Jonsson,S., Gudmundsson,R.L., Asselbergs,F.W., Tragante,V.,
            Gunnarsson,B., Masson,G., Thorleifsson,G., Rafnar,T., Holm,H.,
            Olafsson,I., Onundarson,P.T., Gudbjartsson,D.F., Norddahl,G.L.,
            Thorsteinsdottir,U., Sulem,P. and Stefansson,K.
  TITLE     Predicted loss and gain of function mutations in ACO1 are
            associated with erythropoiesis
  JOURNAL   Commun Biol 3 (1), 189 (2020)
   PUBMED   32327693
  REMARK    GeneRIF: Predicted loss and gain of function mutations in ACO1 are
            associated with erythropoiesis.
            Publication Status: Online-Only
REFERENCE   6  (bases 1 to 7443)
  AUTHORS   Philpott,C.C., Klausner,R.D. and Rouault,T.A.
  TITLE     The bifunctional iron-responsive element binding protein/cytosolic
            aconitase: the role of active-site residues in ligand binding and
            regulation
  JOURNAL   Proc Natl Acad Sci U S A 91 (15), 7321-7325 (1994)
   PUBMED   8041788
  REMARK    GeneRIF: Aco1 encodes a moonlighting protein that has aconitase
            activity as well as mRNA binding ability.
REFERENCE   7  (bases 1 to 7443)
  AUTHORS   Haile,D.J., Rouault,T.A., Harford,J.B., Kennedy,M.C., Blondin,G.A.,
            Beinert,H. and Klausner,R.D.
  TITLE     Cellular regulation of the iron-responsive element binding protein:
            disassembly of the cubane iron-sulfur cluster results in
            high-affinity RNA binding
  JOURNAL   Proc Natl Acad Sci U S A 89 (24), 11735-11739 (1992)
   PUBMED   1281544
REFERENCE   8  (bases 1 to 7443)
  AUTHORS   Hirling,H., Emery-Goodman,A., Thompson,N., Neupert,B., Seiser,C.
            and Kuhn,L.C.
  TITLE     Expression of active iron regulatory factor from a full-length
            human cDNA by in vitro transcription/translation
  JOURNAL   Nucleic Acids Res 20 (1), 33-39 (1992)
   PUBMED   1738601
REFERENCE   9  (bases 1 to 7443)
  AUTHORS   Kaptain,S., Downey,W.E., Tang,C., Philpott,C., Haile,D.,
            Orloff,D.G., Harford,J.B., Rouault,T.A. and Klausner,R.D.
  TITLE     A regulated RNA binding protein also possesses aconitase activity
  JOURNAL   Proc Natl Acad Sci U S A 88 (22), 10109-10113 (1991)
   PUBMED   1946430
REFERENCE   10 (bases 1 to 7443)
  AUTHORS   Hentze,M.W. and Argos,P.
  TITLE     Homology between IRE-BP, a regulatory RNA-binding protein,
            aconitase, and isopropylmalate isomerase
  JOURNAL   Nucleic Acids Res 19 (8), 1739-1740 (1991)
   PUBMED   1903202
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from DA409113.1, BC018103.1 and
            AL161783.20.
            
            On Nov 23, 2018 this sequence version replaced NM_002197.2.
            
            Summary: The protein encoded by this gene is a bifunctional,
            cytosolic protein that functions as an essential enzyme in the TCA
            cycle and interacts with mRNA to control the levels of iron inside
            cells. When cellular iron levels are high, this protein binds to a
            4Fe-4S cluster and functions as an aconitase. Aconitases are
            iron-sulfur proteins that function to catalyze the conversion of
            citrate to isocitrate. When cellular iron levels are low, the
            protein binds to iron-responsive elements (IREs), which are
            stem-loop structures found in the 5' UTR of ferritin mRNA, and in
            the 3' UTR of transferrin receptor mRNA. When the protein binds to
            IRE, it results in repression of translation of ferritin mRNA, and
            inhibition of degradation of the otherwise rapidly degraded
            transferrin receptor mRNA. The encoded protein has been identified
            as a moonlighting protein based on its ability to perform
            mechanistically distinct functions. Alternative splicing results in
            multiple transcript variants [provided by RefSeq, Jan 2014].
