RBCC Red Blood Cell Collection

TTN [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Titin; 2.7.11.1 (Connectin; Rhabdomyosarcoma antigen MU-RMS-40.14)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00179357
IPI00179357 Titin Titin membrane n/a n/a n/a 1 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoskeleton associated n/a found at its expected molecular weight found at molecular weight

UniProt Q8WZ42
ID TITIN_HUMAN Reviewed; 34350 AA.
AC Q8WZ42; A6NKB1; E7EQE6; E7ET18; K7ENY1; Q10465; Q10466; Q15598;
read moreAC Q2XUS3; Q32Q60; Q4U1Z6; Q4ZG20; Q6NSG0; Q6PDB1; Q6PJP0; Q7KYM2;
AC Q7KYN4; Q7KYN5; Q7LDM3; Q7Z2X3; Q8TCG8; Q8WZ51; Q8WZ52; Q8WZ53;
AC Q8WZB3; Q92761; Q92762; Q9UD97; Q9UP84; Q9Y6L9;
DT 13-JUN-2006, integrated into UniProtKB/Swiss-Prot.
DT 18-APR-2012, sequence version 4.
DT 22-JAN-2014, entry version 124.
DE RecName: Full=Titin;
DE EC=2.7.11.1;
DE AltName: Full=Connectin;
DE AltName: Full=Rhabdomyosarcoma antigen MU-RMS-40.14;
GN Name=TTN;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), NUCLEOTIDE SEQUENCE [MRNA] OF
RP 3336-12202 (ISOFORM 4), AND VARIANTS ILE-498; GLU-1201; MET-3261;
RP ASN-3419; SER-3491; GLU-12679; ILE-19762; ILE-20718; ASN-23807;
RP MET-24980 AND THR-27755.
RC TISSUE=Skeletal muscle;
RX PubMed=7569978; DOI=10.1126/science.270.5234.293;
RA Labeit S., Kolmerer B.;
RT "Titins, giant proteins in charge of muscle ultrastructure and
RT elasticity.";
RL Science 270:293-296(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, AND VARIANTS
RP LEU-1295; GLN-1572; ILE-2610; ASN-2831; SER-3491; PRO-4215; PHE-4283
RP AND ARG-12383.
RX PubMed=10850961;
RA Freiburg A., Trombitas K., Hell W., Cazorla O., Fougerousse F.,
RA Centner T., Kolmerer B., Witt C., Beckmann J.S., Gregorio C.C.,
RA Granzier H., Labeit S.;
RT "Series of exon-skipping events in the elastic spring region of titin
RT as the structural basis for myofibrillar elastic diversity.";
RL Circ. Res. 86:1114-1121(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, TISSUE
RP SPECIFICITY, INTERACTION WITH OBSCN, AND VARIANTS LEU-1295; GLN-1572;
RP ILE-2610; ASN-2831; SER-3491; PRO-4215 AND PHE-4283.
RX PubMed=11717165;
RA Bang M.-L., Centner T., Fornoff F., Geach A.J., Gotthardt M.,
RA McNabb M., Witt C.C., Labeit D., Gregorio C.C., Granzier H.,
RA Labeit S.;
RT "The complete gene sequence of titin, expression of an unusual ~700
RT kDa titin isoform and its interaction with obscurin identify a novel
RT Z-line to I-band linking system.";
RL Circ. Res. 89:1065-1072(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-626 AND 34071-34350
RP (ISOFORM 3).
RC TISSUE=Muscle, and Skeletal muscle;
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 NUCLEOTIDE SEQUENCE [MRNA] OF 405-709 (ISOFORMS 1 AND 2).
RC TISSUE=Heart muscle;
RX PubMed=8937992;
RA Gautel M., Goulding D., Bullard B., Weber K., Furst D.O.;
RT "The central Z-disk region of titin is assembled from a novel repeat
RT in variable copy numbers.";
RL J. Cell Sci. 109:2747-2754(1996).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2023-2060, AND TISSUE SPECIFICITY.
RC TISSUE=Heart muscle;
RX PubMed=7819249; DOI=10.1021/bi00002a021;
RA Musco G., Tziatzos C., Schuck P., Pastore A.;
RT "Dissecting titin into its structural motifs: identification of an
RT alpha helix near the N-terminus.";
RL Biochemistry 34:553-561(1995).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 3455-4473, AND VARIANTS PRO-4215
RP AND PHE-4283.
RX PubMed=10051295;
RA Siu B.L., Niimura H., Osborne J.A., Fatkin D., MacRae C., Solomon S.,
RA Benson D.W., Seidman J.G., Seidman C.E.;
RT "Familial dilated cardiomyopathy locus maps to chromosome 2q31.";
RL Circulation 99:1022-1026(1999).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 9806-12017 (ISOFORM 5).
RC TISSUE=Heart ventricle;
RX PubMed=12785098; DOI=10.1023/A:1023410523184;
RA Greaser M.L., Berri M., Warren C.M., Mozdziak P.E.;
RT "Species variations in cDNA sequence and exon splicing patterns in the
RT extensible I-band region of cardiac titin: relation to passive
RT tension.";
RL J. Muscle Res. Cell Motil. 23:473-482(2002).
RN [10]
RP PROTEIN SEQUENCE OF 11773-11783; 17908-17931; 18656-18669;
RP 26545-26553; 28758-28774 AND 32920-32928, AND MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 12947-13797.
RC TISSUE=Embryonic rhabdomyosarcoma;
RA Behrends U., Gotz C., Mautner J.;
RT "Serological identification of rhabdomyosarcoma antigens.";
RL Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE OF 14257-14543.
RX PubMed=8351016;
RA Gautel M., Lakey A., Barlow D.P., Holmes Z., Scales S., Leonard K.,
RA Labeit S., Mygland A., Gilhus N.E., Aarli J.A.;
RT "Titin antibodies in myasthenia gravis: identification of a major
RT immunogenic region of titin.";
RL Neurology 43:1581-1585(1993).
RN [13]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 21021-22120, AND NUCLEOTIDE SEQUENCE
RP [GENOMIC DNA] OF 23754-24284.
RX PubMed=1582406;
RA Labeit S., Gautel M., Lakey A., Trinick J.;
RT "Towards a molecular understanding of titin.";
RL EMBO J. 11:1711-1716(1992).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 29701-34350, AND PHOSPHORYLATION.
RX PubMed=8404852;
RA Gautel M., Leonard K., Labeit S.;
RT "Phosphorylation of KSF motifs in the C-terminal region of titin in
RT differentiating myoblasts.";
RL EMBO J. 12:3827-3834(1993).
RN [15]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 33119-34350.
RC TISSUE=Skeletal muscle;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [16]
RP INTERACTION WITH TCAP.
RX PubMed=9645487; DOI=10.1016/S0014-5793(98)00501-8;
RA Mues A., van der Ven P.F.M., Young P., Furst D.O., Gautel M.;
RT "Two immunoglobulin-like domains of the Z-disc portion of titin
RT interact in a conformation-dependent way with telethonin.";
RL FEBS Lett. 428:111-114(1998).
RN [17]
RP INTERACTION WITH NEB.
RX PubMed=12482578; DOI=10.1016/S0014-5793(02)03655-4;
RA Ma K., Wang K.;
RT "Interaction of nebulin SH3 domain with titin PEVK and myopalladin:
RT implications for the signaling and assembly role of titin and
RT nebulin.";
RL FEBS Lett. 532:273-278(2002).
RN [18]
RP INTERACTION WITH FHL2.
RX PubMed=12432079; DOI=10.1242/jcs.00181;
RA Lange S., Auerbach D., McLoughlin P., Perriard E., Schafer B.W.,
RA Perriard J.-C., Ehler E.;
RT "Subcellular targeting of metabolic enzymes to titin in heart muscle
RT may be mediated by DRAL/FHL-2.";
RL J. Cell Sci. 115:4925-4936(2002).
RN [19]
RP INTERACTION WITH ANK1.
RX PubMed=12444090; DOI=10.1074/jbc.M209012200;
RA Kontrogianni-Konstantopoulos A., Bloch R.J.;
RT "The hydrophilic domain of small ankyrin-1 interacts with the two N-
RT terminal immunoglobulin domains of titin.";
RL J. Biol. Chem. 278:3985-3991(2003).
RN [20]
RP INTERACTION WITH ANKRD1; ANKRD2; ANKRD23 AND CAPN3.
RX PubMed=14583192; DOI=10.1016/j.jmb.2003.09.012;
RA Miller M.K., Bang M.-L., Witt C.C., Labeit D., Trombitas C.,
RA Watanabe K., Granzier H., McElhinny A.S., Gregorio C.C., Labeit S.;
RT "The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a
RT family of titin filament-based stress response molecules.";
RL J. Mol. Biol. 333:951-964(2003).
RN [21]
RP INTERACTION WITH CRYAB.
RX PubMed=14676215; DOI=10.1074/jbc.M307473200;
RA Bullard B., Ferguson C., Minajeva A., Leake M.C., Gautel M.,
RA Labeit D., Ding L., Labeit S., Horwitz J., Leonard K.R., Linke W.A.;
RT "Association of the chaperone alphaB-crystallin with titin in heart
RT muscle.";
RL J. Biol. Chem. 279:7917-7924(2004).
RN [22]
RP INTERACTION WITH TRIM63 AND TRIM55.
RX PubMed=15967462; DOI=10.1016/j.jmb.2005.05.021;
RA Witt S.H., Granzier H., Witt C.C., Labeit S.;
RT "MURF-1 and MURF-2 target a specific subset of myofibrillar proteins
RT redundantly: towards understanding MURF-dependent muscle
RT ubiquitination.";
RL J. Mol. Biol. 350:713-722(2005).
RN [23]
RP INTERACTION WITH LAMIN, AND SUBCELLULAR LOCATION.
RX PubMed=16410549; DOI=10.1242/jcs.02728;
RA Zastrow M.S., Flaherty D.B., Benian G.M., Wilson K.L.;
RT "Nuclear titin interacts with A- and B-type lamins in vitro and in
RT vivo.";
RL J. Cell Sci. 119:239-249(2006).
RN [24]
RP REVIEW.
RX PubMed=16537787; DOI=10.1152/ajpheart.00816.2005;
RA Hoshijima M.;
RT "Mechanical stress-strain sensors embedded in cardiac cytoskeleton: Z
RT disk, titin, and associated structures.";
RL Am. J. Physiol. 290:H1313-H1325(2006).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [26]
RP INTERACTION WITH CMYA5.
RX PubMed=20634290; DOI=10.1074/jbc.M110.108720;
RA Sarparanta J., Blandin G., Charton K., Vihola A., Marchand S.,
RA Milic A., Hackman P., Ehler E., Richard I., Udd B.;
RT "Interactions with M-band titin and calpain 3 link myospryn (CMYA5) to
RT tibial and limb-girdle muscular dystrophies.";
RL J. Biol. Chem. 285:30304-30315(2010).
RN [27]
RP STRUCTURE BY NMR OF 33483-33579.
RX PubMed=7613868; DOI=10.1016/S0969-2126(01)00170-8;
RA Pfuhl M., Pastore A.;
RT "Tertiary structure of an immunoglobulin-like domain from the giant
RT muscle protein titin: a new member of the I set.";
RL Structure 3:391-401(1995).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 32172-32489, FUNCTION, ENZYME
RP REGULATION, INTERACTION WITH CALM, PHOSPHORYLATION AT TYR-32341, AND
RP MUTAGENESIS OF LYS-32207 AND TYR-32341.
RX PubMed=9804419; DOI=10.1038/27603;
RA Mayans O., van der Ven P.F.M., Wilm M., Mues A., Young P., Furst D.O.,
RA Wilmanns M., Gautel M.;
RT "Structural basis for activation of the titin kinase domain during
RT myofibrillogenesis.";
RL Nature 395:863-869(1998).
RN [29]
RP STRUCTURE BY NMR OF 22283-22385.
RX PubMed=9782056; DOI=10.1016/S0969-2126(98)00129-4;
RA Goll C.M., Pastore A., Nilges M.;
RT "The three-dimensional structure of a type I module from titin: a
RT prototype of intracellular fibronectin type III domains.";
RL Structure 6:1291-1302(1998).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 2073-2171, AND DISULFIDE
RP BOND.
RX PubMed=11525170; DOI=10.1016/S0969-2126(01)00591-3;
RA Mayans O., Wuerges J., Canela S., Gautel M., Wilmanns M.;
RT "Structural evidence for a possible role of reversible disulphide
RT bridge formation in the elasticity of the muscle protein titin.";
RL Structure 9:331-340(2001).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.44 ANGSTROMS) OF 1-196 IN COMPLEX WITH TCAP.
RX PubMed=16407954; DOI=10.1038/nature04343;
RA Zou P., Pinotsis N., Lange S., Song Y.-H., Popov A., Mavridis I.,
RA Mayans O.M., Gautel M., Wilmanns M.;
RT "Palindromic assembly of the giant muscle protein titin in the
RT sarcomeric Z-disk.";
RL Nature 439:229-233(2006).
RN [32]
RP VARIANT CMH9 LEU-740.
RX PubMed=10462489; DOI=10.1006/bbrc.1999.1221;
RA Satoh M., Takahashi M., Sakamoto T., Hiroe M., Marumo F., Kimura A.;
RT "Structural analysis of the titin gene in hypertrophic cardiomyopathy:
RT identification of a novel disease gene.";
RL Biochem. Biophys. Res. Commun. 262:411-417(1999).
RN [33]
RP INVOLVEMENT IN LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 2J, AND VARIANT TMD
RP PRO-34315.
RX PubMed=12145747; DOI=10.1086/342380;
RA Hackman P., Vihola A., Haravuori H., Marchand S., Sarparanta J.,
RA De Seze J., Labeit S., Witt C., Peltonen L., Richard I., Udd B.;
RT "Tibial muscular dystrophy is a titinopathy caused by mutations in
RT TTN, the gene encoding the giant skeletal-muscle protein titin.";
RL Am. J. Hum. Genet. 71:492-500(2002).
RN [34]
RP VARIANTS CMD1G MET-54; VAL-743; TYR-3799 AND ASN-4465, VARIANTS
RP CYS-328; GLN-4084 AND PRO-4215, AND CHARACTERIZATION OF VARIANTS CMD1G
RP MET-54 AND VAL-743.
RX PubMed=11846417; DOI=10.1006/bbrc.2002.6448;
RA Itoh-Satoh M., Hayashi T., Nishi H., Koga Y., Arimura T., Koyanagi T.,
RA Takahashi M., Hohda S., Ueda K., Nouchi T., Hiroe M., Marumo F.,
RA Imaizumi T., Yasunami M., Kimura A.;
RT "Titin mutations as the molecular basis for dilated cardiomyopathy.";
RL Biochem. Biophys. Res. Commun. 291:385-393(2002).
RN [35]
RP VARIANT CMD1G ARG-976.
