LOCUS       NM_001348768           12006 bp    mRNA    linear   PRI 07-FEB-2025
DEFINITION  Homo sapiens HECT, C2 and WW domain containing E3 ubiquitin protein
            ligase 2 (HECW2), transcript variant 3, mRNA.
ACCESSION   NM_001348768
VERSION     NM_001348768.2
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 12006)
  AUTHORS   Acharya,A., Kavus,H., Dunn,P., Nasir,A., Folk,L., Withrow,K.,
            Wentzensen,I.M., Ruzhnikov,M.R.Z., Fallot,C., Smol,T., Rama,M.,
            Brown,K., Whalen,S., Ziegler,A., Barth,M., Chassevent,A.,
            Smith-Hicks,C., Afenjar,A., Courtin,T., Heide,S.,
            Font-Montgomery,E., Heid,C., Hamm,J.A., Love,D.R., Thabet,F.,
            Misra,V.K., Cunningham,M., Leal,S.M., Jarvela,I., Normand,E.A.,
            Zou,F., Helal,M., Keren,B., Torti,E., Chung,W.K. and Schrauwen,I.
  TITLE     Delineating the genotypic and phenotypic spectrum of HECW2-related
            neurodevelopmental disorders
  JOURNAL   J Med Genet 59 (7), 669-677 (2022)
   PUBMED   34321324
  REMARK    GeneRIF: Delineating the genotypic and phenotypic spectrum of
            HECW2-related neurodevelopmental disorders.
            Review article
REFERENCE   2  (bases 1 to 12006)
  AUTHORS   Tsunoda,T., Riku,M., Yamada,N., Tsuchiya,H., Tomita,T., Suzuki,M.,
            Kizuki,M., Inoko,A., Ito,H., Murotani,K., Murakami,H., Saeki,Y. and
            Kasai,K.
  TITLE     ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activator that
            is downregulated in breast cancer
  JOURNAL   EMBO Rep 23 (2), e51182 (2022)
   PUBMED   34927784
REFERENCE   3  (bases 1 to 12006)
  AUTHORS   Wang,X., Liu,L., Zhang,L., Guo,J., Yu,L. and Li,T.
  TITLE     Circ_0057583 facilitates brain microvascular endothelial cell
            injury through modulating miR-204-5p/NR4A1 axis
  JOURNAL   Metab Brain Dis 37 (2), 501-511 (2022)
   PUBMED   34767155
  REMARK    GeneRIF: Circ_0057583 facilitates brain microvascular endothelial
            cell injury through modulating miR-204-5p/NR4A1 axis.
REFERENCE   4  (bases 1 to 12006)
  AUTHORS   Heide,E.C., Puk,O., Biskup,S., Krahn,A., Rauf,E., Kreilkamp,B.A.K.,
            Paulus,W. and Focke,N.K.
  TITLE     A novel likely pathogenic heterozygous HECW2 missense variant in a
            family with variable expressivity of neurodevelopmental delay,
            hypotonia, and epileptiform EEG patterns
  JOURNAL   Am J Med Genet A 185 (12), 3838-3843 (2021)
   PUBMED   34327820
  REMARK    GeneRIF: A novel likely pathogenic heterozygous HECW2 missense
            variant in a family with variable expressivity of
            neurodevelopmental delay, hypotonia, and epileptiform EEG patterns.
REFERENCE   5  (bases 1 to 12006)
  AUTHORS   Yanagishita,T., Hirade,T., Shimojima Yamamoto,K., Funatsuka,M.,
            Miyamoto,Y., Maeda,M., Yanagi,K., Kaname,T., Nagata,S., Nagata,M.,
            Ishihara,Y., Miyashita,Y., Asano,Y., Sakata,Y., Kosaki,K. and
            Yamamoto,T.
  TITLE     HECW2-related disorder in four Japanese patients
  JOURNAL   Am J Med Genet A 185 (10), 2895-2902 (2021)
   PUBMED   34047014
  REMARK    GeneRIF: HECW2-related disorder in four Japanese patients.
            Erratum:[Am J Med Genet A. 2021 Dec;185(12):3926-3927. doi:
            10.1002/ajmg.a.62414.. PMID: 34245093]
REFERENCE   6  (bases 1 to 12006)
  AUTHORS   Xie,H., Lee,L., Scicluna,P., Kavak,E., Larsson,C., Sandberg,R. and
            Lui,W.O.
  TITLE     Novel functions and targets of miR-944 in human cervical cancer
            cells
  JOURNAL   Int J Cancer 136 (5), E230-E241 (2015)
   PUBMED   25156441
  REMARK    GeneRIF: Low HECW2 expression is associated with cervical cancer.
REFERENCE   7  (bases 1 to 12006)
  AUTHORS   Wei,R., Qiu,X., Wang,S., Li,Y., Wang,Y., Lu,K., Fu,Y., Xing,G.,
            He,F. and Zhang,L.