            
            Transcript Variant: This variant (2) differs in the 5' UTR compared
            to variant 1. Variants 1, 2 and 3 encode the same protein.
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            Transcript exon combination :: SRR1803617.88108.1,
                                           SRR1803615.81823.1 [ECO:0000332]
            RNAseq introns              :: single sample supports all introns
                                           SAMEA1965299, SAMEA1966682
                                           [ECO:0000348]
            ##Evidence-Data-END##
            
            ##RefSeq-Attributes-START##
            MANE Ensembl match              :: ENST00000309951.8/
                                               ENSP00000309477.5
            multifunctional gene product(s) :: PMID: 8041788
            RefSeq Select criteria          :: based on conservation,
                                               expression
            ##RefSeq-Attributes-END##
            COMPLETENESS: full length.
PRIMARY     REFSEQ_SPAN         PRIMARY_IDENTIFIER PRIMARY_SPAN        COMP
            1-510               DA409113.1         41-550
            511-3510            BC018103.1         433-3432
            3511-7443           AL161783.20        98483-102415
FEATURES             Location/Qualifiers
     source          1..7443
                     /organism="Homo sapiens"
                     /mol_type="mRNA"
                     /db_xref="taxon:9606"
                     /chromosome="9"
                     /map="9p21.1"
     gene            1..7443
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /note="aconitase 1"
                     /db_xref="GeneID:48"
                     /db_xref="HGNC:HGNC:117"
                     /db_xref="MIM:100880"
     exon            1..93
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            94..212
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     CDS             116..2785
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /EC_number="4.2.1.3"
                     /note="iron regulatory protein 1; ferritin repressor
                     protein; epididymis luminal protein 60; citrate
                     hydro-lyase; iron-responsive element-binding protein 1;
                     aconitate hydratase, cytoplasmic; aconitase 1, soluble;
                     soluble aconitase; cytoplasmic aconitase; cytosplasmic
                     aconitase; epididymis secretory sperm binding protein"
                     /codon_start=1
                     /product="cytoplasmic aconitate hydratase"
                     /protein_id="NP_002188.1"
                     /db_xref="CCDS:CCDS6525.1"
                     /db_xref="GeneID:48"
                     /db_xref="HGNC:HGNC:117"
                     /db_xref="MIM:100880"
                     /translation="MSNPFAHLAEPLDPVQPGKKFFNLNKLEDSRYGRLPFSIRVLLE
                     AAIRNCDEFLVKKQDIENILHWNVTQHKNIEVPFKPARVILQDFTGVPAVVDFAAMRD
                     AVKKLGGDPEKINPVCPADLVIDHSIQVDFNRRADSLQKNQDLEFERNRERFEFLKWG
                     SQAFHNMRIIPPGSGIIHQVNLEYLARVVFDQDGYYYPDSLVGTDSHTTMIDGLGILG