RX PubMed=11788824; DOI=10.1038/ng815;
RA Gerull B., Gramlich M., Atherton J., McNabb M., Trombitas K.,
RA Sasse-Klaassen S., Seidman J.G., Seidman C., Granzier H., Labeit S.,
RA Frenneaux M., Thierfelder L.;
RT "Mutations of TTN, encoding the giant muscle filament titin, cause
RT familial dilated cardiomyopathy.";
RL Nat. Genet. 30:201-204(2002).
RN [36]
RP VARIANT TMD ASN-34306.
RX PubMed=12891679; DOI=10.1002/ana.10647;
RA Van den Bergh P.Y.K., Bouquiaux O., Verellen C., Marchand S.,
RA Richard I., Hackman P., Udd B.;
RT "Tibial muscular dystrophy in a Belgian family.";
RL Ann. Neurol. 54:248-251(2003).
RN [37]
RP VARIANT CMD1G GLN-32996.
RX PubMed=16465475; DOI=10.1007/s10974-005-9018-5;
RA Matsumoto Y., Hayashi T., Inagaki N., Takahashi M., Hiroi S.,
RA Nakamura T., Arimura T., Nakamura K., Ashizawa N., Yasunami M.,
RA Ohe T., Yano K., Kimura A.;
RT "Functional analysis of titin/connectin N2-B mutations found in
RT cardiomyopathy.";
RL J. Muscle Res. Cell Motil. 26:367-374(2005).
RN [38]
RP VARIANT HMERF TRP-279, CHARACTERIZATION OF VARIANT HMERF TRP-279, AND
RP INTERACTION WITH NBR1.
RX PubMed=15802564; DOI=10.1126/science.1110463;
RA Lange S., Xiang F., Yakovenko A., Vihola A., Hackman P., Rostkova E.,
RA Kristensen J., Brandmeier B., Franzen G., Hedberg B., Gunnarsson L.G.,
RA Hughes S.M., Marchand S., Sejersen T., Richard I., Edstroem L.,
RA Ehler E., Udd B., Gautel M.;
RT "The kinase domain of titin controls muscle gene expression and
RT protein turnover.";
RL Science 308:1599-1603(2005).
RN [39]
RP INVOLVEMENT IN EOMFC.
RX PubMed=17444505; DOI=10.1002/ana.21089;
RA Carmignac V., Salih M.A.M., Quijano-Roy S., Marchand S.,
RA Al Rayess M.M., Mukhtar M.M., Urtizberea J.A., Labeit S.,
RA Guicheney P., Leturcq F., Gautel M., Fardeau M., Campbell K.P.,
RA Richard I., Estournet B., Ferreiro A.;
RT "C-terminal titin deletions cause a novel early-onset myopathy with
RT fatal cardiomyopathy.";
RL Ann. Neurol. 61:340-351(2007).
RN [40]
RP VARIANTS [LARGE SCALE ANALYSIS] TYR-60; MET-115; CYS-328; THR-360;
RP ILE-498; MET-799; ILE-811; HIS-922; ASP-937; THR-1081; ARG-1137;
RP GLU-1201; ALA-1202; LEU-1295; ASP-1345; THR-1347; HIS-1350; LEU-1353;
RP VAL-1393; CYS-1416; PRO-1441; VAL-1544; GLN-1572; GLY-1658; GLN-1664;
RP ASP-1692; LEU-1744; GLY-1772; ILE-1907; HIS-1998; LEU-2107; THR-2118;
RP THR-2164; TYR-2240; SER-2392; PHE-2432; ILE-2610; MET-2771; PHE-2823;
RP ASN-2831; ILE-2930; ARG-3154; GLU-3191; LEU-3238; GLY-3250; MET-3261;
RP GLN-3367; LYS-3482; LYS-3570; VAL-3590; VAL-3762; PHE-3877; LEU-3965;
RP PRO-4215; TRP-4238; PHE-4283; THR-4291; ASP-4303; GLU-4427; GLU-12310;
RP ALA-12469; CYS-12642; LYS-12657; GLU-12679; PHE-12720; CYS-12798;
RP GLY-13049; LYS-13083; LEU-13096; ARG-13099; ALA-13297; MET-13399;
RP THR-13418; VAL-13428; THR-13430; LYS-13434; ASN-13469; ASN-13495;
RP SER-13785; HIS-13870; ILE-14109; GLN-14131; THR-14208; VAL-14728;
RP THR-14999; THR-15021; VAL-15520; ILE-15555; GLN-15620; ILE-15629;
RP CYS-15635; GLN-15700; PRO-15705; MET-15837; HIS-16058; ILE-16067;
RP THR-16090; HIS-16195; CYS-16409; PRO-16424; MET-16629; ARG-16877;
RP ASP-17060; VAL-17637; HIS-17838; ASN-17866; GLU-17906; ALA-18094;
RP SER-18109; THR-18164; LEU-18221; THR-18222; GLN-18726; ALA-18835;
RP LYS-18881; SER-18939; GLN-19000; GLN-19060; LYS-19091; SER-19224;
RP ILE-19367; LYS-19392; SER-19480; GLY-19495; HIS-19665; ILE-19762;
RP ARG-19947; MET-19956; GLN-19992; CYS-20057; LEU-20075; LYS-20179;
RP THR-20198; VAL-20198; HIS-20331; THR-20408; LYS-20564; ILE-20718;
RP PRO-20726; ASN-20892; ARG-20894; GLU-21125; SER-21403; CYS-21730;
RP GLN-21747; ARG-21851; ARG-21851; ARG-21925; HIS-21995; VAL-22045;
RP HIS-22149; ILE-22160; THR-22261; ASN-22306; HIS-22357; PRO-22408;
RP HIS-22537; LEU-22584; PRO-22646; ALA-22670; ASP-22770; THR-22801;
RP TRP-22823; GLN-22968; LEU-23074; PHE-23079; ASN-23282; TYR-23303;
RP CYS-23306; SER-23515; GLN-23551; ASN-23807; ASN-23872; ALA-23891;
RP HIS-23933; MET-23939; LEU-23952; GLY-24098; SER-24119; ILE-24133;
RP ALA-24159; ALA-24239; LYS-24265; THR-24584; THR-24781; HIS-24799;
RP HIS-24954; MET-24980; HIS-25659; THR-25679; ALA-25720; LYS-25821;
RP LYS-25859; LYS-25879; VAL-25923; ILE-26045; GLU-26059; VAL-26134;
RP CYS-26477; TYR-26843; ARG-27346; CYS-27652; VAL-27728; LEU-27754;
RP THR-27755; VAL-27929; LEU-28132; GLN-28168; HIS-28538; THR-28572;
RP THR-28948; VAL-28986; GLU-28993; VAL-28998; MET-29070; VAL-29090;
RP CYS-29419; PRO-29479; LEU-29880; GLU-29976; GLY-30042; CYS-30107;
RP PHE-30125; PRO-30211; THR-30412; SER-30617; ILE-30674; ILE-30809;
RP ILE-30818; LYS-30825; THR-30856; ASP-30887; SER-30887; HIS-30897;
RP HIS-30907; HIS-30946; PHE-31081; CYS-31107; GLY-31124; SER-31156;
RP THR-31246; HIS-31330; ARG-31690; GLN-31724; ILE-31725; SER-31732;
RP ILE-31886; CYS-32097; ASN-32171; ILE-32248; HIS-32281; HIS-32323;
RP TRP-32411; VAL-32558; VAL-32610; VAL-32637; ALA-32922; ARG-32943;
RP HIS-32953; LEU-33213; CYS-33242; MET-33387; ASP-33419; MET-33536;
RP GLN-33568; LYS-33616; LEU-33620; VAL-33886; THR-33899; PRO-33904;
RP ILE-33955 AND ALA-34115.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [41]
RP VARIANTS VAL-16046 AND GLN-32742.
RX PubMed=23033978; DOI=10.1056/NEJMoa1206524;
RA de Ligt J., Willemsen M.H., van Bon B.W., Kleefstra T., Yntema H.G.,
RA Kroes T., Vulto-van Silfhout A.T., Koolen D.A., de Vries P.,
RA Gilissen C., del Rosario M., Hoischen A., Scheffer H., de Vries B.B.,
RA Brunner H.G., Veltman J.A., Vissers L.E.;
RT "Diagnostic exome sequencing in persons with severe intellectual
RT disability.";
RL N. Engl. J. Med. 367:1921-1929(2012).
CC -!- FUNCTION: Key component in the assembly and functioning of
CC vertebrate striated muscles. By providing connections at the level
CC of individual microfilaments, it contributes to the fine balance
CC of forces between the two halves of the sarcomere. The size and
CC extensibility of the cross-links are the main determinants of
CC sarcomere extensibility properties of muscle. In non-muscle cells,
CC seems to play a role in chromosome condensation and chromosome
CC segregation during mitosis. Might link the lamina network to
CC chromatin or nuclear actin, or both during interphase.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: Full activation of the protein kinase domain
CC requires both phosphorylation of Tyr-32341, preventing it from
CC blocking the catalytic aspartate residue, and binding of Ca/CALM
CC to the C-terminal regulatory tail of the molecule which results in
CC ATP binding to the kinase.
CC -!- SUBUNIT: Interacts with MYOM1, MYOM2, tropomyosin and myosin.
CC Interacts with actin, primarily via the PEVK domains and with MYPN
CC (By similarity). Interacts with FHL2, NEB, CRYAB, LMNA/lamin-A and
CC LMNB/lamin-B. Interacts with TCAP/telethonin and/or ANK1 isoform
CC Mu17/ank1.5, via the first two N-terminal immunoglobulin domains.
CC Interacts with TRIM63 and TRIM55, through several domains
CC including immunoglobulin domains 141 and 142. Interacts with
CC ANKRD1, ANKRD2 and ANKRD23, via the region between immunoglobulin
CC domains 77 and 78 and interacts with CAPN3, via immunoglobulin
CC domain 79. Interacts with NBR1 through the protein kinase domain.
CC Interacts with CALM/calmodulin. Isoform 6 interacts with OBSCN
CC isoform 3. Interacts with CMYA5.
CC -!- INTERACTION:
CC Self; NbExp=16; IntAct=EBI-681210, EBI-681210;
CC P12814:ACTN1; NbExp=2; IntAct=EBI-681210, EBI-351710;
CC P35609:ACTN2; NbExp=16; IntAct=EBI-681210, EBI-77797;
CC P62158:CALM3; NbExp=2; IntAct=EBI-681210, EBI-397435;
CC P20807:CAPN3; NbExp=4; IntAct=EBI-681210, EBI-5655000;
CC O75953:DNAJB5; NbExp=4; IntAct=EBI-681210, EBI-5655937;
CC O75923:DYSF; NbExp=17; IntAct=EBI-681210, EBI-2799016;
CC P06733:ENO1; NbExp=3; IntAct=EBI-681210, EBI-353877;
CC Q14324:MYBPC2; NbExp=14; IntAct=EBI-681210, EBI-5653200;
CC Q13203:MYBPH; NbExp=3; IntAct=EBI-681210, EBI-5655165;
CC P54296:MYOM2; NbExp=2; IntAct=EBI-681210, EBI-5357134;
CC P20929:NEB; NbExp=6; IntAct=EBI-681210, EBI-1049657;
CC Q5VST9:OBSCN; NbExp=11; IntAct=EBI-681210, EBI-941850;
CC O75147:OBSL1; NbExp=8; IntAct=EBI-681210, EBI-1223896;
CC Q96CV9:OPTN; NbExp=2; IntAct=EBI-681210, EBI-748974;
CC O15273:TCAP; NbExp=7; IntAct=EBI-681210, EBI-954089;
CC Q969Q1:TRIM63; NbExp=3; IntAct=EBI-681210, EBI-5661333;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (Probable). Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=13;
CC Comment=A number of isoforms may be produced, ranging from 27000
CC to 33000 residues in different striated muscle tissues, the size
CC of the full length protein may be up to 38138 residues;
CC Name=1;
CC IsoId=Q8WZ42-1; Sequence=Displayed;
CC Note=No experimental confirmation available;
CC Name=2;
CC IsoId=Q8WZ42-2; Sequence=VSP_019138;
CC Note=No experimental confirmation available;
CC Name=3; Synonyms=Small cardiac N2-B;
CC IsoId=Q8WZ42-3; Sequence=VSP_019139, VSP_019145;
CC Name=4; Synonyms=Soleus;
CC IsoId=Q8WZ42-4; Sequence=VSP_019142, VSP_019151;
CC Note=No experimental confirmation available;
CC Name=5;
CC IsoId=Q8WZ42-5; Sequence=VSP_019147, VSP_019148, VSP_019149,
CC VSP_019150, VSP_019152;
CC Note=No experimental confirmation available;
CC Name=6; Synonyms=Small cardiac novex-3;
CC IsoId=Q8WZ42-6; Sequence=VSP_019143, VSP_019146;
CC Note=Contains a phosphothreonine at position 5304. Contains a
CC phosphoserine at position 5306. Ref.3 (CAD12457) sequence is in
CC conflict in positions: 3732:L->F and 5139:R->M;
CC Name=7; Synonyms=Cardiac novex-2;
CC IsoId=Q8WZ42-7; Sequence=VSP_019141, VSP_019144;
CC Name=8; Synonyms=Cardiac novex-1;
CC IsoId=Q8WZ42-8; Sequence=VSP_019140;
CC Name=9;
CC IsoId=Q8WZ42-9; Sequence=VSP_019139, VSP_042903, VSP_019145;
CC Name=10;
CC IsoId=Q8WZ42-10; Sequence=VSP_019139, VSP_019140, VSP_019145;
CC Name=11;
CC IsoId=Q8WZ42-11; Sequence=VSP_019142;
CC Name=12;
CC IsoId=Q8WZ42-12; Sequence=VSP_045935, VSP_045929, VSP_045930,
CC VSP_045931, VSP_045932, VSP_045933,
CC VSP_045934;
CC Note=No experimental confirmation available;
CC Name=13;
CC IsoId=Q8WZ42-13; Sequence=VSP_047142;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Isoforms 3, 7 and 8 are expressed in cardiac
CC muscle. Isoform 4 is expressed in vertebrate skeletal muscle.
CC Isoform 6 is expressed in skeletal muscle (at protein level).
CC -!- DOMAIN: ZIS1 and ZIS5 regions contain multiple SPXR consensus
CC sites for ERK- and CDK-like protein kinases as well as multiple SP
CC motifs. ZIS1 could adopt a closed conformation which would block
CC the TCAP-binding site.
CC -!- DOMAIN: The PEVK region may serve as an entropic spring of a chain
CC of structural folds and may also be an interaction site to other
CC myofilament proteins to form interfilament connectivity in the
CC sarcomere.
CC -!- PTM: Autophosphorylated (By similarity).