  TITLE     NEDL2 is an essential regulator of enteric neural development and
            GDNF/Ret signaling
  JOURNAL   Cell Signal 27 (3), 578-586 (2015)
   PUBMED   25555806
REFERENCE   8  (bases 1 to 12006)
  AUTHORS   Lu,L., Hu,S., Wei,R., Qiu,X., Lu,K., Fu,Y., Li,H., Xing,G., Li,D.,
            Peng,R., He,F. and Zhang,L.
  TITLE     The HECT type ubiquitin ligase NEDL2 is degraded by
            anaphase-promoting complex/cyclosome (APC/C)-Cdh1, and its tight
            regulation maintains the metaphase to anaphase transition
  JOURNAL   J Biol Chem 288 (50), 35637-35650 (2013)
   PUBMED   24163370
  REMARK    GeneRIF: NEDL2 is a novel substrate of APC/C-Cdh1 as cells exit
            mitosis and functions as a regulator of the metaphase to anaphase
            transition
REFERENCE   9  (bases 1 to 12006)
  AUTHORS   Ingham,R.J., Gish,G. and Pawson,T.
  TITLE     The Nedd4 family of E3 ubiquitin ligases: functional diversity
            within a common modular architecture
  JOURNAL   Oncogene 23 (11), 1972-1984 (2004)
   PUBMED   15021885
  REMARK    Review article
REFERENCE   10 (bases 1 to 12006)
  AUTHORS   Miyazaki,K., Ozaki,T., Kato,C., Hanamoto,T., Fujita,T., Irino,S.,
            Watanabe,K., Nakagawa,T. and Nakagawara,A.
  TITLE     A novel HECT-type E3 ubiquitin ligase, NEDL2, stabilizes p73 and
            enhances its transcriptional activity
  JOURNAL   Biochem Biophys Res Commun 308 (1), 106-113 (2003)
   PUBMED   12890487
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from AC068544.7, AC074090.7 and
            AC020571.9.
            This sequence is a reference standard in the RefSeqGene project.
            
            On Nov 22, 2018 this sequence version replaced NM_001348768.1.
            
            Summary: This gene encodes a member of a family of E3 ubiquitin
            ligases which plays an important role in the proliferation,
            migration and differentiation of neural crest cells as a regulator
            of glial cell line-derived neurotrophic factor (GDNF)/Ret
            signaling. This gene also plays an important role in angiogenesis
            through stabilization of endothelial cell-to-cell junctions as a
            regulator of angiomotin-like 1 stability. The encoded protein
            contains an N-terminal calcium/lipid-binding (C2) domain involved
            in membrane targeting, two-four WW domains responsible for cellular
            localization and substrate recognition, and a C-terminal homologous
            with E6-associated protein C-terminus (HECT) catalytic domain.
            Naturally occurring mutations in this gene are associated with
            neurodevelopmental delay, hypotonia, and epilepsy. The decreased
            expression of this gene in the aganglionic colon is associated with
            Hirschsprung's disease. Alternative splicing results in multiple
            transcript variants. [provided by RefSeq, Feb 2017].
            
            Transcript Variant: This variant (3) uses an alternate exon in the
            5' UTR, compared to variant 1. Both variants 1 and 3 encode the
            same isoform (1).
            
            Sequence Note: This RefSeq record was created from transcript and
            genomic sequence data to make the sequence consistent with the
            reference genome assembly. The genomic coordinates used for the
            transcript record were based on transcript alignments.
            
            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 :: SRR1803614.108988.1 [ECO:0000332]
            ##Evidence-Data-END##
            
            ##RefSeq-Attributes-START##
            MANE Ensembl match     :: ENST00000644978.2/ ENSP00000495418.1
            RefSeq Select criteria :: based on conservation, expression
            ##RefSeq-Attributes-END##
            COMPLETENESS: full length.