                     WGVGGIEAEAVMLGQPISMVLPQVIGYRLMGKPHPLVTSTDIVLTITKHLRQVGVVGK
                     FVEFFGPGVAQLSIADRATIANMCPEYGATAAFFPVDEVSITYLVQTGRDEEKLKYIK
                     KYLQAVGMFRDFNDPSQDPDFTQVVELDLKTVVPCCSGPKRPQDKVAVSDMKKDFESC
                     LGAKQGFKGFQVAPEHHNDHKTFIYDNTEFTLAHGSVVIAAITSCTNTSNPSVMLGAG
                     LLAKKAVDAGLNVMPYIKTSLSPGSGVVTYYLQESGVMPYLSQLGFDVVGYGCMTCIG
                     NSGPLPEPVVEAITQGDLVAVGVLSGNRNFEGRVHPNTRANYLASPPLVIAYAIAGTI
                     RIDFEKEPLGVNAKGQQVFLKDIWPTRDEIQAVERQYVIPGMFKEVYQKIETVNESWN
                     ALATPSDKLFFWNSKSTYIKSPPFFENLTLDLQPPKSIVDAYVLLNLGDSVTTDHISP
                     AGNIARNSPAARYLTNRGLTPREFNSYGSRRGNDAVMARGTFANIRLLNRFLNKQAPQ
                     TIHLPSGEILDVFDAAERYQQAGLPLIVLAGKEYGAGSSRDWAAKGPFLLGIKAVLAE
                     SYERIHRSNLVGMGVIPLEYLPGENADALGLTGQERYTIIIPENLKPQMKVQVKLDTG
                     KTFQAVMRFDTDVELTYFLNGGILNYMIRKMAK"
     exon            213..381
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            382..519
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            520..589
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            590..773
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            774..913
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            914..1085
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            1086..1186
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            1187..1303
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            1304..1463
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            1464..1599
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            1600..1684
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            1685..1841
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            1842..1966
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            1967..2071
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            2072..2214
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            2215..2362
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            2363..2485
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            2486..2671
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     exon            2672..7443
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /inference="alignment:Splign:2.1.0"
     regulatory      3487..3492
                     /regulatory_class="polyA_signal_sequence"
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /note="hexamer: AATGAA"
     polyA_site      3510
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /note="major polyA site"
     regulatory      7423..7428
                     /regulatory_class="polyA_signal_sequence"
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
                     /note="hexamer: ATTAAA"
     polyA_site      7443
                     /gene="ACO1"
                     /gene_synonym="ACONS; HEL60; IREB1; IREBP; IREBP1; IRP1"
ORIGIN      
        1 gaggcggcag ctggaaccgc gcagcgcacg ggaacgcgtc ccgctgcttg ggtcaggttc