CC -!- DISEASE: Hereditary myopathy with early respiratory failure
CC (HMERF) [MIM:603689]: Autosomal dominant, adult-onset myopathy
CC with early respiratory muscle involvement. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Cardiomyopathy, familial hypertrophic 9 (CMH9)
CC [MIM:613765]: A hereditary heart disorder characterized by
CC ventricular hypertrophy, which is usually asymmetric and often
CC involves the interventricular septum. The symptoms include
CC dyspnea, syncope, collapse, palpitations, and chest pain. They can
CC be readily provoked by exercise. The disorder has inter- and
CC intrafamilial variability ranging from benign to malignant forms
CC with high risk of cardiac failure and sudden cardiac death.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Cardiomyopathy, dilated 1G (CMD1G) [MIM:604145]: A
CC disorder characterized by ventricular dilation and impaired
CC systolic function, resulting in congestive heart failure and
CC arrhythmia. Patients are at risk of premature death. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Tardive tibial muscular dystrophy (TMD) [MIM:600334]:
CC Autosomal dominant, late-onset distal myopathy. Muscle weakness
CC and atrophy are usually confined to the anterior compartment of
CC the lower leg, in particular the tibialis anterior muscle.
CC Clinical symptoms usually occur at age 35-45 years or much later.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Limb-girdle muscular dystrophy 2J (LGMD2J) [MIM:608807]:
CC An autosomal recessive degenerative myopathy characterized by
CC progressive weakness of the pelvic and shoulder girdle muscles.
CC Severe disability is observed within 20 years of onset. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Early-onset myopathy with fatal cardiomyopathy (EOMFC)
CC [MIM:611705]: Early-onset myopathies are inherited muscle
CC disorders that manifest typically from birth or infancy with
CC hypotonia, muscle weakness, and delayed motor development. EOMFC
CC is a titinopathy that, in contrast with the previously described
CC examples, involves both heart and skeletal muscle, has a
CC congenital onset, and is purely recessive. This phenotype is due
CC to homozygous out-of-frame TTN deletions, which lead to a total
CC absence of titin's C-terminal end from striated muscles and to
CC secondary CAPN3 depletion. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: In some isoforms, after the PEVK repeat region
CC there is a long PEVK duplicated region. On account of this region,
CC it has been very difficult to sequence the whole protein. The
CC length of this region (ranging from 183 to 2174 residues), may be
CC a key elastic element of titin.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK
CC Ser/Thr protein kinase family.
CC -!- SIMILARITY: Contains 132 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 152 Ig-like (immunoglobulin-like) domains.
CC -!- SIMILARITY: Contains 19 Kelch repeats.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 17 RCC1 repeats.
CC -!- SIMILARITY: Contains 14 TPR repeats.
CC -!- SIMILARITY: Contains 15 WD repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH58824.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 553;
CC Sequence=AAH70170.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 627;
CC Sequence=CAA62188.1; Type=Frameshift; Positions=17036, 17043;
CC Sequence=CAD12455.1; Type=Frameshift; Positions=17036, 17043;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TTN";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Titin entry;
CC URL="http://en.wikipedia.org/wiki/Titin";
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DR EMBL; X90568; CAA62188.1; ALT_FRAME; mRNA.
DR EMBL; X90569; CAA62189.1; -; mRNA.
DR EMBL; AJ277892; CAD12455.1; ALT_FRAME; Genomic_DNA.
DR EMBL; AJ277893; CAD12456.1; -; Genomic_DNA.
DR EMBL; AJ277892; CAD12457.1; -; Genomic_DNA.
DR EMBL; AJ277892; CAD12458.1; -; Genomic_DNA.
DR EMBL; AJ277892; CAD12459.1; -; Genomic_DNA.
DR EMBL; AC009948; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC010680; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; FJ695199; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC023270; AAX88844.1; -; Genomic_DNA.
DR EMBL; BC013396; AAH13396.1; -; mRNA.
DR EMBL; BC058824; AAH58824.1; ALT_SEQ; mRNA.
DR EMBL; BC070170; AAH70170.1; ALT_SEQ; mRNA.
DR EMBL; BC107797; AAI07798.1; -; mRNA.
DR EMBL; X98114; CAA66795.1; -; mRNA.
DR EMBL; X98115; CAA66796.1; -; mRNA.
DR EMBL; X83270; CAA58243.1; -; mRNA.
DR EMBL; AF058332; AAD22603.1; -; Genomic_DNA.
DR EMBL; AF058332; AAD22604.1; -; Genomic_DNA.
DR EMBL; AF525413; AAP80791.1; -; mRNA.
DR EMBL; DQ248309; ABB55264.1; -; mRNA.
DR EMBL; X64698; CAA45939.1; -; mRNA.
DR EMBL; X64699; CAA45940.1; -; Genomic_DNA.
DR EMBL; X64697; CAA45938.1; -; mRNA.
DR EMBL; X69490; CAA49245.1; -; mRNA.
DR EMBL; AL713647; CAD28458.1; -; mRNA.
DR PIR; I38344; I38344.
DR PIR; I38346; I38346.
DR RefSeq; NP_001243779.1; NM_001256850.1.
DR RefSeq; NP_001254479.1; NM_001267550.1.
DR RefSeq; NP_003310.4; NM_003319.4.
DR RefSeq; NP_596869.4; NM_133378.4.
DR RefSeq; NP_596870.2; NM_133379.4.
DR RefSeq; NP_597676.3; NM_133432.3.
DR RefSeq; NP_597681.3; NM_133437.3.
DR UniGene; Hs.134602; -.
DR PDB; 1BPV; NMR; -; A=22283-22385.
DR PDB; 1G1C; X-ray; 2.10 A; A/B=2073-2171.
DR PDB; 1NCT; NMR; -; A=33483-33579.
DR PDB; 1NCU; NMR; -; A=33483-33579.
DR PDB; 1TIT; NMR; -; A=12677-12765.
DR PDB; 1TIU; NMR; -; A=12677-12765.
DR PDB; 1TKI; X-ray; 2.00 A; A/B=32172-32492.
DR PDB; 1TNM; NMR; -; A=33489-33579.
DR PDB; 1TNN; NMR; -; A=33489-33579.
DR PDB; 1WAA; X-ray; 1.80 A; A/B/C/D/E/F=12677-12765.
DR PDB; 1YA5; X-ray; 2.44 A; A/B=1-196.
DR PDB; 2A38; X-ray; 2.00 A; A/B/C=1-194.
DR PDB; 2BK8; X-ray; 1.69 A; A=32497-32590.
DR PDB; 2F8V; X-ray; 2.75 A; A/B/C/D=1-196.
DR PDB; 2ILL; X-ray; 2.20 A; A=31854-32047.
DR PDB; 2J8H; X-ray; 1.99 A; A=31854-32047.
DR PDB; 2J8O; X-ray; 2.49 A; A/B=31854-32047.
DR PDB; 2NZI; X-ray; 2.90 A; A/B=31854-32155.
DR PDB; 2RQ8; NMR; -; A=12677-12765.
DR PDB; 2WP3; X-ray; 1.48 A; T=34252-34350.
DR PDB; 2WWK; X-ray; 1.70 A; T=34252-34350.
DR PDB; 2WWM; X-ray; 2.30 A; D/T=34252-34350.
DR PDB; 2Y9R; X-ray; 1.90 A; T=34252-34350.
DR PDB; 3B43; X-ray; 3.30 A; A=7945-8511.
DR PDB; 3KNB; X-ray; 1.40 A; A=34253-34350.
DR PDB; 3LCY; X-ray; 2.50 A; A/B/C/D=31456-31649.
DR PDB; 3LPW; X-ray; 1.65 A; A/B=22877-23070.
DR PDB; 3PUC; X-ray; 0.96 A; A=33774-33871.
DR PDB; 3Q5O; X-ray; 2.05 A; A/B=34253-34350.
DR PDB; 3QP3; X-ray; 2.00 A; A/B/C=33294-33395.
DR PDBsum; 1BPV; -.
DR PDBsum; 1G1C; -.
DR PDBsum; 1NCT; -.
DR PDBsum; 1NCU; -.
DR PDBsum; 1TIT; -.
DR PDBsum; 1TIU; -.
DR PDBsum; 1TKI; -.
DR PDBsum; 1TNM; -.
DR PDBsum; 1TNN; -.
DR PDBsum; 1WAA; -.
DR PDBsum; 1YA5; -.
DR PDBsum; 2A38; -.
DR PDBsum; 2BK8; -.
DR PDBsum; 2F8V; -.
DR PDBsum; 2ILL; -.
DR PDBsum; 2J8H; -.
DR PDBsum; 2J8O; -.
DR PDBsum; 2NZI; -.
DR PDBsum; 2RQ8; -.
DR PDBsum; 2WP3; -.
DR PDBsum; 2WWK; -.
DR PDBsum; 2WWM; -.
DR PDBsum; 2Y9R; -.
DR PDBsum; 3B43; -.
DR PDBsum; 3KNB; -.
DR PDBsum; 3LCY; -.
DR PDBsum; 3LPW; -.
DR PDBsum; 3PUC; -.
DR PDBsum; 3Q5O; -.
DR PDBsum; 3QP3; -.
DR DisProt; DP00072; -.
DR ProteinModelPortal; Q8WZ42; -.
DR DIP; DIP-33449N; -.
DR IntAct; Q8WZ42; 81.
DR MINT; MINT-2881875; -.
DR MEROPS; I43.001; -.
DR PhosphoSite; Q8WZ42; -.
DR DMDM; 108861911; -.
DR PRIDE; Q8WZ42; -.
DR Ensembl; ENST00000342175; ENSP00000340554; ENSG00000155657.
DR Ensembl; ENST00000342992; ENSP00000343764; ENSG00000155657.
DR Ensembl; ENST00000359218; ENSP00000352154; ENSG00000155657.
DR Ensembl; ENST00000360870; ENSP00000354117; ENSG00000155657.
DR Ensembl; ENST00000436599; ENSP00000405517; ENSG00000155657.
DR Ensembl; ENST00000460472; ENSP00000434586; ENSG00000155657.
DR Ensembl; ENST00000589042; ENSP00000467141; ENSG00000155657.
DR Ensembl; ENST00000591111; ENSP00000465570; ENSG00000155657.
DR GeneID; 7273; -.
DR KEGG; hsa:7273; -.
DR UCSC; uc031rqd.1; human.
DR CTD; 7273; -.
DR GeneCards; GC02M179355; -.
DR H-InvDB; HIX0030529; -.
DR H-InvDB; HIX0161887; -.
DR HGNC; HGNC:12403; TTN.
DR HPA; CAB022682; -.
DR HPA; HPA007042; -.
DR MIM; 188840; gene.
DR MIM; 600334; phenotype.
DR MIM; 603689; phenotype.
DR MIM; 604145; phenotype.
DR MIM; 608807; phenotype.
DR MIM; 611705; phenotype.
DR MIM; 613765; phenotype.
DR neXtProt; NX_Q8WZ42; -.
DR Orphanet; 140922; Autosomal recessive limb-girdle muscular dystrophy type 2J.
DR Orphanet; 289377; Early-onset myopathy with fatal cardiomyopathy.
DR Orphanet; 293899; Familial isolated arrhythmogenic ventricular dysplasia, biventricular form.
DR Orphanet; 293888; Familial isolated arrhythmogenic ventricular dysplasia, left dominant form.
DR Orphanet; 293910; Familial isolated arrhythmogenic ventricular dysplasia, right dominant form.
DR Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR Orphanet; 155; Familial isolated hypertrophic cardiomyopathy.
DR Orphanet; 178464; Hereditary proximal myopathy with early respiratory failure.
DR Orphanet; 609; Tibial muscular dystrophy.
DR PharmGKB; PA37067; -.
DR HOGENOM; HOG000203078; -.
DR HOVERGEN; HBG080473; -.
DR KO; K12567; -.
DR OMA; TWFHNNR; -.
DR OrthoDB; EOG7N8ZTK; -.
DR Reactome; REACT_17044; Muscle contraction.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; Q8WZ42; -.
DR ChiTaRS; TTN; human.
DR EvolutionaryTrace; Q8WZ42; -.
DR GeneWiki; Titin; -.
DR GenomeRNAi; 7273; -.
DR NextBio; 28431; -.
DR PRO; PR:Q8WZ42; -.
DR ArrayExpress; Q8WZ42; -.
DR Bgee; Q8WZ42; -.
DR Genevestigator; Q8WZ42; -.
DR GO; GO:0000794; C:condensed nuclear chromosome; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0031430; C:M band; IDA:BHF-UCL.
DR GO; GO:0005865; C:striated muscle thin filament; IDA:BHF-UCL.
DR GO; GO:0030018; C:Z disc; IDA:BHF-UCL.
DR GO; GO:0051015; F:actin filament binding; IDA:BHF-UCL.
DR GO; GO:0042805; F:actinin binding; IDA:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005509; F:calcium ion binding; IDA:BHF-UCL.
DR GO; GO:0005516; F:calmodulin binding; TAS:UniProtKB.
DR GO; GO:0043621; F:protein self-association; IDA:BHF-UCL.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:InterPro.
DR GO; GO:0008307; F:structural constituent of muscle; TAS:UniProtKB.
DR GO; GO:0097493; F:structural molecule activity conferring elasticity; TAS:BHF-UCL.
DR GO; GO:0031433; F:telethonin binding; ISS:BHF-UCL.
DR GO; GO:0007512; P:adult heart development; IEA:Ensembl.
DR GO; GO:0060048; P:cardiac muscle contraction; IMP:BHF-UCL.
DR GO; GO:0048739; P:cardiac muscle fiber development; IMP:BHF-UCL.
DR GO; GO:0003300; P:cardiac muscle hypertrophy; IMP:BHF-UCL.
DR GO; GO:0055008; P:cardiac muscle tissue morphogenesis; IMP:BHF-UCL.
DR GO; GO:0055003; P:cardiac myofibril assembly; IMP:BHF-UCL.
DR GO; GO:0035995; P:detection of muscle stretch; TAS:BHF-UCL.
DR GO; GO:0043056; P:forward locomotion; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0007076; P:mitotic chromosome condensation; IEP:BHF-UCL.
DR GO; GO:0030049; P:muscle filament sliding; TAS:Reactome.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IEA:GOC.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0045859; P:regulation of protein kinase activity; IMP:BHF-UCL.
DR GO; GO:0051592; P:response to calcium ion; IDA:BHF-UCL.
DR GO; GO:0045214; P:sarcomere organization; IMP:BHF-UCL.
DR GO; GO:0048769; P:sarcomerogenesis; IMP:BHF-UCL.
DR GO; GO:0030241; P:skeletal muscle myosin thick filament assembly; IMP:BHF-UCL.
DR GO; GO:0030240; P:skeletal muscle thin filament assembly; IMP:BHF-UCL.