PRIMARY     REFSEQ_SPAN         PRIMARY_IDENTIFIER PRIMARY_SPAN        COMP
            1-47                AC068544.7         9430-9476           c
            48-374              AC074090.7         88977-89303         c
            375-482             AC020571.9         164408-164515       c
            483-577             AC020571.9         155175-155269       c
            578-653             AC020571.9         150326-150401       c
            654-823             AC020571.9         145731-145900       c
            824-966             AC020571.9         143229-143371       c
            967-1067            AC020571.9         141090-141190       c
            1068-2420           AC020571.9         139303-140655       c
            2421-2516           AC020571.9         138025-138120       c
            2517-2667           AC020571.9         128686-128836       c
            2668-2771           AC020571.9         127881-127984       c
            2772-2896           AC020571.9         127239-127363       c
            2897-3082           AC020571.9         113316-113501       c
            3083-3217           AC020571.9         99279-99413         c
            3218-3320           AC020571.9         94772-94874         c
            3321-3417           AC020571.9         91944-92040         c
            3418-3501           AC020571.9         78574-78657         c
            3502-3611           AC020571.9         74671-74780         c
            3612-3732           AC020571.9         62835-62955         c
            3733-3846           AC020571.9         61200-61313         c
            3847-3999           AC020571.9         48853-49005         c
            4000-4098           AC020571.9         46523-46621         c
            4099-4228           AC020571.9         42962-43091         c
            4229-4375           AC020571.9         41546-41692         c
            4376-4490           AC020571.9         40790-40904         c
            4491-4576           AC020571.9         37759-37844         c
            4577-4689           AC020571.9         36616-36728         c
            4690-12006          AC020571.9         14823-22139         c
FEATURES             Location/Qualifiers
     source          1..12006
                     /organism="Homo sapiens"
                     /mol_type="mRNA"
                     /db_xref="taxon:9606"
                     /chromosome="2"
                     /map="2q32.3"
     gene            1..12006
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /note="HECT, C2 and WW domain containing E3 ubiquitin
                     protein ligase 2"
                     /db_xref="GeneID:57520"
                     /db_xref="HGNC:HGNC:29853"
                     /db_xref="MIM:617245"
     exon            1..47
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            48..374
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     CDS             83..4801
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /EC_number="2.3.2.26"
                     /note="isoform 1 is encoded by transcript variant 3;
                     NEDD4-related E3 ubiquitin ligase NEDL2; E3
                     ubiquitin-protein ligase HECW2; NEDD4-like E3
                     ubiquitin-protein ligase 2; HECT-type E3 ubiquitin
                     transferase HECW2"
                     /codon_start=1
                     /product="E3 ubiquitin-protein ligase HECW2 isoform 1"
                     /protein_id="NP_001335697.1"
                     /db_xref="CCDS:CCDS33354.1"
                     /db_xref="GeneID:57520"
                     /db_xref="HGNC:HGNC:29853"
                     /db_xref="MIM:617245"
                     /translation="MASSAREHLLFVRRRNPQMRYTLSPENLQSLAAQSSMPENMTLQ
                     RANSDTDLVTSESRSSLTASMYEYTLGQAQNLIIFWDIKEEVDPSDWIGLYHIDENSP
                     ANFWDSKNRGVTGTQKGQIVWRIEPGPYFMEPEIKICFKYYHGISGALRATTPCITVK
                     NPAVMMGAEGMEGGASGNLHSRKLVSFTLSDLRAVGLKKGMFFNPDPYLKMSIQPGKK
                     SSFPTCAHHGQERRSTIISNTTNPIWHREKYSFFALLTDVLEIEIKDKFAKSRPIIKR