       61 gccggtcgcg ggagccccgc cgtgcagtcg gaggaacacg tggccatcag taatcatgag
      121 caacccattc gcacaccttg ctgagccatt ggatcctgta caaccaggaa agaaattctt
      181 caatttgaat aaattggagg attcaagata tgggcgctta ccattttcga tcagagttct
      241 tctggaagca gccattcgga attgtgatga gtttttggtg aagaaacagg atattgaaaa
      301 tattctacat tggaatgtca cgcagcacaa gaacatagaa gtgccattta agcctgctcg
      361 tgtcatcctg caggacttta cgggtgtgcc cgctgtggtt gactttgctg caatgcgtga
      421 tgctgtgaaa aagttaggag gagatccaga gaaaataaac cctgtctgcc ctgctgatct
      481 tgtaatagat cattccatcc aggttgattt caacagaagg gcagacagtt tacagaagaa
      541 tcaagacctg gaatttgaaa gaaatagaga gcgatttgaa tttttaaagt ggggttccca
      601 ggcttttcac aacatgcgga ttattccccc tggctcagga atcatccacc aggtgaattt
      661 ggaatatttg gcaagagtgg tatttgatca ggatggatat tattacccag acagcctcgt
      721 gggcacagac tcgcacacta ccatgattga tggcttgggc attcttggtt ggggtgtcgg
      781 tggtattgaa gcagaagctg tcatgctggg tcagccaatc agtatggtgc ttcctcaggt
      841 gattggctac aggctgatgg ggaagcccca ccctctggta acatccactg acatcgtgct
      901 caccattacc aagcacctcc gccaggttgg ggtagtgggc aaatttgtcg agttcttcgg
      961 gcctggagta gcccagttgt ccattgctga ccgagctacg attgctaaca tgtgtccaga
     1021 gtacggagca actgctgcct ttttcccagt tgatgaagtt agtatcacgt acctggtgca
     1081 aacaggtcgt gatgaagaaa aattaaagta tattaaaaaa tatcttcagg ctgtaggaat
     1141 gtttcgagat ttcaatgacc cttctcaaga cccagacttc acccaggttg tggaattaga
     1201 tttgaaaaca gtagtgcctt gctgtagtgg acccaaaagg cctcaggaca aagttgctgt
     1261 gtccgacatg aaaaaggact ttgagagctg ccttggagcc aagcaaggat ttaaaggatt
     1321 ccaagttgct cctgaacatc ataatgacca taagaccttt atctatgata acactgaatt
     1381 cacccttgct catggttctg tggtcattgc tgccattact agctgcacaa acaccagtaa
     1441 tccgtctgtg atgttagggg caggattgtt agcaaagaaa gctgtggatg ctggcctgaa
     1501 cgtgatgcct tacatcaaaa ctagcctgtc tcctgggagt ggcgtggtca cctactacct
     1561 acaagaaagc ggagtcatgc cttatctgtc tcagcttggg tttgacgtgg tgggctatgg
     1621 ctgcatgacc tgcattggca acagtgggcc tttacctgaa cctgtggtag aagccatcac
     1681 acagggagac cttgtagctg ttggagtact atctggaaac aggaattttg aaggtcgagt
     1741 tcaccccaac acccgggcca actatttagc ctctcccccc ttagtaatag catatgcaat
     1801 tgctggaacc atcagaatcg actttgagaa agagccattg ggagtaaatg caaagggaca
     1861 gcaggtattt ctgaaagata tctggccgac tagagacgag atccaggcag tggagcgtca
     1921 gtatgtcatc ccggggatgt ttaaggaagt ctatcagaaa atagagactg tgaatgaaag
     1981 ctggaatgcc ttagcaaccc catcagataa gctgtttttc tggaattcca aatctacgta
     2041 tatcaaatca ccaccattct ttgaaaacct gactttggat cttcagcccc ctaaatctat
     2101 agtggatgcc tatgtgctgc taaatttggg agattcggta acaactgacc acatctcccc
     2161 agctggaaat attgcaagaa acagtcctgc tgctcgctac ttaactaaca gaggcctaac
     2221 tccacgagaa ttcaactcct atggctcccg ccgaggtaat gacgccgtca tggcacgggg
     2281 aacatttgcc aacattcgct tgttaaacag atttttgaac aagcaggcac cacagactat
     2341 ccatctgcct tctggggaaa tccttgatgt gtttgatgct gctgagcggt accagcaggc
     2401 aggccttccc ctgatcgttc tggctggcaa agagtacggt gcaggcagct cccgagactg
     2461 ggcagctaag ggccctttcc tgctgggaat caaagccgtc ctggccgaga gctacgagcg