DR Gene3D; 2.60.40.10; -; 299.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013098; Ig_I-set.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR004168; PPAK_motif.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR015129; Titin_Z.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR Pfam; PF00041; fn3; 132.
DR Pfam; PF07679; I-set; 162.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF02818; PPAK; 15.
DR Pfam; PF09042; Titin_Z; 6.
DR SMART; SM00060; FN3; 132.
DR SMART; SM00409; IG; 95.
DR SMART; SM00408; IGc2; 65.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF49265; SSF49265; 83.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50853; FN3; 132.
DR PROSITE; PS50835; IG_LIKE; 140.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; FALSE_NEG.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; FALSE_NEG.
DR PROSITE; PS00625; RCC1_1; FALSE_NEG.
DR PROSITE; PS00626; RCC1_2; FALSE_NEG.
DR PROSITE; PS50012; RCC1_3; FALSE_NEG.
DR PROSITE; PS50005; TPR; FALSE_NEG.
DR PROSITE; PS50293; TPR_REGION; FALSE_NEG.
DR PROSITE; PS00678; WD_REPEATS_1; FALSE_NEG.
DR PROSITE; PS50082; WD_REPEATS_2; FALSE_NEG.
DR PROSITE; PS50294; WD_REPEATS_REGION; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Calcium;
KW Calmodulin-binding; Cardiomyopathy; Coiled coil; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Disease mutation;
KW Disulfide bond; Immunoglobulin domain; Isopeptide bond; Kelch repeat;
KW Kinase; Limb-girdle muscular dystrophy; Magnesium; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat; Serine/threonine-protein kinase;
KW TPR repeat; Transferase; Ubl conjugation; WD repeat.
FT CHAIN 1 34350 Titin.
FT /FTId=PRO_0000239311.
FT DOMAIN 6 96 Ig-like 1.
FT DOMAIN 104 192 Ig-like 2.
FT REPEAT 417 462 Z-repeat 1.
FT REPEAT 466 511 Z-repeat 2.
FT REPEAT 512 554 Z-repeat 3.
FT REPEAT 555 600 Z-repeat 4.
FT REPEAT 601 646 Z-repeat 5.
FT REPEAT 647 691 Z-repeat 6.
FT REPEAT 692 740 Z-repeat 7.
FT DOMAIN 943 1031 Ig-like 3.
FT DOMAIN 1082 1172 Ig-like 4.
FT DOMAIN 1291 1382 Ig-like 5.
FT DOMAIN 1457 1546 Ig-like 6.
FT DOMAIN 1556 1646 Ig-like 7.
FT DOMAIN 1703 1793 Ig-like 8.
FT DOMAIN 1841 1928 Ig-like 9.
FT DOMAIN 2078 2167 Ig-like 10.
FT REPEAT 2089 2122 TPR 1.
FT DOMAIN 2171 2262 Ig-like 11.
FT DOMAIN 2264 2354 Ig-like 12.
FT DOMAIN 2353 2443 Ig-like 13.
FT DOMAIN 2430 2529 Ig-like 14.
FT DOMAIN 2620 2703 Ig-like 15.
FT REPEAT 2804 2838 TPR 2.
FT DOMAIN 2880 2965 Ig-like 16.
FT DOMAIN 2968 3050 Ig-like 17.
FT REPEAT 3022 3062 WD 1.
FT DOMAIN 3058 3141 Ig-like 18.
FT DOMAIN 3239 3327 Ig-like 19.
FT DOMAIN 3344 3432 Ig-like 20.
FT DOMAIN 3503 3586 Ig-like 21.
FT DOMAIN 3621 3712 Ig-like 22.
FT REPEAT 4168 4203 TPR 3.
FT DOMAIN 4289 4376 Ig-like 23.
FT DOMAIN 4383 4471 Ig-like 24.
FT DOMAIN 4478 4566 Ig-like 25.
FT DOMAIN 4571 4659 Ig-like 26.
FT DOMAIN 4664 4753 Ig-like 27.
FT DOMAIN 4758 4846 Ig-like 28.
FT DOMAIN 4851 4936 Ig-like 29.
FT REPEAT 4860 4904 Kelch 1.
FT DOMAIN 4943 5032 Ig-like 30.
FT DOMAIN 5040 5128 Ig-like 31.
FT DOMAIN 5133 5221 Ig-like 32.
FT REPEAT 5170 5203 TPR 4.
FT DOMAIN 5225 5314 Ig-like 33.
FT DOMAIN 5320 5408 Ig-like 34.
FT DOMAIN 5413 5501 Ig-like 35.
FT DOMAIN 5505 5594 Ig-like 36.
FT DOMAIN 5602 5690 Ig-like 37.
FT DOMAIN 5695 5783 Ig-like 38.
FT DOMAIN 5788 5877 Ig-like 39.
FT DOMAIN 5882 5970 Ig-like 40.
FT DOMAIN 5975 6063 Ig-like 41.
FT DOMAIN 6067 6156 Ig-like 42.
FT DOMAIN 6164 6252 Ig-like 43.
FT DOMAIN 6257 6347 Ig-like 44.
FT DOMAIN 6350 6440 Ig-like 45.
FT DOMAIN 6444 6534 Ig-like 46.
FT REPEAT 6474 6507 TPR 5.
FT DOMAIN 6537 6626 Ig-like 47.
FT DOMAIN 6630 6721 Ig-like 48.
FT REPEAT 6654 6692 WD 2.
FT DOMAIN 6727 6815 Ig-like 49.
FT DOMAIN 6820 6908 Ig-like 50.
FT DOMAIN 6912 7001 Ig-like 51.
FT DOMAIN 7005 7093 Ig-like 52.
FT DOMAIN 7102 7190 Ig-like 53.
FT DOMAIN 7198 7286 Ig-like 54.
FT DOMAIN 7291 7380 Ig-like 55.
FT DOMAIN 7385 7473 Ig-like 56.
FT REPEAT 7415 7448 TPR 6.
FT DOMAIN 7478 7567 Ig-like 57.
FT DOMAIN 7571 7662 Ig-like 58.
FT DOMAIN 7668 7756 Ig-like 59.
FT DOMAIN 7761 7849 Ig-like 60.
FT DOMAIN 7853 7942 Ig-like 61.
FT DOMAIN 7946 8035 Ig-like 62.
FT DOMAIN 8042 8133 Ig-like 63.
FT DOMAIN 8138 8229 Ig-like 64.
FT DOMAIN 8232 8321 Ig-like 65.
FT DOMAIN 8326 8414 Ig-like 66.
FT DOMAIN 8419 8508 Ig-like 67.
FT DOMAIN 8512 8603 Ig-like 68.
FT DOMAIN 8609 8697 Ig-like 69.
FT DOMAIN 8702 8790 Ig-like 70.
FT DOMAIN 8794 8883 Ig-like 71.
FT DOMAIN 8888 8976 Ig-like 72.
FT DOMAIN 8984 9074 Ig-like 73.
FT DOMAIN 9079 9168 Ig-like 74.
FT DOMAIN 9176 9265 Ig-like 75.
FT REPEAT 9184 9221 TPR 7.
FT DOMAIN 9272 9361 Ig-like 76.
FT DOMAIN 9366 9470 Ig-like 77.
FT DOMAIN 9660 9755 Ig-like 78.
FT REPEAT 9701 9734 TPR 8.
FT DOMAIN 9760 9851 Ig-like 79.
FT REPEAT 10031 10064 TPR 9.
FT REPEAT 10041 10087 Kelch 2.
FT REPEAT 10216 10242 PEVK 1.
FT REPEAT 10244 10270 PEVK 2.
FT REPEAT 10272 10298 PEVK 3.
FT REPEAT 10300 10326 PEVK 4.
FT REPEAT 10327 10353 PEVK 5.
FT REPEAT 10355 10381 PEVK 6.
FT REPEAT 10508 10534 PEVK 7.
FT REPEAT 10536 10562 PEVK 8.
FT REPEAT 10592 10618 PEVK 9.
FT REPEAT 10878 10904 PEVK 10.
FT REPEAT 10906 10930 PEVK 11.
FT REPEAT 10932 10958 PEVK 12.
FT REPEAT 10960 10986 PEVK 13.
FT REPEAT 10987 11014 PEVK 14.
FT REPEAT 11363 11396 PEVK 15.
FT REPEAT 11397 11421 PEVK 16.
FT REPEAT 11453 11479 PEVK 17.
FT REPEAT 11481 11507 PEVK 18.
FT REPEAT 11509 11535 PEVK 19.
FT REPEAT 11537 11563 PEVK 20.
FT REPEAT 11565 11591 PEVK 21.
FT REPEAT 11657 11683 PEVK 22.
FT REPEAT 11703 11729 PEVK 23.
FT REPEAT 11745 11771 PEVK 24.
FT REPEAT 11775 11801 PEVK 25.
FT REPEAT 11836 11862 PEVK 26.
FT REPEAT 11864 11890 PEVK 27.
FT REPEAT 11893 11919 PEVK 28.
FT REPEAT 11929 11955 PEVK 29.
FT REPEAT 11966 11992 PEVK 30.
FT REPEAT 11996 12022 PEVK 31.
FT DOMAIN 12041 12133 Ig-like 80.
FT DOMAIN 12138 12222 Ig-like 81.
FT DOMAIN 12233 12318 Ig-like 82.
FT DOMAIN 12499 12584 Ig-like 83.
FT DOMAIN 12590 12672 Ig-like 84.
FT DOMAIN 12766 12850 Ig-like 85.
FT DOMAIN 12945 13032 Ig-like 86.
FT REPEAT 12955 12988 TPR 10.
FT DOMAIN 13120 13206 Ig-like 87.
FT DOMAIN 13210 13295 Ig-like 88.
FT DOMAIN 13299 13384 Ig-like 89.
FT DOMAIN 13388 13478 Ig-like 90.
FT REPEAT 13391 13432 WD 3.
FT REPEAT 13443 13485 WD 4.
FT DOMAIN 13479 13562 Ig-like 91.
FT DOMAIN 13565 13655 Ig-like 92.
FT DOMAIN 13659 13748 Ig-like 93.
FT REPEAT 13714 13753 WD 5.
FT DOMAIN 13749 13833 Ig-like 94.
FT DOMAIN 13927 14012 Ig-like 95.
FT DOMAIN 14019 14114 Fibronectin type-III 1.
FT REPEAT 14084 14136 RCC1 1.
FT DOMAIN 14120 14215 Fibronectin type-III 2.
FT REPEAT 14185 14238 RCC1 2.
FT DOMAIN 14221 14316 Fibronectin type-III 3.
FT DOMAIN 14417 14513 Fibronectin type-III 4.
FT DOMAIN 14517 14614 Fibronectin type-III 5.
FT DOMAIN 14615 14708 Ig-like 96.
FT DOMAIN 14713 14806 Fibronectin type-III 6.
FT DOMAIN 14812 14907 Fibronectin type-III 7.
FT REPEAT 14828 14876 Kelch 3.
FT DOMAIN 14913 15007 Fibronectin type-III 8.
FT REPEAT 14986 15036 Kelch 4.
FT DOMAIN 15010 15107 Fibronectin type-III 9.
FT REPEAT 15077 15130 RCC1 3.
FT DOMAIN 15113 15207 Fibronectin type-III 10.
FT DOMAIN 15214 15310 Fibronectin type-III 11.
FT DOMAIN 15314 15402 Ig-like 97.
FT DOMAIN 15409 15503 Fibronectin type-III 12.
FT DOMAIN 15509 15604 Fibronectin type-III 13.
FT REPEAT 15574 15630 RCC1 4.
FT DOMAIN 15608 15724 Ig-like 98.
FT DOMAIN 15731 15826 Fibronectin type-III 14.
FT DOMAIN 15832 15926 Fibronectin type-III 15.
FT DOMAIN 15929 16025 Fibronectin type-III 16.
FT DOMAIN 16029 16119 Ig-like 99.
FT DOMAIN 16126 16218 Fibronectin type-III 17.
FT REPEAT 16134 16180 WD 6.
FT DOMAIN 16224 16318 Fibronectin type-III 18.
FT DOMAIN 16322 16420 Ig-like 100.
FT DOMAIN 16427 16522 Fibronectin type-III 19.
FT DOMAIN 16528 16628 Fibronectin type-III 20.
FT DOMAIN 16634 16734 Fibronectin type-III 21.
FT DOMAIN 16727 16834 Ig-like 101.
FT DOMAIN 16841 16934 Fibronectin type-III 22.
FT DOMAIN 16941 17041 Fibronectin type-III 23.
FT DOMAIN 17044 17139 Ig-like 102.
FT DOMAIN 17147 17240 Fibronectin type-III 24.
FT DOMAIN 17246 17345 Fibronectin type-III 25.
FT DOMAIN 17348 17445 Fibronectin type-III 26.
FT DOMAIN 17449 17536 Ig-like 103.
FT DOMAIN 17545 17640 Fibronectin type-III 27.
FT DOMAIN 17646 17741 Fibronectin type-III 28.
FT REPEAT 17711 17769 RCC1 5.
FT DOMAIN 17745 17834 Ig-like 104.
FT DOMAIN 17842 17935 Fibronectin type-III 29.
FT REPEAT 17930 17969 WD 7.
FT DOMAIN 17941 18036 Fibronectin type-III 30.
FT REPEAT 18006 18055 RCC1 6.
FT DOMAIN 18042 18139 Fibronectin type-III 31.
FT DOMAIN 18143 18228 Ig-like 105.
FT DOMAIN 18239 18333 Fibronectin type-III 32.
FT REPEAT 18258 18303 Kelch 5.
FT REPEAT 18303 18358 RCC1 7.
FT DOMAIN 18339 18431 Fibronectin type-III 33.
FT DOMAIN 18435 18526 Ig-like 106.
FT DOMAIN 18533 18632 Fibronectin type-III 34.
FT REPEAT 18553 18598 Kelch 6.
FT DOMAIN 18633 18727 Fibronectin type-III 35.
FT DOMAIN 18733 18829 Fibronectin type-III 36.
FT DOMAIN 18833 18924 Ig-like 107.
FT DOMAIN 18931 19025 Fibronectin type-III 37.
FT DOMAIN 19030 19124 Fibronectin type-III 38.
FT DOMAIN 19128 19219 Ig-like 108.
FT DOMAIN 19226 19321 Fibronectin type-III 39.
FT REPEAT 19290 19346 RCC1 8.
FT DOMAIN 19325 19420 Fibronectin type-III 40.
FT REPEAT 19389 19452 RCC1 9.
FT DOMAIN 19426 19527 Fibronectin type-III 41.
FT DOMAIN 19531 19617 Ig-like 109.
FT DOMAIN 19628 19722 Fibronectin type-III 42.
FT REPEAT 19647 19692 Kelch 7.
FT DOMAIN 19728 19823 Fibronectin type-III 43.
FT DOMAIN 19826 19914 Ig-like 110.