                     FLGKLTIPVQRLLERQAIGDQMLSYNLGRRLPADHVSGYLQFKVEVTSSVHEDASPEA
                     VGTILGVNSVNGDLGSPSDDEDMPGSHHDSQVCSNGPVSEDSAADGTPKHSFRTSSTL
                     EIDTEELTSTSSRTSPPRGRQDSLNDYLDAIEHNGHSRPGTATCSERSMGASPKLRSS
                     FPTDTRLNAMLHIDSDEEDHEFQQDLGYPSSLEEEGGLIMFSRASRADDGSLTSQTKL
                     EDNPVENEEASTHEAASFEDKPENLPELAESSLPAGPAPEEGEGGPEPQPSADQGSAE
                     LCGSQEVDQPTSGADTGTSDASGGSRRAVSETESLDQGSEPSQVSSETEPSDPARTES
                     VSEASTRPEGESDLECADSSCNESVTTQLSSVDTRCSSLESARFPETPAFSSQEEEDG
                     ACAAEPTSSGPAEGSQESVCTAGSLPVVQVPSGEDEGPGAESATVPDQEELGEVWQRR
                     GSLEGAAAAAESPPQEEGSAGEAQGTCEGATAQEEGATGGSQANGHQPLRSLPSVRQD
                     VSRYQRVDEALPPNWEARIDSHGRIFYVDHVNRTTTWQRPTAPPAPQVLQRSNSIQQM
                     EQLNRRYQSIRRTMTNERPEENTNAIDGAGEEADFHQASADFRRENILPHSTSRSRIT
                     LLLQSPPVKFLISPEFFTVLHSNPSAYRMFTNNTCLKHMITKVRRDTHHFERYQHNRD
                     LVGFLNMFANKQLELPRGWEMKHDHQGKAFFVDHNSRTTTFIDPRLPLQSSRPTSALV
                     HRQHLTRQRSHSAGEVGEDSRHAGPPVLPRPSSTFNTVSRPQYQDMVPVAYNDKIVAF
                     LRQPNIFEILQERQPDLTRNHSLREKIQFIRTEGTPGLVRLSSDADLVMLLSLFEEEI
                     MSYVPPHALLHPSYCQSPRGSPVSSPQNSPGTQRANARAPAPYKRDFEAKLRNFYRKL
                     ETKGYGQGPGKLKLIIRRDHLLEDAFNQIMGYSRKDLQRNKLYVTFVGEEGLDYSGPS
                     REFFFLVSRELFNPYYGLFEYSANDTYTVQISPMSAFVDNHHEWFRFSGRILGLALIH
                     QYLLDAFFTRPFYKALLRILCDLSDLEYLDEEFHQSLQWMKDNDIHDILDLTFTVNEE
                     VFGQITERELKPGGANIPVTEKNKKEYIERMVKWRIERGVVQQTESLVRGFYEVVDAR
                     LVSVFDARELELVIAGTAEIDLSDWRNNTEYRGGYHDNHIVIRWFWAAVERFNNEQRL
                     RLLQFVTGTSSIPYEGFASLRGSNGPRRFCVEKWGKITALPRAHTCFNRLDLPPYPSF
                     SMLYEKLLTAVEETSTFGLE"
     exon            375..482
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            483..577
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            578..653
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            654..823
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            824..966
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            967..1067
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            1068..2420
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            2421..2516
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            2517..2667
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            2668..2771
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            2772..2896
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            2897..3082
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            3083..3217
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            3218..3320
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            3321..3417
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            3418..3501
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            3502..3611
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            3612..3732
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            3733..3846
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            3847..3999
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            4000..4098
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            4099..4228
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            4229..4375
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            4376..4490
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            4491..4576
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            4577..4689
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     exon            4690..12006
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /inference="alignment:Splign:2.1.0"
     regulatory      6801..6806
                     /regulatory_class="polyA_signal_sequence"
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /note="hexamer: AATACA"
     polyA_site      6828
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /note="major polyA site"