     2521 cattcaccgc agtaacctgg ttgggatggg tgtgatccca cttgaatatc tccctggtga
     2581 gaatgcagat gccctggggc tcacagggca agaacgatac actatcatta ttccagaaaa
     2641 cctcaaacca caaatgaaag tccaggtcaa gctggatact ggcaagacct tccaggctgt
     2701 catgaggttt gacactgatg tggagctcac ttatttcctc aacgggggca tcctcaacta
     2761 catgatccgc aagatggcca agtaggagac gtgcacttgg tgctgcgccc agggaggaag
     2821 ccgcaccacc agccagcgca ggccctggtg gagaggcctc cctggctgcc tctgggaggg
     2881 gtgctgcctt gtagatggag caagtgagca ctgagggtct ggtgccaatc ctgtaggcac
     2941 aaaaccagaa gtttctacat tctctatttt tgttaatcat cttctctttt tccagaattt
     3001 ggaagctaga atggtgggaa tgtcagtagt gccagaaaga gagaaccaag cttgtcttta
     3061 aagttactga tcacaggacg ttgctttttc actgtttcct attaatcttc agctgaacac
     3121 aagcaaacct tctcaggagg tgtctcctac cctcttattg ttcctcttac gctctgctca
     3181 atgaaacctt cctcttgagg gtcattttcc tttctgtatt aattatacca gtgttaagtg
     3241 acatagataa gaactttgca cacttcaaat cagagcagtg attctctctt ctctcccctt
     3301 ttccttcaga gtgaatcatc cagactcctc atggataggt cgggtgttaa agttgttttg
     3361 attatgtacc ttttgataga tccacataaa aagaaatgtg aagttttctt ttactatctt
     3421 ttcatttatc aagcagagac ctttgttggg aggcggtttg ggagaacaca tttctaattt
     3481 gaatgaaatg aaatctattt tcagtgaaaa cttgttgact ttgagttttg ctgtgtttgt
     3541 ggctagagtt ttgggatatt tagtacagag tgaatctcac accatatcat tgggaagcct
     3601 gaataacctt catattctcc catttttaca actctatcag aactgtacgg gtataacgga
     3661 aatgtttagg aaccattatg ctcgctcttc cctgtttggg agcagacaag aaggaagagt
     3721 agcctggtgg cagtggcaac gatataagta cataaggaaa agcagataaa cttcaggaca
     3781 ctaaaaacca attatctgct catttttacc cctgtagtca tttctgggca tgccttagtt
     3841 tgcttgggtt gctataatgt aatgccatag actggctgaa agaacagaaa tgtattttct
     3901 cacagttatg gaggctggaa ttctgagatc aaagttgaag ccacttcatt ttctggtgag
     3961 gacactcttc ctggtttaca gatggccacc ttcttgcttg ttctcacatg gcatttcttt
     4021 ggtatgtgcc tggtggggga gagagaaaat aggctctcat gtctcttctt acagcaacac
     4081 taattgtatt ggatcagggt cccactctta tggagaccca ggaaagctgg tggtataaca
     4141 acttggttca agtccaaatg cctaagaacc tggggagggg catggggaat gctggtataa
     4201 gtcccagagt ctgaatgccc aggaacaagc aggagctgtg atgtccaagg acaggagggc
     4261 aggatctttg taatgaattt ttaatgtcaa ccttagcact caggggatat ggcctggtca
     4321 tcagaacatc tggaatctaa tcctctttct acttctcacc agatgaggga tcaagacagg
     4381 ttatttagca tccctgcact tgcggtcctg gggatcttat ttatattcat ttaaaaaata
     4441 aattacaaac aaacagccag gcgcagtggc tcatgcctat aattccatca ctttgggagg
     4501 ccgaggtggg tagatcacct gaggtcagga gttctagacc agcctggcca acatggtgaa
     4561 accccgtctc tactaaaaat acaaaaaatt agccaggtgt ggtattgtgt gcctgtaatc
     4621 ccagctacac aggaggctga ggcaggagaa ttgcttaaac ccgggatgca gaggctgcag
     4681 tgagccgaga tcgtgccatt gcacgcccgc ctgggctaca agagcaaagc tccgtctcaa
     4741 aaaaaaaaaa aaattacaaa caaacagaac tccattgtac aaaaaaacct gtgatcctca
     4801 agttaagatc agtcctagaa taaaaacact aagaatggct gagaaaacag acctccaccc
     4861 tctcagctct ccattactga gcagctgggg agctgtctcg ctccccgcat tcagtggctc
     4921 ctgtggtctg tatttttgta tcctccccaa aattcaggtg gtgaaacctt aaccccccag