FT DOMAIN 19921 20017 Fibronectin type-III 44.
FT DOMAIN 20018 20116 Fibronectin type-III 45.
FT DOMAIN 20119 20217 Fibronectin type-III 46.
FT DOMAIN 20220 20311 Ig-like 111.
FT DOMAIN 20318 20411 Fibronectin type-III 47.
FT DOMAIN 20417 20512 Fibronectin type-III 48.
FT DOMAIN 20518 20613 Fibronectin type-III 49.
FT DOMAIN 20716 20813 Fibronectin type-III 50.
FT DOMAIN 20814 20908 Fibronectin type-III 51.
FT REPEAT 20833 20876 Kelch 8.
FT DOMAIN 20893 20996 Ig-like 112.
FT DOMAIN 21006 21101 Fibronectin type-III 52.
FT REPEAT 21069 21125 RCC1 10.
FT DOMAIN 21105 21200 Fibronectin type-III 53.
FT DOMAIN 21203 21299 Fibronectin type-III 54.
FT REPEAT 21222 21267 Kelch 9.
FT DOMAIN 21303 21395 Ig-like 113.
FT DOMAIN 21402 21495 Fibronectin type-III 55.
FT DOMAIN 21501 21596 Fibronectin type-III 56.
FT REPEAT 21565 21620 RCC1 11.
FT DOMAIN 21602 21697 Fibronectin type-III 57.
FT DOMAIN 21701 21793 Ig-like 114.
FT DOMAIN 21797 21891 Fibronectin type-III 58.
FT REPEAT 21860 21910 RCC1 12.
FT DOMAIN 21894 21986 Fibronectin type-III 59.
FT DOMAIN 21990 22083 Ig-like 115.
FT DOMAIN 22088 22182 Fibronectin type-III 60.
FT DOMAIN 22188 22283 Fibronectin type-III 61.
FT DOMAIN 22286 22382 Fibronectin type-III 62.
FT REPEAT 22306 22350 Kelch 10.
FT DOMAIN 22386 22477 Ig-like 116.
FT DOMAIN 22484 22578 Fibronectin type-III 63.
FT DOMAIN 22584 22679 Fibronectin type-III 64.
FT DOMAIN 22685 22781 Fibronectin type-III 65.
FT DOMAIN 22785 22874 Ig-like 117.
FT DOMAIN 22881 22976 Fibronectin type-III 66.
FT DOMAIN 22978 23071 Fibronectin type-III 67.
FT REPEAT 23041 23091 RCC1 13.
FT DOMAIN 23075 23163 Ig-like 118.
FT DOMAIN 23170 23264 Fibronectin type-III 68.
FT DOMAIN 23270 23364 Fibronectin type-III 69.
FT DOMAIN 23368 23463 Fibronectin type-III 70.
FT DOMAIN 23468 23555 Ig-like 119.
FT DOMAIN 23566 23660 Fibronectin type-III 71.
FT REPEAT 23651 23694 WD 8.
FT DOMAIN 23666 23761 Fibronectin type-III 72.
FT DOMAIN 23767 23863 Fibronectin type-III 73.
FT DOMAIN 23867 23954 Ig-like 120.
FT DOMAIN 23963 24057 Fibronectin type-III 74.
FT REPEAT 24027 24076 RCC1 14.
FT DOMAIN 24060 24153 Fibronectin type-III 75.
FT REPEAT 24079 24124 Kelch 11.
FT DOMAIN 24157 24241 Ig-like 121.
FT DOMAIN 24252 24346 Fibronectin type-III 76.
FT REPEAT 24261 24307 WD 9.
FT DOMAIN 24352 24446 Fibronectin type-III 77.
FT DOMAIN 24450 24546 Fibronectin type-III 78.
FT DOMAIN 24550 24641 Ig-like 122.
FT DOMAIN 24648 24742 Fibronectin type-III 79.
FT DOMAIN 24748 24843 Fibronectin type-III 80.
FT DOMAIN 24849 24945 Fibronectin type-III 81.
FT REPEAT 24868 24916 Kelch 12.
FT DOMAIN 24949 25038 Ig-like 123.
FT DOMAIN 25045 25139 Fibronectin type-III 82.
FT DOMAIN 25142 25235 Fibronectin type-III 83.
FT DOMAIN 25239 25325 Ig-like 124.
FT DOMAIN 25335 25428 Fibronectin type-III 84.
FT REPEAT 25343 25389 WD 10.
FT REPEAT 25419 25462 WD 11.
FT DOMAIN 25434 25529 Fibronectin type-III 85.
FT DOMAIN 25532 25627 Fibronectin type-III 86.
FT DOMAIN 25632 25722 Ig-like 125.
FT DOMAIN 25731 25825 Fibronectin type-III 87.
FT DOMAIN 25831 25926 Fibronectin type-III 88.
FT DOMAIN 25932 26028 Fibronectin type-III 89.
FT REPEAT 25951 25997 Kelch 13.
FT DOMAIN 26032 26121 Ig-like 126.
FT DOMAIN 26128 26222 Fibronectin type-III 90.
FT DOMAIN 26225 26318 Fibronectin type-III 91.
FT REPEAT 26244 26289 Kelch 14.
FT DOMAIN 26322 26410 Ig-like 127.
FT DOMAIN 26417 26510 Fibronectin type-III 92.
FT REPEAT 26501 26544 WD 12.
FT DOMAIN 26516 26611 Fibronectin type-III 93.
FT DOMAIN 26614 26710 Fibronectin type-III 94.
FT DOMAIN 26714 26801 Ig-like 128.
FT DOMAIN 26812 26906 Fibronectin type-III 95.
FT DOMAIN 26912 27007 Fibronectin type-III 96.
FT DOMAIN 27013 27107 Fibronectin type-III 97.
FT REPEAT 27077 27127 RCC1 15.
FT DOMAIN 27101 27196 Ig-like 129.
FT DOMAIN 27205 27296 Fibronectin type-III 98.
FT REPEAT 27271 27320 RCC1 16.
FT DOMAIN 27302 27392 Fibronectin type-III 99.
FT REPEAT 27323 27368 Kelch 15.
FT DOMAIN 27499 27593 Fibronectin type-III 100.
FT DOMAIN 27599 27694 Fibronectin type-III 101.
FT DOMAIN 27697 27793 Fibronectin type-III 102.
FT DOMAIN 27797 27888 Ig-like 130.
FT DOMAIN 27895 27989 Fibronectin type-III 103.
FT DOMAIN 27995 28090 Fibronectin type-III 104.
FT REPEAT 28062 28095 TPR 11.
FT DOMAIN 28096 28192 Fibronectin type-III 105.
FT DOMAIN 28196 28286 Ig-like 131.
FT DOMAIN 28295 28389 Fibronectin type-III 106.
FT DOMAIN 28392 28484 Fibronectin type-III 107.
FT DOMAIN 28488 28577 Ig-like 132.
FT DOMAIN 28583 28680 Fibronectin type-III 108.
FT REPEAT 28606 28651 Kelch 16.
FT REPEAT 28671 28714 WD 13.
FT DOMAIN 28686 28781 Fibronectin type-III 109.
FT DOMAIN 28784 28879 Fibronectin type-III 110.
FT DOMAIN 28882 28974 Ig-like 133.
FT DOMAIN 28979 29071 Fibronectin type-III 111.
FT REPEAT 29046 29101 RCC1 17.
FT DOMAIN 29081 29177 Fibronectin type-III 112.
FT DOMAIN 29180 29278 Fibronectin type-III 113.
FT DOMAIN 29282 29367 Ig-like 134.
FT DOMAIN 29378 29473 Fibronectin type-III 114.
FT DOMAIN 29475 29568 Fibronectin type-III 115.
FT DOMAIN 29568 29663 Ig-like 135.
FT DOMAIN 29670 29764 Fibronectin type-III 116.
FT DOMAIN 29770 29865 Fibronectin type-III 117.
FT DOMAIN 29868 29967 Fibronectin type-III 118.
FT DOMAIN 29971 30059 Ig-like 136.
FT DOMAIN 30070 30163 Fibronectin type-III 119.
FT DOMAIN 30169 30265 Fibronectin type-III 120.
FT DOMAIN 30271 30367 Fibronectin type-III 121.
FT DOMAIN 30371 30460 Ig-like 137.
FT DOMAIN 30467 30561 Fibronectin type-III 122.
FT DOMAIN 30564 30658 Fibronectin type-III 123.
FT DOMAIN 30663 30754 Ig-like 138.
FT DOMAIN 30761 30855 Fibronectin type-III 124.
FT DOMAIN 30861 30956 Fibronectin type-III 125.
FT REPEAT 30880 30925 Kelch 17.
FT DOMAIN 30962 31058 Fibronectin type-III 126.
FT DOMAIN 31061 31150 Ig-like 139.
FT DOMAIN 31158 31254 Fibronectin type-III 127.
FT DOMAIN 31258 31354 Fibronectin type-III 128.
FT DOMAIN 31360 31455 Fibronectin type-III 129.
FT DOMAIN 31460 31548 Ig-like 140.
FT DOMAIN 31653 31748 Fibronectin type-III 130.
FT REPEAT 31739 31782 WD 14.
FT DOMAIN 31754 31849 Fibronectin type-III 131.
FT DOMAIN 31855 31945 Ig-like 141.
FT REPEAT 31892 31937 WD 15.
FT DOMAIN 31955 32046 Ig-like 142.
FT DOMAIN 32051 32144 Fibronectin type-III 132.
FT REPEAT 32070 32115 Kelch 18.
FT DOMAIN 32178 32432 Protein kinase.
FT DOMAIN 32496 32584 Ig-like 143.
FT REPEAT 32503 32549 Kelch 19.
FT DOMAIN 32617 32710 Ig-like 144.
FT DOMAIN 32722 32811 Ig-like 145.
FT REPEAT 32927 32960 TPR 12.
FT REPEAT 33235 33268 TPR 13.
FT DOMAIN 33301 33391 Ig-like 146.
FT DOMAIN 33488 33576 Ig-like 147.
FT REPEAT 33518 33551 TPR 14.
FT DOMAIN 33645 33732 Ig-like 148.
FT DOMAIN 33779 33867 Ig-like 149.
FT DOMAIN 33963 34052 Ig-like 150.
FT DOMAIN 34061 34149 Ig-like 151.
FT DOMAIN 34256 34344 Ig-like 152.
FT NP_BIND 32184 32192 ATP (By similarity).
FT REGION 253 341 ZIS1.
FT REGION 1410 1440 ZIS5.
FT COILED 529 561 Potential.
FT COILED 2025 2052 Potential.
FT COILED 3462 3487 Potential.
FT COILED 9534 9577 Potential.
FT COMPBIAS 391 436 Ala-rich.
FT COMPBIAS 453 456 Poly-Thr.
FT COMPBIAS 9500 9503 Poly-Glu.
FT COMPBIAS 9861 9952 Pro-rich.
FT COMPBIAS 9974 11917 Glu-rich.
FT COMPBIAS 9974 10089 Glu-rich.
FT COMPBIAS 10102 10105 Poly-Pro.
FT COMPBIAS 10211 12032 Pro-rich.
FT COMPBIAS 33188 33193 Poly-Ser.
FT COMPBIAS 33197 33200 Poly-Arg.
FT COMPBIAS 34102 34244 Ser-rich.
FT ACT_SITE 32298 32298 Proton acceptor (By similarity).
FT BINDING 32207 32207 ATP (By similarity).
FT MOD_RES 263 263 Phosphoserine (By similarity).
FT MOD_RES 265 265 Phosphoserine (By similarity).
FT MOD_RES 267 267 Phosphothreonine (By similarity).
FT MOD_RES 4065 4065 Phosphoserine.
FT MOD_RES 4068 4068 Phosphoserine.
FT MOD_RES 6920 6920 Phosphoserine (By similarity).
FT MOD_RES 8490 8490 Phosphotyrosine.
FT MOD_RES 9122 9122 Phosphoserine (By similarity).
FT MOD_RES 9203 9203 Phosphoserine.
FT MOD_RES 9207 9207 Phosphothreonine.
FT MOD_RES 11503 11503 Phosphoserine (By similarity).
FT MOD_RES 12007 12007 Phosphothreonine (By similarity).
FT MOD_RES 12009 12009 Phosphoserine (By similarity).
FT MOD_RES 12022 12022 Phosphoserine (By similarity).
FT MOD_RES 22525 22525 Phosphoserine.
FT MOD_RES 22534 22534 Phosphoserine.
FT MOD_RES 30443 30443 Phosphothreonine (By similarity).
FT MOD_RES 32341 32341 Phosphotyrosine.
FT MOD_RES 33245 33245 Phosphoserine (By similarity).
FT MOD_RES 33247 33247 Phosphoserine (By similarity).
FT MOD_RES 33602 33602 Phosphoserine (By similarity).
FT MOD_RES 33614 33614 Phosphoserine (By similarity).
FT MOD_RES 33938 33938 Phosphoserine.
FT MOD_RES 33942 33942 Phosphoserine.
FT DISULFID 964 1015 By similarity.
FT DISULFID 1724 1777 By similarity.
FT DISULFID 2109 2134
FT DISULFID 2196 2246 By similarity.
FT DISULFID 3259 3311 By similarity.
FT DISULFID 4404 4455 By similarity.
FT DISULFID 4499 4550 By similarity.
FT DISULFID 4592 4643 By similarity.
FT DISULFID 4686 4737 By similarity.
FT DISULFID 4779 4830 By similarity.
FT DISULFID 5061 5112 By similarity.
FT DISULFID 5248 5299 By similarity.
FT DISULFID 5623 5674 By similarity.
FT DISULFID 5810 5861 By similarity.
FT DISULFID 5903 5954 By similarity.
FT DISULFID 6185 6236 By similarity.
FT DISULFID 6372 6423 By similarity.
FT DISULFID 6465 6516 By similarity.
FT DISULFID 6748 6799 By similarity.
FT DISULFID 7027 7078 By similarity.
FT DISULFID 7123 7174 By similarity.
FT DISULFID 7219 7270 By similarity.
FT DISULFID 7313 7364 By similarity.
FT DISULFID 7406 7457 By similarity.
FT DISULFID 7689 7740 By similarity.
FT DISULFID 7968 8019 By similarity.
FT DISULFID 8064 8115 By similarity.
FT DISULFID 8160 8211 By similarity.
FT DISULFID 8254 8305 By similarity.
FT DISULFID 8347 8398 By similarity.
FT DISULFID 8630 8681 By similarity.
FT DISULFID 8909 8960 By similarity.
FT DISULFID 9005 9056 By similarity.
FT DISULFID 9101 9152 By similarity.
FT DISULFID 9294 9345 By similarity.
FT DISULFID 9693 9743 By similarity.
FT DISULFID 12067 12117 By similarity.
FT DISULFID 12611 12660 By similarity.
FT DISULFID 12966 13016 By similarity.