     regulatory      6946..6951
                     /regulatory_class="polyA_signal_sequence"
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /note="hexamer: GATAAA"
     polyA_site      6975
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
     regulatory      7056..7061
                     /regulatory_class="polyA_signal_sequence"
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /note="hexamer: AATAAA"
     polyA_site      7085
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
     regulatory      8119..8124
                     /regulatory_class="polyA_signal_sequence"
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /note="hexamer: AATAAA"
     polyA_site      8154
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
     regulatory      11882..11887
                     /regulatory_class="polyA_signal_sequence"
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /note="hexamer: AATAAA"
     polyA_site      11910
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
     regulatory      11981..11986
                     /regulatory_class="polyA_signal_sequence"
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
                     /note="hexamer: AATACA"
     polyA_site      12006
                     /gene="HECW2"
                     /gene_synonym="NDHSAL; NEDL2"
ORIGIN      
        1 agatgccgcc gaagcgtcta gcgggaaggg cgccggcgcg gctggagctt tgtaggcagc
       61 caatcccaga gaagcagacg ggatggctag ttcagcccgg gagcacctgc tttttgtgag
      121 gcgtcgaaat ccccagatgc ggtacacatt gagcccagag aacctccaga gccttgccgc
      181 ccagagctcc atgccagaga acatgaccct gcagcgggcc aacagcgaca ccgacctggt
      241 gacttctgag agccgctcca gcttaactgc cagcatgtac gagtacacgc tggggcaagc
      301 ccagaacctc attatcttct gggacattaa agaggaggtg gaccccagtg attggattgg
      361 actttatcat atagatgaga attctccagc caacttctgg gattctaaga acaggggtgt
      421 gactggaaca caaaaagggc aaattgtatg gagaattgag cctgggccct atttcatgga
      481 accggagata aaaatctgtt ttaaatatta ccacggcatt agtggagccc tgcgagccac
      541 gaccccctgc atcaccgtga agaacccagc tgtgatgatg ggggcagaag gcatggaggg
      601 aggtgcttca ggaaacctgc attctcgaaa acttgttagc tttacattgt cagatcttag
      661 ggcagttggg ctaaagaaag ggatgttctt caatcctgac ccttatctta agatgtcaat
      721 tcagccagga aagaagagca gtttccccac ctgtgcccac cacgggcagg agagacggtc
      781 tactatcatc agtaacacca ccaatccaat ttggcaccga gagaaatatt ccttttttgc
      841 acttcttact gatgtcttag aaattgaaat taaagacaaa tttgccaaga gccgtcccat
      901 catcaagcgt tttctgggga aactaaccat tccagtccag aggctgctgg agcgacaagc
      961 catcggtgat caaatgctca gctacaacct tggcagaagg ctcccagctg accacgtgag
     1021 tgggtacctc cagtttaaag tggaggttac gtcttctgtt catgaagatg cctctccaga
     1081 agctgttggc acaatacttg gagtcaattc tgtgaatgga gacttaggta gcccttccga
     1141 tgacgaggac atgccaggga gccatcacga cagccaggtg tgctctaatg ggccagtttc
     1201 tgaggacagt gctgccgatg gaacccccaa gcattcattc aggactagct ccactctgga
     1261 aatagacaca gaggaattaa cctctacgtc ttcaaggacc tcacctccca gaggacgtca
     1321 ggattcactc aatgattact tagatgctat cgaacacaat ggccactcca ggccggggac
     1381 agcgacctgc tctgagaggt ccatgggtgc ctctccgaaa ctgaggagta gttttcccac
     1441 tgacacaaga ctcaatgcca tgcttcatat tgattcagat gaagaagatc acgagttcca
     1501 gcaagacctg ggttacccat cttccttgga ggaggaggga ggcctgatca tgtttagcag
     1561 ggcatccaga gctgatgatg gaagcctgac atctcagaca aagctggagg acaaccctgt
     1621 tgagaatgag gaagcctcca cacacgaagc tgcttccttt gaggataagc cagaaaatct
     1681 tccagagctt gcagagagct ccttacctgc aggcccagcc ccagaggaag gtgaaggcgg
     1741 cccagagcct caacccagtg ctgaccaggg cagtgctgaa ctgtgtggct ctcaagaggt
     1801 agatcagccc acaagtggcg cagacacagg gacttccgat gcatcaggag gaagccgaag
     1861 agccgtcagt gagaccgagt ctctcgatca gggctctgag ccttcccagg tgtcctctga
     1921 aacagaaccc agtgatcctg ccaggacaga gagtgtgagc gaagccagca ccaggcctga
     1981 gggagagagt gacctggaat gcgctgacag ctcctgcaat gagagtgtga ccacgcagct
     2041 gtcctctgtg gacacacggt gctcctctct tgagagcgca cggtttcctg aaaccccagc
     2101 cttttcttct caggaggagg aagacggagc ctgtgcagca gagcccacca gcagtggccc
     2161 tgccgaaggg tcgcaggaat ccgtgtgcac tgctggttct ttacctgtgg tacaggtgcc