     4981 gtaatggtaa tagaagctgg ggcctttgga aggtgattag atcatgaggg tagtgccttt
     5041 taaaagagac tcaagataag atagagaccc cctcatttct tctgccatgg gagaacacag
     5101 caagaagtca ccatccgtga accagaaagt gggttctcac cagatactga atctgccagt
     5161 gccttgaacc tagactttcc agccagaact gtgagaaatt tctattgttt ataagccacc
     5221 cagttgatat ttagttacag cagcccaacc aagactgtgg ttatgaggaa acaaacacat
     5281 tattgtggct agactaatgg aattgggtcc cttacctcca agtacaccct ctgtcctttt
     5341 cggtaaaaat atcttcgcca ggcacggtgt ctcatgccta tgatcccaac actttgggag
     5401 gccgaggctg gagggttgct tgagcccaga agtttgagac cagcctgggc aacactctac
     5461 aaaaaaaaaa ataaataaat aaataaataa aataaatcag ccaggtgtgc acctgtggtc
     5521 ccagctgttc aggaggctga ggtgggagga tcacttgagc ctgggaggtc gtggctatga
     5581 ttgctccact gcactccagc ctgggcaata gagtgagacc ctatcaatca atcaccaccc
     5641 cccccccccc caaaaaaaaa agtatcttgg ccagtgtctc aaccttgccc actaacaagc
     5701 ctaaataaac caacttcttt tacctggttc tttaagggct gctcgtctta ctatccaaat
     5761 taaaaatctg ctgttctccc tcccatattc tttgcgaatg aagattcccc tgtttgtttg
     5821 gatagttttc caaattcatt actgcattcc tggcatccgc agcaagctaa gagttagtta
     5881 atatttttaa tatagcaaat aaggatgagg gatgcccttc atgtgtattt acacaccaga
     5941 tttttatggt acatagggag taatctaggg aaaagatata ttaggcatga atcttagctg
     6001 tggtagaagc acagctcaaa ttagcttaag gaaaaaaaaa aaaaagctgg ctcatagaac
     6061 ttgaggacag tggtggccat gactatgggc ttgattggat ctagtgactc aagctccctt
     6121 ccatttgccc ctccaaccac ccccccatcc ctccaccaat cataccttct gttggcctct
     6181 gcagtagagt ggcctcttct gggcccttcc acatgccagg ggatatggcc accagcagtt
     6241 ctggggaaac cattagtaat ttgtgatcgt agagatttgt ctcccagtat tccctagggc
     6301 aaaaatattg ggagttccta gtcacctaaa tgaagaacct tatttttagc agtttccctt
     6361 tcagggctct aacaggactg tggagtaatg tacggggtta tgtaggagca atgcagagcc
     6421 acttttgaaa aacagtagcc aaggttctac tggctgcctt cttaggacat tattaaatat
     6481 cataaacaca agtggaattt aacacccagc cagtttgtgt tcaaccagac agcgtcatta
     6541 tgaacaaaga ttatataacg atagctgata ttaagtaagt tttaaaagtt gacatcccaa
     6601 gagtgaagcc tacttattca gtacagattt gttgaatgaa attcgtagtt ttattttacg
     6661 gcataatgaa acagagttcc agacatgtac ctgccaaatt tggttctggt tgtcttatcg
     6721 tatgcaggct ggatacctgc tactgtgctt ctacaggatg ttaacagtgt cccctgagta
     6781 aaacagttcc acggtcagta catttgggaa ccactgagtt aaatgggttt tatcactgca
     6841 gaacagacac aagaacaatg tgtgctgtaa atcactgttt gcagggaagg tggcagcaaa
     6901 tggcacagaa acccacctga ccacagactg ctttcttctg ggcgttcacg cactgtgctc
     6961 cacaggatac tcttgagaaa cattgagcta tggttggtct gttgtttgaa attcaaataa
     7021 taatgaatcc attttaagga caggaattgg tttactgacc ttgatgttgg gatgactctt
     7081 catttcaggg tgaaaatatc acagcatcag cacaggccag gaccacagag ataacaaggt
     7141 ggtagttgtg taacaggttg tgtctgaacc acaggagctt caaaacatac acggctggac
     7201 accctgccag gatgctctaa tggggctggg catgtgtcca tgaaaaagac tccccagttg
     7261 tttctaaaat gtggcctttg ttctagaaat gcaatgacca gcatttggga gtcagtcaaa
     7321 agatccactt cctaaaagcc tacctgctca tttctttcat tcaatacata ttaaccaagt
     7381 gcctactttg tttgagtcca tgcctggcaa tgacattatt ccattaaaag tcaaacaagg
     7441 aaa
//