FT DISULFID 13233 13283 By similarity.
FT DISULFID 13322 13372 By similarity.
FT DISULFID 13411 13461 By similarity.
FT DISULFID 13771 13821 By similarity.
FT DISULFID 31481 31532 By similarity.
FT DISULFID 32516 32568 By similarity.
FT DISULFID 33664 33718 By similarity.
FT CROSSLNK 10718 10718 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT CROSSLNK 10733 10733 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT CROSSLNK 10740 10740 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT CROSSLNK 29566 29566 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT CROSSLNK 30146 30146 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT VAR_SEQ 555 646 Missing (in isoform 2).
FT /FTId=VSP_019138.
FT VAR_SEQ 556 601 Missing (in isoform 3, isoform 9 and
FT isoform 10).
FT /FTId=VSP_019139.
FT VAR_SEQ 3434 3434 E -> EGFSKFEENTSNSQWHVSLSVSFKKEPLGQKPSFIQ
FT PLSSLRVHNGETVRFHARVSGIPKPEIQWFHNQQLILPTKD
FT VVFHFEESTGMALMLIVDAYSEHAGQYSCKAANSAGEATCA
FT ATLTVTPKVQALDRQSSGKDVRESAKSQAVADSSFTKEESK
FT ISQKEIKSFQGSSYEYEVQVFESVSQSSIHTAASVQDTQLC
FT HTASLSQIAESTELSKECAKESTGEAPKIFLHLQDVTVKCG
FT DTAQFLCVLKDDSFIDVTWTHEGAKIEESERLKQSQNGNIQ
FT FLTICNVQLVDQGLYSCIVHNDCGERTTSAVLSVEG (in
FT isoform 12).
FT /FTId=VSP_045935.
FT VAR_SEQ 3434 3434 E -> EGFSKFEENTSNSQWHVSLSVSFKKEPLGQKPSFIQ
FT PLSSLRVHNGETVRFHARVSGIPKPEIQWFHNQQLILPTKD
FT VVFHFEESTGMALMLIVDAYSEHAGQYSCKAANSAGEATCA
FT ATLTVTPK (in isoform 8 and isoform 10).
FT /FTId=VSP_019140.
FT VAR_SEQ 3434 3434 E -> EVQALDRQSSGKDVRESAKSQAVADSSFTKEESKIS
FT QKEIKSFQGSSYEYEVQVFESVSQSSIHTAASVQDTQLCHT
FT ASLSQIAESTELSKECAKESTGEAPKIFLHLQDVTVKCGDT
FT AQFLCVLKDDSFIDVTWTHEGAKIEESERLKQSQNGNIQFL
FT TICNVQLVDQGLYSCIVHNDCGERTTSAVLSVEG (in
FT isoform 9).
FT /FTId=VSP_042903.
FT VAR_SEQ 3435 3645 APESILHERIEQEIEMEMKEFSSSFLSAEEEGLHSAELQLS
FT KINETLELLSESPVYPTKFDSEKEGTGPIFIKEVSNADISM
FT GDVATLSVTVIGIPKPKIQWFFNGVLLTPSADYKFVFDGDD
FT HSLIILFTKLEDEGEYTCMASNDYGKTICSAYLKINSKGEG
FT HKDTETESAVAKSLEKLGGPCPPHFLKELKPIRCAQGLPAI
FT FEYTVV -> VQALDRQSSGKDVRESTKSQAVADSSFTKEE
FT SKISQKEIKSFQGSSYEYEVQVFESVSQSSIHTAASVQDTQ
FT LCHTASLSQIAESTELSKECAKESTGEAPKIFLHLQDVTVK
FT CGDTAQFLCVLKDDSFIDVTWTHEGAKIEESERLKQSQNGN
FT IQFLTICNVQLVDQGLYSCIVHNDCGERTTSAVLSVEGAPE
FT SILHERIEQEIEMEMK (in isoform 7).
FT /FTId=VSP_019141.
FT VAR_SEQ 3454 4380 Missing (in isoform 4 and isoform 11).
FT /FTId=VSP_019142.
FT VAR_SEQ 3455 5604 FSSSFLSAEEEGLHSAELQLSKINETLELLSESPVYPTKFD
FT SEKEGTGPIFIKEVSNADISMGDVATLSVTVIGIPKPKIQW
FT FFNGVLLTPSADYKFVFDGDDHSLIILFTKLEDEGEYTCMA
FT SNDYGKTICSAYLKINSKGEGHKDTETESAVAKSLEKLGGP
FT CPPHFLKELKPIRCAQGLPAIFEYTVVGEPAPTVTWFKENK
FT QLCTSVYYTIIHNPNGSGTFIVNDPQREDSGLYICKAENML
FT GESTCAAELLVLLEDTDMTDTPCKAKSTPEAPEDFPQTPLK
FT GPAVEALDSEQEIATFVKDTILKAALITEENQQLSYEHIAK
FT ANELSSQLPLGAQELQSILEQDKLTPESTREFLCINGSIHF
FT QPLKEPSPNLQLQIVQSQKTFSKEGILMPEEPETQAVLSDT
FT EKIFPSAMSIEQINSLTVEPLKTLLAEPEGNYPQSSIEPPM
FT HSYLTSVAEEVLSPKEKTVSDTNREQRVTLQKQEAQSALIL
FT SQSLAEGHVESLQSPDVMISQVNYEPLVPSEHSCTEGGKIL
FT IESANPLENAGQDSAVRIEEGKSLRFPLALEEKQVLLKEEH
FT SDNVVMPPDQIIESKREPVAIKKVQEVQGRDLLSKESLLSG
FT IPEEQRLNLKIQICRALQAAVASEQPGLFSEWLRNIEKVEV
FT EAVNITQEPRHIMCMYLVTSAKSVTEEVTIIIEDVDPQMAN
FT LKMELRDALCAIIYEEIDILTAEGPRIQQGAKTSLQEEMDS
FT FSGSQKVEPITEPEVESKYLISTEEVSYFNVQSRVKYLDAT
FT PVTKGVASAVVSDEKQDESLKPSEEKEESSSESGTEEVATV
FT KIQEAEGGLIKEDGPMIHTPLVDTVSEEGDIVHLTTSITNA
FT KEVNWYFENKLVPSDEKFKCLQDQNTYTLVIDKVNTEDHQG
FT EYVCEALNDSGKTATSAKLTVVKRAAPVIKRKIEPLEVALG
FT HLAKFTCEIQSAPNVRFQWFKAGREIYESDKCSIRSSKYIS
FT SLEILRTQVVDCGEYTCKASNEYGSVSCTATLTVTEAYPPT
FT FLSRPKSLTTFVGKAAKFICTVTGTPVIETIWQKDGAALSP
FT SPNWRISDAENKHILELSNLTIQDRGVYSCKASNKFGADIC
FT QAELIIIDKPHFIKELEPVQSAINKKVHLECQVDEDRKVTV
FT TWSKDGQKLPPGKDYKICFEDKIATLEIPLAKLKDSGTYVC
FT TASNEAGSSSCSATVTVREPPSFVKKVDPSYLMLPGESARL
FT HCKLKGSPVIQVTWFKNNKELSESNTVRMYFVNSEAILDIT
FT DVKVEDSGSYSCEAVNDVGSDSCSTEIVIKEPPSFIKTLEP
FT ADIVRGTNALLQCEVSGTGPFEISWFKDKKQIRSSKKYRLF
FT SQKSLVCLEIFSFNSADVGEYECVVANEVGKCGCMATHLLK
FT EPPTFVKKVDDLIALGGQTVTLQAAVRGSEPISVTWMKGQE
FT VIREDGKIKMSFSNGVAVLIIPDVQISFGGKYTCLAENEAG
FT SQTSVGELIVKEPAKIIERAELIQVTAGDPATLEYTVAGTP
FT ELKPKWYKDGRPLVASKKYRISFKNNVAQLKFYSAELHDSG
FT QYTFEISNEVGSSSCETTFTVLDRDIAPFFTKPLRNVDSVV
FT NGTCRLDCKIAGSLPMRVSWFKDGKEIAASDRYRIAFVEGT
FT ASLEIIRVDMNDAGNFTCRATNSVGSKDSSGALIVQEPPSF
FT VTKPGSKDVLPGSAVCLKSTFQGSTPLTIRWFKGNKELVSG
FT GSCYITKEALESSLELYLVKTSDSGTYTCKVSNVAGGVECS
FT ANLFVKEPATFVEKLEPSQLLKKGDATQLACKVTGTPPIKI
FT TWFANDREIKESSKHRMSFVESTAVLRLTDVGIEDSGEYMC
FT EAQNEAGSDHCSSIVIVKESPYFTKEFKPIEVLKEYDVMLL
FT AEVAGTPPFEITWFKDNTILRSGRKYKTFIQDHLVSLQILK
FT FVAADAGEYQCRVTNEVGSSICSARVTLREPPSFIKKIEST
FT SSLRGGTAAFQATLKGSLPITVTWLKDSDEITEDDNIRMTF
FT ENNVASLYLSGIEVKHDGKYVCQAKNDAGIQRCSALLSVKE
FT PATITEEAVSIDVTQGDPATLQVKFSGTKEITAKWFKDGQE
FT LTLGSKYKISVTDTVSILKIISTEKKDSGEYTFEVQNDVGR
FT SSCKARINVLDLIIPPSF -> LFSEGESEHSERDTRDAFS
FT DSEDIDHKSMAAKRYASRISSTSSWPEYFKPSFTQKLTFKY
FT VLEGEPVVFTCRLIACPTPEMTWFHNNRPIPTGLRRIIKAE
FT SDLHHHSSSLEIKRVQDRDSGSYRLLAINSEGSAESTASLL
FT VIQKGQDEKYLEFLKRAERTHENVEALVERGEDRIKVDLRF
FT TGSPFNKKQDVEQKGMMRTIHFKTMSSAKKTDYMYDEEYLE
FT SKSDIRGWLNVGESFLDKETKVKLQRLREARKTLMEKKKLS
FT LLDTSSEISSRTLRSEASDKDILFSREDMKIRSMSDLAESY
FT KVDHSAESIVQNPHALSNQMDQNIESEELPTSFQTIVDEEI
FT FQTEIRMSQEALVKESLPKDHLYGEILVNENTQARGQLEEI
FT MANTTIGESSTYITNVCEKEEVYETPENVSQAITPHASESF
FT GTLVNVEESEEIASERIKKDDLRELQLSASTRIDEFKTEQK
FT EENMRFFENSFRKRPQRCPPSFLQEIESQEVYEGDSCNFVC
FT HFQGYPQPIVTWYNNDMPIPRNQNFIIHSLENYSILTLSSV
FT HHQNEGSITCVLFNQYGTVKTTSMLKVKAKQKHDVKAHKVP
FT VFHDYLDEEEELALVFDQAKGAHPSMSQEGQTNLHLLKTNP
FT PVPPSGDTELLSFPVEIQVTAATPIPEQDKESKEVFQTEEL
FT EPKAMPQDQVTQSPKHRFVFLSDITNEPPKMLQEMPKHARC
FT REGDSIILECLISGEPQPVVTWFQNGVLLKQNQKFQFEEVN
FT CSHQLYIKDVNSQDSGKYKCVAENNSGAVESVSDLTVEPVT
FT YRENSQFENIGEIYGKYSRDQQLQDQGESVRAHFYDYPAGP
FT FTPWTNVKEYSVRDYFQSLETIEQIDQKEQVRCIPSREKIP
FT RFVHGASRTIKISKPIRAEFIQCQAEGKERHVSEKSKLHQA
FT EGTVYPFVDDFSDVTIKKEIRNNFGKLGRSEKENVQECAQS
FT DYLPNIHSERISDSYNTKDSSAIVYEESLGEEIHYPGKKVK
FT HRIIEFEKLHVEKGVLEKRPTRTSIVNPPQKKIDDKAFSLK
FT QRESRSSNLNANMYQAEKMSPNTESDSSNIAINLKLLSSQT
FT HKEFDAQEREQQEKISLIDKPAISKRAEHESPITFDLKQFH
FT TQIKHTDVKFQELDSGQPEEAYFKIQHPADTENIVFDLKQM
FT YSHIGDPALEFQGQETREQQEIHYKEKIPSPETLQPDTHNI
FT SKSVQNNVFASQEISSSQELSNRTMVEKSSIDENSISLEKE
FT VRHVQEQNLDILKTDLSLKSFSEEIYSESCALLPTSSADIE
FT ETDLSEKSCPLENGGRSSISHLKKAASEEKPLGVGEMEEEC
FT TLEPELAAFPKQDGGTQEYTDATLEDHRGDVQEADTLHRQL
FT SLSQCFPLLMTEEQQNPGEQISTNIHASGEEKCYEEVQVQN
FT EASFSTLEGEMIETSFSQNIPKLDEAHTTEAAESETSLTQY
FT LLAAGKREVPETKDTRDQAKLVQSESITSMEVEEVTFNTVY
FT EYYNQKQESLGRPLSPESDISIGVGSTTSEEISELDQFYTP
FT PSSVEYFESPKSPDLYFNPSDITKQSSIHSGGETVERYSTP
FT LGEVAERYSTPSEGEVGERYSTPPGETLERYSTPPGETLER
FT YSTPPGETLERYSTPPGETLERYSTPPGETLERYSTPPGEA
FT LERYSIPTGGPNPTGTFKTYPSKIEREDGTPNEHFYTPTEE
FT RGSAYEIWRSDSFGTPNEAIEPKDNEMPPSFIEPLTKRKVY
FT ENTTLGFIVEVEGLPVPGVKWYRNKSLLEPDERIKMERVGN
FT VCSLEISNIQKGEGGEYMCHAVNIIGEAKSFANVDIMPQEE
FT RVVALPPPVTHQHVMEFDLEHTTSSRTPSPQEIVLEVELSE
FT KDVKEFEKQVKIVTVPEFTPDHKSMIVSLDVLPFNFVDPNM
FT DSREGEDKELKIDLEVFEMPPRFIMPICDFKIPENSDAVFK
FT CSVIGIPTPEVKWYKEYMCIEPDNIKYVISEEKGSHTLKIR
FT NVCLSDSATYRCRAVNCVGEAICRGFLTMGDSEIFAVIAKK
FT SKVTLSSLMEELVLKSNYTDSFFEFQVVEGPPRFIKGISDC
FT YAPIGTAAYFQCLVRGSPRPTVYWYKDGKLVQGRRFTVEES
FT GTGFHNLFITSLVKSDEGEYRCVATNKSGMAESFAALTLT
FT (in isoform 6).
FT /FTId=VSP_019143.
FT VAR_SEQ 3646 4380 Missing (in isoform 7).
FT /FTId=VSP_019144.
FT VAR_SEQ 4474 11851 Missing (in isoform 3, isoform 9 and
FT isoform 10).