     2221 cagtggggag gatgaagggc caggggcaga atcggccact gtacctgacc aggaggagct
     2281 gggggaggtc tggcagcgga gggggagcct ggagggagct gcagctgctg ccgagagccc
     2341 accgcaagaa gaaggcagtg ctggggaggc ccaaggcacc tgtgaagggg caactgccca
     2401 ggaggagggc gctactggag gttctcaagc caacggccac cagccactgc gatcactacc
     2461 ttcagtgcgc caggatgtta gccggtacca gagggtggac gaggctctcc caccaaactg
     2521 ggaggcacgc attgacagcc acggcaggat cttctacgtg gatcacgtaa acagaaccac
     2581 gacgtggcag cgaccgacag ctcccccagc cccgcaggtg ctgcagagat ctaactccat
     2641 acagcaaatg gagcagctga accggcgata tcagagtatc cgcagaacca tgaccaatga
     2701 gaggcctgag gaaaatacca atgctattga tggggcaggg gaggaagctg actttcacca
     2761 agccagtgca gatttccgac gggagaacat cctgcctcac tctacctcca gatccaggat
     2821 cacgttgctg ttacagtctc cccccgtgaa gttcctcatc agcccagagt tcttcaccgt
     2881 gctgcattct aaccctagtg cctaccgcat gtttacaaac aacacgtgtt tgaagcacat
     2941 gatcaccaaa gtccggaggg acacccacca ctttgaacgc taccagcata accgcgacct
     3001 tgtgggattc ctcaacatgt tcgcgaacaa acagctagag ctgccgcggg gatgggaaat
     3061 gaaacatgat caccagggca aggcattctt tgtggaccac aactcccgca ccaccacttt
     3121 cattgatccc cggctcccac ttcagagcag tagacccaca agtgcgctgg ttcatcggca
     3181 acacctgaca aggcaacgca gccacagtgc gggtgaggta ggagaagatt ctcgacatgc
     3241 aggaccacca gttcttccca ggccatccag tacattcaat acagtcagta ggccacagta
     3301 ccaggacatg gttccagtgg cttacaatga caagattgtt gcatttctac gtcaacccaa
     3361 tatctttgaa attctacagg agcgtcaacc tgatcttacc aggaatcact cactcaggga
     3421 gaagatccaa tttatccgaa ctgaagggac tccaggattg gtgcgccttt caagcgatgc
     3481 agaccttgtt atgttgctga gcttatttga agaagagata atgtcgtatg tgcctccaca
     3541 tgccttactc caccccagct actgtcagtc cccacgtggc tctcccgtgt catctcctca
     3601 gaactcgcca ggtacccagc gtgccaatgc ccgggctcca gccccttaca agcgggattt
     3661 cgaagccaaa ctgaggaact tttacaggaa gttagagact aaaggatatg gacaaggccc
     3721 agggaagtta aagttaatta tccgaagaga tcacttacta gaagatgctt ttaatcagat
     3781 tatgggctac tccagaaaag acctgcagag aaataagcta tatgtcacct tcgttgggga
     3841 ggaagggctg gattacagtg ggccttctag agagtttttc ttcctggtat ccagagaact
     3901 ctttaaccca tattatggct tatttgaata ttcagccaat gacacataca cagtacaaat
     3961 aagtcctatg tctgcttttg tagacaatca ccatgaatgg ttccgattca gtggtaggat
     4021 ccttggtctt gcactaatac accagtattt gttggatgcc ttcttcacac ggccctttta
     4081 taaggctctt ctcagaattc tatgtgacct gagtgaccta gaataccttg atgaagagtt
     4141 ccatcagagc ctgcagtgga tgaaagacaa tgatatccat gacatcctag acctcacgtt
     4201 cactgtgaac gaagaagtat ttgggcagat aactgaacga gaattaaagc cagggggtgc
     4261 caatatccca gttacagaga agaacaagaa ggagtacatc gagaggatgg tgaagtggag
     4321 gattgagagg ggtgttgtac agcaaacaga gagcttagtg cgtggcttct atgaggtggt
     4381 ggatgccagg ctggtatctg tttttgatgc aagagaactg gaattggtca tcgcaggcac
     4441 agctgaaata gacctaagtg attggagaaa caacacagaa tatagaggag gataccatga
     4501 caatcatatt gtaattcggt ggttctgggc tgcagtggaa agattcaaca atgaacaacg
     4561 actaaggttg ttacagtttg ttacaggcac atccagcatt ccctatgaag gatttgcttc
     4621 actccgaggg agtaacggcc caagaagatt ctgtgtggag aaatggggga aaatcactgc
     4681 tcttcccaga gcgcatacat gttttaaccg tctggatctg cctccctacc catccttttc
     4741 catgctttat gaaaaactgt tgacagcagt tgaagaaacc agtacttttg gacttgagtg
     4801 acctggaagc tgaatgccca tctctgtgga caggcaggtt cagaagctgc cttctagaag
     4861 aatgattgaa cattggaagt ttcaagagga tgcttccttt aggataaagc tatgtgctgt
     4921 tgttttccag gaacaagtgc tctgtcacat ttggggactg gagatgagtc ctcttggaag
     4981 gatttgggtg agcttgatgc ccagggaaca acccaaccgt ctttcaatca acagttcttg
     5041 actgccaaac tttttccatt tgttatgttc caagacaaag atgaacccat acatgatcag
     5101 ctccacggta atttttaggg actcaggaga atcttgaaac ttacccttga acgtggttca
     5161 agccaaactg gcagcatttg gcccaatctc caaattagag caagttaaat aatataataa
     5221 aagtaaatat atttcctgaa agtacattca tttaagccct aagttataac agaatattca
     5281 tttcttgctt atgagtgcct gcatggtgtg caccataggt ttccgctttc atgggacatg
     5341 agtgaaaatg aaaccaagtc aatatgaggt acctttacag atttgcaata agatggtctg
     5401 tgacaatgta tatgcaagtg gtatgtgtgt aattatggct aaagacaaac cattattcag