FT /FTId=VSP_019145.
FT VAR_SEQ 5605 34350 Missing (in isoform 6).
FT /FTId=VSP_019146.
FT VAR_SEQ 10382 10645 Missing (in isoform 5).
FT /FTId=VSP_019147.
FT VAR_SEQ 10742 10931 Missing (in isoform 5).
FT /FTId=VSP_019148.
FT VAR_SEQ 11015 11163 Missing (in isoform 5).
FT /FTId=VSP_019149.
FT VAR_SEQ 11117 11117 I -> VPKKPVPEKKVPVPAPKKVEPPPPPKVPEI (in
FT isoform 12).
FT /FTId=VSP_045929.
FT VAR_SEQ 11133 11133 E -> EAPPAKVSVVPKKPEPEKKVPPPGLKKAV (in
FT isoform 12).
FT /FTId=VSP_045930.
FT VAR_SEQ 11223 11852 Missing (in isoform 5).
FT /FTId=VSP_019150.
FT VAR_SEQ 11421 11421 K -> KAPEVPKKIVPEEKVREAVLKKPEVPPAKVPGMPKK
FT SVQEEKSPIVISEDTEMYIYEASEEAVLEEKVLVTQPQKTK
FT PKLAKVPEPPKKVVPEDKIYVTIPKKRETPATKEPDTTRGI
FT FPEVEPPEAIPEIPEHPPTEEFEVFKEVIPEGETPIVKRRK
FT TPSPTVPESPREIVPVKETPMAAPLEIEIPPTKAPEAMKEV
FT VPEMKIFEDVPEEPETPRMKTPEAPQEIIPAKTVPSKKREP
FT PSVKVPEALQEIVPEKKTLVVPLRKPEVLPDEVPEALREVV
FT PEKKVHPPQRAEVVPVKVHEAPKEIIPEKKVSVVPPKKPEV
FT PPVKVPEASKEVIREEKVPLAPPKEPEVPPVKVPEPPKEVV
FT PEKKAPVAPPKEPEVPPVKVPEAPKEVVPEKKVPVPPPKKP
FT EVPPTKVPEVPKAAVPEKKLPEAIPPKPESPPPE (in
FT isoform 12).
FT /FTId=VSP_045931.
FT VAR_SEQ 11450 11450 P -> PKVPEAPKEVVLEKKASVAVPKKPEAPRAKVPEAAQ
FT EVVPEKKIPKAPIKKPEAPAVTVPEVPQEATEKEIPVAPPK
FT KPEAPIVPVPEAQEVVPEKKVPKAPPTKPEAPPATVPEVPQ
FT EIVPEKKTLVLPKKPEVPPVTVPEAPKEVVLEKKVPSAPPK
FT KPEVPPV (in isoform 12).
FT /FTId=VSP_045932.
FT VAR_SEQ 11507 11507 E -> EVPEVLPPKEVVPEKKVPVPPAKKPEAPPPKVPEAP
FT KEVVLEKKASVAVPKKPEAPRAKVPEAAQEVVPEKKIPKAP
FT IKKPEAPAVTVPEVPQEAAEKEIPVAPPKKPEAPIVPVPEA
FT QEVVPEKKVPKAPPTKPEAPPATVPEVPQEIVPEKKTLVLP
FT KKPEVPPVTVPEAPKEVVLEKKVPSTPPKKPEVPPVKVPEA
FT PKEVVPEKKVPVPPPKKPEVPPTKVPEVPKAAVPEKKVPEA
FT IPPKPESPPPEVPEVLPPKEVVPEKKVPVPPAKKPEAPPPK
FT VPEAPKEVVLEKKVSVAVPKKPEAPRAKVPEAAQEVVPEKK
FT IPKAPIKKPEAPAVTVPEVPQEAAEKEIPVAPPKKPEAPIV
FT PVPEAQEVVPEKKVPKAPPTKPEAPPATVPEVPQEIVPEKK
FT TLVLPKKPEVPPVTVPEAPKEVVLEKKVPLAPPKKPEVPPV
FT KVPEAPKEVVPEKKVPVTPPKKPEVPPVKVPEAPIEVVPEK
FT KMPLAPPKKPEVPPVKVPEAPKEVVPEKKVPSAPPKKPEVP
FT PVK (in isoform 12).
FT /FTId=VSP_045933.
FT VAR_SEQ 11507 11507 E -> EVFEEPEESPSAPPKKPEVPPVR (in isoform
FT 4).
FT /FTId=VSP_019151.
FT VAR_SEQ 11790 11790 P -> PKEPEMPKKVVPVKKVPTVKKPETPAAKVPEVPKKL
FT VPVKKEPVPVTKKPEVLPEKVPKVPEKIIPEKEVSVPIPAE
FT PEVPPAEVEETPEEIIYEEKASITIGRKETPPVEEREIEKY
FT IKPEEPEPEPQPEEIPV (in isoform 13).
FT /FTId=VSP_047142.
FT VAR_SEQ 11793 11793 P -> PEMPKKVVPVKKVPTVKKPETPAAKVPEVPKKLVPV
FT KKEPVPVTKKPEVLPEKVPKVPEKIIPEKEVSVPIPAEPEV
FT PPAEVEETPEEIIYEEKASITIGRKETPPVEEREIEKYIKP
FT EEPEPEPQPEEIPVKEP (in isoform 12).
FT /FTId=VSP_045934.
FT VAR_SEQ 11985 12201 Missing (in isoform 5).
FT /FTId=VSP_019152.
FT VARIANT 54 54 V -> M (in CMD1G; affects interaction
FT with TCAP/telethonin).
FT /FTId=VAR_026685.
FT VARIANT 60 60 D -> Y (in dbSNP:rs35683768).
FT /FTId=VAR_040078.
FT VARIANT 115 115 V -> M (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040079.
FT VARIANT 279 279 R -> W (in HMERF; disrupts NBR1-binding).
FT /FTId=VAR_026634.
FT VARIANT 328 328 R -> C (in dbSNP:rs16866538).
FT /FTId=VAR_026686.
FT VARIANT 360 360 R -> T (in dbSNP:rs56128843).
FT /FTId=VAR_040080.
FT VARIANT 498 498 V -> I.
FT /FTId=VAR_040081.
FT VARIANT 740 740 R -> L (in CMH9; dbSNP:rs28933405).
FT /FTId=VAR_026687.
FT VARIANT 743 743 A -> V (in CMD1G; affects interaction
FT with TCAP/telethonin).
FT /FTId=VAR_026688.
FT VARIANT 799 799 T -> M (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040082.
FT VARIANT 811 811 T -> I (in dbSNP:rs35813871).
FT /FTId=VAR_040083.
FT VARIANT 922 922 R -> H (in dbSNP:rs56046320).
FT /FTId=VAR_040084.
FT VARIANT 937 937 E -> D (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040085.
FT VARIANT 976 976 W -> R (in CMD1G).
FT /FTId=VAR_026689.
FT VARIANT 1081 1081 A -> T (in dbSNP:rs55914517).
FT /FTId=VAR_040086.
FT VARIANT 1137 1137 G -> R.
FT /FTId=VAR_040087.
FT VARIANT 1201 1201 K -> E (in dbSNP:rs10497520).
FT /FTId=VAR_040088.
FT VARIANT 1202 1202 V -> A.
FT /FTId=VAR_040089.
FT VARIANT 1249 1249 S -> L (in dbSNP:rs1552280).
FT /FTId=VAR_056081.
FT VARIANT 1295 1295 S -> L (in dbSNP:rs1552280).
FT /FTId=VAR_040090.
FT VARIANT 1345 1345 G -> D (in dbSNP:rs36021856).
FT /FTId=VAR_040091.
FT VARIANT 1347 1347 A -> T (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040092.
FT VARIANT 1350 1350 R -> H (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040093.
FT VARIANT 1353 1353 V -> L (in dbSNP:rs36062108).
FT /FTId=VAR_040094.
FT VARIANT 1393 1393 I -> V (in dbSNP:rs16866531).
FT /FTId=VAR_040095.
FT VARIANT 1416 1416 R -> C.
FT /FTId=VAR_040096.
FT VARIANT 1441 1441 R -> P.
FT /FTId=VAR_040097.
FT VARIANT 1544 1544 I -> V.
FT /FTId=VAR_040098.
FT VARIANT 1572 1572 R -> Q (in dbSNP:rs12476289).
FT /FTId=VAR_040099.
FT VARIANT 1658 1658 R -> G (in dbSNP:rs56270960).
FT /FTId=VAR_040100.
FT VARIANT 1664 1664 R -> Q (in an ovarian mucinous carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040101.
FT VARIANT 1692 1692 G -> D (in a lung squamous cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040102.
FT VARIANT 1744 1744 P -> L.
FT /FTId=VAR_040103.
FT VARIANT 1772 1772 S -> G.
FT /FTId=VAR_040104.
FT VARIANT 1907 1907 T -> I (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040105.
FT VARIANT 1998 1998 R -> H.
FT /FTId=VAR_040106.
FT VARIANT 2107 2107 P -> L (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040107.
FT VARIANT 2118 2118 I -> T (in dbSNP:rs56404770).
FT /FTId=VAR_040108.
FT VARIANT 2164 2164 A -> T (in dbSNP:rs56285559).
FT /FTId=VAR_040109.
FT VARIANT 2240 2240 D -> Y.
FT /FTId=VAR_040110.
FT VARIANT 2392 2392 G -> S (in dbSNP:rs4894048).
FT /FTId=VAR_040111.
FT VARIANT 2432 2432 L -> F (in a lung neuroendocrine
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_040112.
FT VARIANT 2610 2610 M -> I (in dbSNP:rs56142888).
FT /FTId=VAR_040113.
FT VARIANT 2771 2771 I -> M (in a breast infiltrating ductal
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_040114.
FT VARIANT 2823 2823 V -> F (in dbSNP:rs33917087).
FT /FTId=VAR_040115.
FT VARIANT 2831 2831 S -> N (in dbSNP:rs2306636).
FT /FTId=VAR_040116.
FT VARIANT 2930 2930 V -> I (in dbSNP:rs56373393).
FT /FTId=VAR_040117.
FT VARIANT 3026 3026 N -> I (in dbSNP:rs11900987).
FT /FTId=VAR_056082.
FT VARIANT 3154 3154 K -> R.
FT /FTId=VAR_040118.
FT VARIANT 3191 3191 Q -> E.
FT /FTId=VAR_040119.
FT VARIANT 3238 3238 P -> L (in a bladder carcinoma sample;
FT somatic mutation).
FT /FTId=VAR_040120.
FT VARIANT 3250 3250 V -> G.
FT /FTId=VAR_040121.
FT VARIANT 3261 3261 V -> M.
FT /FTId=VAR_040122.
FT VARIANT 3367 3367 R -> Q.
FT /FTId=VAR_040123.
FT VARIANT 3419 3419 S -> N (in dbSNP:rs2291310).
FT /FTId=VAR_056083.
FT VARIANT 3482 3482 E -> K (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040124.
FT VARIANT 3491 3491 P -> S.
FT /FTId=VAR_040125.
FT VARIANT 3570 3570 E -> K (in a breast pleomorphic lobular
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_040126.
FT VARIANT 3590 3590 L -> V.
FT /FTId=VAR_040127.
FT VARIANT 3637 3637 P -> S (in dbSNP:rs2627037).
FT /FTId=VAR_056084.
FT VARIANT 3762 3762 I -> V.
FT /FTId=VAR_040128.
FT VARIANT 3799 3799 S -> Y (in CMD1G).
FT /FTId=VAR_026690.
FT VARIANT 3877 3877 I -> F.
FT /FTId=VAR_040129.
FT VARIANT 3965 3965 I -> L.
FT /FTId=VAR_040130.
FT VARIANT 4084 4084 R -> Q.
FT /FTId=VAR_026691.
FT VARIANT 4215 4215 T -> P.
FT /FTId=VAR_026635.
FT VARIANT 4238 4238 G -> W.
FT /FTId=VAR_040131.
FT VARIANT 4283 4283 L -> F.
FT /FTId=VAR_026636.
FT VARIANT 4291 4291 I -> T (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040132.
FT VARIANT 4303 4303 G -> D.
FT /FTId=VAR_040133.
FT VARIANT 4427 4427 D -> E.
FT /FTId=VAR_040134.
FT VARIANT 4465 4465 S -> N (in CMD1G).
FT /FTId=VAR_026692.
FT VARIANT 8288 8288 A -> V (in dbSNP:rs16866412).
FT /FTId=VAR_056085.
FT VARIANT 8474 8474 I -> T (in dbSNP:rs4893852).
FT /FTId=VAR_056086.
FT VARIANT 12310 12310 G -> E.
FT /FTId=VAR_040135.
FT VARIANT 12383 12383 H -> R.
FT /FTId=VAR_040136.
FT VARIANT 12469 12469 V -> A.
FT /FTId=VAR_040137.
FT VARIANT 12642 12642 R -> C (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040138.
FT VARIANT 12657 12657 E -> K (in a Wilms tumor; somatic
FT mutation).
FT /FTId=VAR_040139.
FT VARIANT 12679 12679 K -> E.
FT /FTId=VAR_040140.
FT VARIANT 12720 12720 S -> F (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040141.
FT VARIANT 12798 12798 R -> C.
FT /FTId=VAR_040142.
FT VARIANT 13049 13049 E -> G.
FT /FTId=VAR_040143.
FT VARIANT 13083 13083 E -> K (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040144.
FT VARIANT 13096 13096 R -> L.
FT /FTId=VAR_040145.
FT VARIANT 13099 13099 Q -> R (in a lung small cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040146.
FT VARIANT 13297 13297 V -> A.
FT /FTId=VAR_040147.
FT VARIANT 13399 13399 I -> M.
FT /FTId=VAR_040148.
FT VARIANT 13418 13418 A -> T.
FT /FTId=VAR_040149.
FT VARIANT 13428 13428 E -> V.
FT /FTId=VAR_040150.
FT VARIANT 13430 13430 I -> T.
FT /FTId=VAR_040151.
FT VARIANT 13434 13434 R -> K (in a breast pleomorphic lobular
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_040152.
FT VARIANT 13469 13469 D -> N.
FT /FTId=VAR_040153.
FT VARIANT 13495 13495 K -> N.
FT /FTId=VAR_040154.
FT VARIANT 13785 13785 N -> S (in a breast pleomorphic lobular
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_040155.
FT VARIANT 13870 13870 Q -> H (in a lung small cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040156.
FT VARIANT 14109 14109 V -> I.
FT /FTId=VAR_040157.
FT VARIANT 14131 14131 R -> Q.
FT /FTId=VAR_040158.
FT VARIANT 14208 14208 P -> T.
FT /FTId=VAR_040159.
FT VARIANT 14728 14728 L -> V (in a lung adenocarcinoma sample;
FT somatic mutation).
FT /FTId=VAR_040160.