     5461 tgaattacta atgacagatt ttatgcttta taatgcatga aaacaatttt aaaataacta
     5521 gcaattaatc acagcatatc aggaaaaagt acacagtgag ttctgtttat tttttgtagg
     5581 ttcattatgt ttatgttctt taagatgtat ataagaacct acctatcatg ctgtatgtat
     5641 cactcattcc attttcatgt tccatgcata ctcgggcatc atgctaatat gtatcctttt
     5701 aagcactctc aaggaaacaa aagggccttt tatttttata aaggtaaaaa aaattcccca
     5761 aatattttgc actgaatgta ccaaaggtga agggacatta caatatgact aacagcaact
     5821 ccatcacttg agaagtataa tagaaaatag cttctaaatc aaacttcctt cacagtgccg
     5881 tgtctaccac tacaaggact gtgcatctaa gtaataattt tttaagattc actatatgtg
     5941 atagtatgat atgcatttat ttaaaatgca ttagactctc ttccatccat caaatacttt
     6001 acaggatggc atttaataca gatatttcgt atttccccca ctgcttttta tttgtacagc
     6061 atcattaaac actaagctca gttaaggagc catcagcaac actgaagaga tcagtagtaa
     6121 gaattccatt ttccctcatc agtgaagaca ccacaaattg aaactcagaa ctatatttct
     6181 aagcctgcat tttcactgat gcataatttt cttattaata ttaagagaca gtttttctat
     6241 ggcatctcca aaactgcatg acatcactag tcttacttct gcttaatttt atgagaaggt
     6301 attcttcatt ttaattgctt ttgggattac tccacatctt tgtttatttc ttgactaatc
     6361 agattttcaa tagagtgaag ttaaattggg ggtcataaaa gcattggatt gacatatggt
     6421 ttgccagcct atgggtttac aggcattgcc caaacatttc tttgagatct atatttataa
     6481 gcagccatgg aattcctatt atgggatgtt ggcaatctta cattttatag aggtcatatg
     6541 catagttttc ataggtgttt tgtaagaact gattgctctc ctgtgagtta agctatgttt
     6601 actactggga ccctcaagag gaataccact tatgttacac tcctgcacta aaggcacgta
     6661 ctgcagtgtg aagaaatgtt ctgaaaaagg gttatagaaa tctggaaata agaaaggaag
     6721 agctctctgt attctataat tggaagagaa aaaaagaaaa acttttaact ggaaatgtta
     6781 gtttgtactt attgatcatg aatacaagta tatatttaat tttgcaaact tttcacttgt
     6841 ttgtattctt ttcattataa ggaaaagtag tataacacac ttttttttaa gtcacatatt
     6901 tgatggtata caagatgttt cagggctggc attctccaag cagcagataa aggttgcatt
     6961 tctttcaaaa atacattcaa agaccatgtt atccttcatt ttggtttgag acatttagtt
     7021 atggtatttc atattattag gtaaaagata tttgaaataa aatgtatctc tttaattatt
     7081 tctaacaaat atatttcttt attaaggcat ccaacttttt cccaaataac agtacacttt
     7141 aatgtatgta gacattctta attagtataa tcatctagtt gatactgttc tcagattggg
     7201 aattatcaaa gatgtactta tcatatcaga acaccatgct aacttatcta ttattctttc
     7261 ttagtaaaac aaaacagcca gtaataacta tataaaatat taaataacat ttccacagaa
     7321 taaattagac tttcatgtac tctacaatta gaaatatcca taaatatttt cttctggact
     7381 gtgaacccag ataactaggc tttctggtct tattttaagt gatgctcttt atactataga
     7441 agacactctt aatacatcat atatgtatgc agaacatctc ttagatgaga gaacaagcac
     7501 atcattggca ttccctctgt gccagtttga tgtttgtttg acgatggagc tacaagagtc
     7561 taaatctgcc tttgaaaagc tcagctcaca gtgtagtaga gtagactcca aggttcaaaa
     7621 aagtgttttt aataaaattt ggtaagttct acaatcaagg aatgaagaga gaagagaaca
     7681 gctttttcca tctgggagat tcaataatgg cttcatatat agatgatagt gtggctaaaa
     7741 aaaattacat caatgctgtt tctattggga agcaatggca agtaatagta tgtcaatact
     7801 ggtcaagtgt tgaagccagg atgcacttac acaacgagag tgtaaagtgt gtagggagct
     7861 gatctgtgaa ggagcaactc aaagattttg aaattatcag tgaaatgcca aaacagggaa
     7921 agtttccctg tttcccttca tctattctac aatgcaccat tggttttcag tgtgaaaaat
     7981 cccaatccct gagcccaaac cacttctggg gtcaaaacat ttttcttgtg cacaaaatga
     8041 atggatcttg gtcaaagaag tatggtcaca attttctagc atatattgcg tttataattt
     8101 agcagaaatt ctgcaataaa taaaggaaaa tctgttttac ctgtgcaaca atcagaaatg
     8161 gtaaaaatgc attcaagtgt ttgaaagaaa tggtagaata tgcttgcata gtgctttata
     8221 gtttcaaagt gctgtcaggt acatcgtccg tttagctcct cacgcacttt gtagggtaca
     8281 agcatcatgt tccatctggg ttgtggctga ttttcatgga tggcttgtgg catcagtttc
     8341 attacttcat agtcacaatt ctgtgtttca tcttgagaaa tgtggagact aatgtttgta
     8401 ccagtatatt ccacattcag tgaggtttcc aagatgcttc ctccaaactc tcactttctt
     8461 aaacagatac atttaaaata tgacaccttc tgaaaagtcc ataaagaaat tagtatattc
     8521 atggaaaaaa tttccccgta gacttatttg catttcatga cttgacatga gaaatttaaa
     8581 aaacagaagg caaaatgtga ttgcttttga tggatttata cagaatagtc atttaatttt
     8641 ctcaagtatt atttggaaac aagataatgg aaaacattaa tcagaagcct tattttattt
     8701 ttaaattttt aatagggatg gatctagtaa gccctaatag ctgagttcca gtgataaaat
     8761 tcacaaattt tatttatgat tggaccactt ctaacaaggc aaatatctta taatgaagat
     8821 aggagtctgt tcaatttaac cttattcagg aaactccgta tttatgtgaa atgatgcaat
     8881 gccattatta agaggtatct gtaaccctgc ataataaaaa catgcataag aagaatgtgg
     8941 tctaatctcc aaactgagtc tcagtttcag ggccttttgc tttctttgtt tgtttgtttg
     9001 agacagtctg gctctgtcat ccaggctgga gtgcagtggc acatgagctc actgcaacct
     9061 ccacctccca ggctcaagcg atcctcccac ctcagcctcc tgagtaactg ggactacagg
     9121 cgcataccac cacacctggc taatttttgt atttttgtag agacaaggcc caggcacgtc
     9181 tcaaactctt gagctcaagc gatccgcccg ccttggcctc ccaaagtgct aggagtaatt
     9241 ataggtgtga gccaccatgc tggcagttgt ttttgtttat ttgtgataag gtctggctgt
     9301 cacccatgct ggagtgcagt ggcatgatct tggctcactg caacctctgc cttccaggct
     9361 caagccagcc tcccacctca gcctccgagt agctaggact acaggcatgc accaccatgc
     9421 ccagctaatt tttttatatt ttttgtagac acagggtttt gccacgttgc ccaggctggt
     9481 cttgaactcc tgagctcaag cagtcctccc accttggcct cccgaagtgc tgggattaca
     9541 gacgtgagcc tctgggcctt gctctgtttt gtctgctttc tgatttagta ggtgagggac
     9601 agcactctgg accttagcca ttttacttcc atcttactgc cgtgagtttg atgagaatgt
     9661 cacttttaga ctctaatttt caaaaactta gtttctttcc cattcatttg tgttttccaa
     9721 attaatttgt ttgtctagta tggatgcaaa ggaatgctga agacattaaa gctttctgaa
     9781 ttgtggctta aggccagcta ctgcccactg aaaggatgat aaaaataaaa aaggaggaaa
     9841 gaggagccca gcagttgtgc caccccgcaa gaatataatg ctaattattg accaactgtc
     9901 aagattcaga gtggtaactg cattccgagg agctgtcagg aaggatgacc gtgtgtgtgc
     9961 tgtccatatc atagccatct gggtcagaag gagcgaaagg atggttagga caggagtgta
    10021 gtggagggaa agttaaaaca acggtagatg gatcatctta gggcttgctg gtgggggtag
    10081 gaacatactt caatttggtt tcagactgag aagaagaaag ctatgctccc tgatgaaggc
    10141 acagtttgat ctactagatg ggaaataccc tcattttata acttcagtaa tttaacattt
    10201 tctgtattgc aaagtggaat ttagtcccaa agtattaaag ctaaccatag cttgatcagg
    10261 agatttgaca atttagcata aaattatgtt gtggattttt ttatttaaga attattgtta
    10321 ctattattga acaccatgta tgaaatgaaa gaaagggtgc ttttatttca ttatacttat
    10381 ttggtttttt tagcggacat cccttgacat tagaatagca tttgagacat tttcatgatt
    10441 tctaaagata acttaaatgc tctctgttaa tctggaaagt gaaatcctaa gagtgaggtt
    10501 gcaaatggag actaaattag tgtttccaag tcaggaagtt aatcaagacc ggaaatagat
    10561 ttgcttagat tttatctgca gagtcgttta tttggctttc gtaattgaac agctcagcag
    10621 aataagatgg ccctagttgt atggtttctg gggaacacag gagaattaaa tttatatatg
    10681 tgatttttat gtgtagtgcc cttgggcagg tgatatcttt ctatatgact tttaagatat
    10741 tacaacctga ggagtgtgga tagccgtgtt gtgtgattca aactgaatca gctattactg
    10801 atgcaggtaa ggaaccatca gtcaacttct ggttactatc accttcataa aaaagaatgg
    10861 atgatgttca ggaattacct tggaaggatt aaccaggaat taacacagaa tgggatgttc
    10921 ttttaggacc ctaatgctct aaaagataaa attacaacct atttttcttt atatgatagc
    10981 ataagtaaaa tttggggctg ttaatatgtt ggaaagtgct taaaattaca tgtttttata
    11041 atagggatgc aggcattcca aaataaatga ataaaaatac atgcatctct ctcgcctctt
    11101 actgaaagta ttaatctaat tttatagtaa tgattacttt ttaatattaa ggctctgtaa
    11161 aaaaattatt tctaagattt cagtagaaca caggtggtgt atttttttaa gcttttaatt
    11221 tctcttcacc aacctcagtc attacgttca ccacacagtg tgtcacagtt aatagtggta
    11281 tttcagtttt tgcgttgatt taagcttcat atttatttaa tgtgactttt gatggagaat
    11341 aataatggga gatgcttgct gttagcatta aggttataca gctctcactt caccttatat
    11401 gtaatttttt tttcaaagta aataatgcag attgttgaca tcctagaaat ggtttctggg
    11461 tggtattata tggggcctag gactctgaac tgggactagt tgtttatttt ctgggaagtc
    11521 tgtattctta ttctcaactg aacccctgac tcttttgttg tattttttat gattccgaaa
    11581 tgctttgagg gaaagatatt ttaatgtgta caatttgttt tattttcata ctgatctcta
    11641 tttttgttta aaaccatgtt gcatcatgaa atcacttaat ccaaaataaa tcttctttaa
    11701 aaaaaataga ttatgacttt tctgtaatac ttttggggag ggaaaactca gaagggagga
    11761 gaatagaagt agagataaag atttcatggc attagtttgc agctctataa atattggagg
    11821 ttctgttttc atagtattta tagtattttg tttattttta tttatatttt tattatttat
    11881 taataaaata tttgtttatt ttgtttggaa tctactttgt ttatccctac aagaatattt
    11941 tactgtttga tgggctgtta atgttaaagg aatgaattat aatacaaatc ataatttctt
    12001 aactca
//