FT VARIANT 14999 14999 S -> T.
FT /FTId=VAR_040161.
FT VARIANT 15021 15021 N -> T.
FT /FTId=VAR_040162.
FT VARIANT 15520 15520 A -> V.
FT /FTId=VAR_040163.
FT VARIANT 15555 15555 R -> I (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040164.
FT VARIANT 15620 15620 R -> Q.
FT /FTId=VAR_040165.
FT VARIANT 15629 15629 S -> I.
FT /FTId=VAR_040166.
FT VARIANT 15635 15635 Y -> C (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040167.
FT VARIANT 15700 15700 R -> Q.
FT /FTId=VAR_040168.
FT VARIANT 15705 15705 L -> P.
FT /FTId=VAR_040169.
FT VARIANT 15837 15837 I -> M.
FT /FTId=VAR_040170.
FT VARIANT 16046 16046 G -> V.
FT /FTId=VAR_069432.
FT VARIANT 16058 16058 R -> H.
FT /FTId=VAR_040171.
FT VARIANT 16067 16067 K -> I.
FT /FTId=VAR_040172.
FT VARIANT 16090 16090 I -> T.
FT /FTId=VAR_040173.
FT VARIANT 16195 16195 R -> H (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040174.
FT VARIANT 16409 16409 R -> C.
FT /FTId=VAR_040175.
FT VARIANT 16424 16424 R -> P.
FT /FTId=VAR_040176.
FT VARIANT 16575 16575 V -> M (in dbSNP:rs3813243).
FT /FTId=VAR_056087.
FT VARIANT 16629 16629 I -> M.
FT /FTId=VAR_040177.
FT VARIANT 16877 16877 K -> R.
FT /FTId=VAR_040178.
FT VARIANT 17060 17060 N -> D.
FT /FTId=VAR_040179.
FT VARIANT 17637 17637 I -> V.
FT /FTId=VAR_040180.
FT VARIANT 17838 17838 R -> H.
FT /FTId=VAR_040181.
FT VARIANT 17866 17866 D -> N.
FT /FTId=VAR_040182.
FT VARIANT 17906 17906 G -> E (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040183.
FT VARIANT 18094 18094 E -> A.
FT /FTId=VAR_040184.
FT VARIANT 18109 18109 G -> S.
FT /FTId=VAR_040185.
FT VARIANT 18164 18164 R -> T (in an ovarian serous carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040186.
FT VARIANT 18221 18221 P -> L.
FT /FTId=VAR_040187.
FT VARIANT 18222 18222 A -> T.
FT /FTId=VAR_040188.
FT VARIANT 18726 18726 R -> Q.
FT /FTId=VAR_040189.
FT VARIANT 18835 18835 V -> A (in a breast infiltrating ductal
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_040190.
FT VARIANT 18881 18881 R -> K (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040191.
FT VARIANT 18939 18939 N -> S.
FT /FTId=VAR_040192.
FT VARIANT 19000 19000 R -> Q.
FT /FTId=VAR_040193.
FT VARIANT 19060 19060 L -> Q (in a lung large cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040194.
FT VARIANT 19091 19091 R -> K (in a lung large cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040195.
FT VARIANT 19224 19224 P -> S (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040196.
FT VARIANT 19367 19367 T -> I.
FT /FTId=VAR_040197.
FT VARIANT 19392 19392 E -> K (in a lung neuroendocrine
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_040198.
FT VARIANT 19480 19480 A -> S (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040199.
FT VARIANT 19495 19495 D -> G.
FT /FTId=VAR_040200.
FT VARIANT 19665 19665 R -> H.
FT /FTId=VAR_040201.
FT VARIANT 19762 19762 T -> I.
FT /FTId=VAR_040202.
FT VARIANT 19947 19947 G -> R.
FT /FTId=VAR_040203.
FT VARIANT 19956 19956 V -> M.
FT /FTId=VAR_040204.
FT VARIANT 19992 19992 R -> Q.
FT /FTId=VAR_040205.
FT VARIANT 20057 20057 R -> C.
FT /FTId=VAR_040206.
FT VARIANT 20075 20075 S -> L.
FT /FTId=VAR_040207.
FT VARIANT 20179 20179 T -> K.
FT /FTId=VAR_040208.
FT VARIANT 20198 20198 A -> T.
FT /FTId=VAR_040209.
FT VARIANT 20198 20198 A -> V.
FT /FTId=VAR_040210.
FT VARIANT 20331 20331 R -> H.
FT /FTId=VAR_040211.
FT VARIANT 20359 20359 R -> K (in dbSNP:rs9808036).
FT /FTId=VAR_056088.
FT VARIANT 20408 20408 A -> T (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040212.
FT VARIANT 20564 20564 R -> K.
FT /FTId=VAR_040213.
FT VARIANT 20718 20718 V -> I.
FT /FTId=VAR_040214.
FT VARIANT 20726 20726 S -> P.
FT /FTId=VAR_040215.
FT VARIANT 20892 20892 T -> N.
FT /FTId=VAR_040216.
FT VARIANT 20894 20894 S -> R.
FT /FTId=VAR_040217.
FT VARIANT 21125 21125 D -> E.
FT /FTId=VAR_040218.
FT VARIANT 21403 21403 P -> S.
FT /FTId=VAR_040219.
FT VARIANT 21730 21730 R -> C.
FT /FTId=VAR_040220.
FT VARIANT 21747 21747 R -> Q.
FT /FTId=VAR_040221.
FT VARIANT 21851 21851 C -> R (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040222.
FT VARIANT 21925 21925 G -> R.
FT /FTId=VAR_040223.
FT VARIANT 21995 21995 R -> H.
FT /FTId=VAR_040224.
FT VARIANT 22045 22045 A -> V.
FT /FTId=VAR_040225.
FT VARIANT 22149 22149 R -> H.
FT /FTId=VAR_040226.
FT VARIANT 22160 22160 V -> I.
FT /FTId=VAR_040227.
FT VARIANT 22261 22261 I -> T.
FT /FTId=VAR_040228.
FT VARIANT 22306 22306 K -> N.
FT /FTId=VAR_040229.
FT VARIANT 22357 22357 R -> H.
FT /FTId=VAR_040230.
FT VARIANT 22408 22408 L -> P.
FT /FTId=VAR_040231.
FT VARIANT 22537 22537 Q -> H (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040232.
FT VARIANT 22584 22584 P -> L.
FT /FTId=VAR_040233.
FT VARIANT 22646 22646 L -> P (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040234.
FT VARIANT 22670 22670 T -> A.
FT /FTId=VAR_040235.
FT VARIANT 22770 22770 A -> D.
FT /FTId=VAR_040236.
FT VARIANT 22801 22801 A -> T (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040237.
FT VARIANT 22823 22823 R -> W (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040238.
FT VARIANT 22968 22968 E -> Q.
FT /FTId=VAR_040239.
FT VARIANT 23074 23074 P -> L.
FT /FTId=VAR_040240.
FT VARIANT 23079 23079 L -> F (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040241.
FT VARIANT 23282 23282 D -> N (in a breast infiltrating ductal
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_040242.
FT VARIANT 23303 23303 H -> Y (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040243.
FT VARIANT 23306 23306 R -> C.
FT /FTId=VAR_040244.
FT VARIANT 23515 23515 A -> S (in a lung squamous cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040245.
FT VARIANT 23551 23551 E -> Q (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040246.
FT VARIANT 23807 23807 S -> N.
FT /FTId=VAR_040247.
FT VARIANT 23872 23872 D -> N (in an ovarian serous carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040248.
FT VARIANT 23891 23891 V -> A.
FT /FTId=VAR_040249.
FT VARIANT 23933 23933 Y -> H.
FT /FTId=VAR_040250.
FT VARIANT 23939 23939 T -> M.
FT /FTId=VAR_040251.
FT VARIANT 23952 23952 F -> L (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040252.
FT VARIANT 24098 24098 A -> G.
FT /FTId=VAR_040253.
FT VARIANT 24098 24098 A -> T (in dbSNP:rs4894028).
FT /FTId=VAR_056089.
FT VARIANT 24119 24119 N -> S.
FT /FTId=VAR_040254.
FT VARIANT 24133 24133 V -> I.
FT /FTId=VAR_040255.
FT VARIANT 24159 24159 V -> A (in a head and neck squamous cell
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_040256.
FT VARIANT 24239 24239 T -> A.
FT /FTId=VAR_040257.
FT VARIANT 24265 24265 E -> K.
FT /FTId=VAR_040258.
FT VARIANT 24584 24584 I -> T.
FT /FTId=VAR_040259.
FT VARIANT 24781 24781 I -> T.
FT /FTId=VAR_040260.
FT VARIANT 24799 24799 R -> H.
FT /FTId=VAR_040261.
FT VARIANT 24954 24954 D -> H.
FT /FTId=VAR_040262.
FT VARIANT 24980 24980 T -> M.
FT /FTId=VAR_040263.
FT VARIANT 25659 25659 R -> H.
FT /FTId=VAR_040264.
FT VARIANT 25679 25679 A -> T.
FT /FTId=VAR_040265.
FT VARIANT 25720 25720 P -> A.
FT /FTId=VAR_040266.
FT VARIANT 25821 25821 T -> K.
FT /FTId=VAR_040267.
FT VARIANT 25859 25859 E -> K (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040268.
FT VARIANT 25879 25879 N -> K.
FT /FTId=VAR_040269.
FT VARIANT 25923 25923 A -> V.
FT /FTId=VAR_040270.
FT VARIANT 26045 26045 V -> I.
FT /FTId=VAR_040271.
FT VARIANT 26059 26059 K -> E (in a lung small cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040272.
FT VARIANT 26134 26134 I -> V.
FT /FTId=VAR_040273.
FT VARIANT 26477 26477 R -> C.
FT /FTId=VAR_040274.
FT VARIANT 26843 26843 D -> Y.
FT /FTId=VAR_040275.
FT VARIANT 27346 27346 K -> R.
FT /FTId=VAR_040276.
FT VARIANT 27652 27652 R -> C.
FT /FTId=VAR_040277.
FT VARIANT 27728 27728 G -> V.
FT /FTId=VAR_040278.
FT VARIANT 27754 27754 F -> L.
FT /FTId=VAR_040279.
FT VARIANT 27755 27755 I -> T.
FT /FTId=VAR_040280.
FT VARIANT 27929 27929 I -> V.
FT /FTId=VAR_040281.
FT VARIANT 28132 28132 I -> L.
FT /FTId=VAR_040282.
FT VARIANT 28168 28168 R -> Q.
FT /FTId=VAR_040283.
FT VARIANT 28538 28538 R -> H.
FT /FTId=VAR_040284.
FT VARIANT 28572 28572 I -> T.
FT /FTId=VAR_040285.
FT VARIANT 28948 28948 A -> T.
FT /FTId=VAR_040286.
FT VARIANT 28986 28986 I -> V.
FT /FTId=VAR_040287.
FT VARIANT 28993 28993 G -> E.
FT /FTId=VAR_040288.
FT VARIANT 28998 28998 L -> V.
FT /FTId=VAR_040289.
FT VARIANT 29070 29070 V -> M.
FT /FTId=VAR_040290.
FT VARIANT 29090 29090 I -> V.
FT /FTId=VAR_040291.
FT VARIANT 29419 29419 R -> C.
FT /FTId=VAR_040292.
FT VARIANT 29479 29479 L -> P.
FT /FTId=VAR_040293.
FT VARIANT 29880 29880 S -> L (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040294.
FT VARIANT 29976 29976 D -> E.
FT /FTId=VAR_040295.
FT VARIANT 30042 30042 S -> G.
FT /FTId=VAR_040296.
FT VARIANT 30107 30107 R -> C.
FT /FTId=VAR_040297.
FT VARIANT 30125 30125 S -> F.
FT /FTId=VAR_040298.
FT VARIANT 30211 30211 L -> P.
FT /FTId=VAR_040299.
FT VARIANT 30412 30412 I -> T.
FT /FTId=VAR_040300.
FT VARIANT 30617 30617 T -> S (in a renal chromophobe cancer
FT sample; somatic mutation).
FT /FTId=VAR_040301.
FT VARIANT 30674 30674 T -> I.
FT /FTId=VAR_040302.
FT VARIANT 30809 30809 V -> I (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040303.
FT VARIANT 30818 30818 F -> I.
FT /FTId=VAR_040304.
FT VARIANT 30825 30825 E -> K.
FT /FTId=VAR_040305.
FT VARIANT 30856 30856 I -> T.
FT /FTId=VAR_040306.
FT VARIANT 30887 30887 G -> D.
FT /FTId=VAR_040307.
FT VARIANT 30887 30887 G -> S.
FT /FTId=VAR_040308.
FT VARIANT 30897 30897 R -> H.
FT /FTId=VAR_040309.
FT VARIANT 30907 30907 R -> H.
FT /FTId=VAR_040310.
FT VARIANT 30946 30946 R -> H.
FT /FTId=VAR_040311.
FT VARIANT 31081 31081 I -> F.
FT /FTId=VAR_040312.
FT VARIANT 31107 31107 R -> C.
FT /FTId=VAR_040313.
FT VARIANT 31124 31124 A -> G.
FT /FTId=VAR_040314.
FT VARIANT 31156 31156 N -> S.
FT /FTId=VAR_040315.
FT VARIANT 31246 31246 P -> T.
FT /FTId=VAR_040316.
FT VARIANT 31330 31330 R -> H.
FT /FTId=VAR_040317.
FT VARIANT 31690 31690 C -> R.
FT /FTId=VAR_040318.
FT VARIANT 31724 31724 R -> Q.
FT /FTId=VAR_040319.
FT VARIANT 31725 31725 V -> I.
FT /FTId=VAR_040320.
FT VARIANT 31732 31732 G -> S.
FT /FTId=VAR_040321.
FT VARIANT 31886 31886 V -> I.
FT /FTId=VAR_040322.
FT VARIANT 32097 32097 R -> C.
FT /FTId=VAR_040323.
FT VARIANT 32171 32171 T -> N (in a lung large cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040324.
FT VARIANT 32248 32248 V -> I.
FT /FTId=VAR_040325.
FT VARIANT 32281 32281 Q -> H.
FT /FTId=VAR_040326.
FT VARIANT 32323 32323 R -> H.
FT /FTId=VAR_040327.
FT VARIANT 32411 32411 R -> W (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040328.
FT VARIANT 32558 32558 I -> V.
FT /FTId=VAR_040329.
FT VARIANT 32610 32610 M -> V.
FT /FTId=VAR_040330.
FT VARIANT 32637 32637 G -> V.
FT /FTId=VAR_040331.
FT VARIANT 32742 32742 E -> Q.
FT /FTId=VAR_069433.
FT VARIANT 32922 32922 V -> A.
FT /FTId=VAR_040332.
FT VARIANT 32943 32943 L -> R (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040333.
FT VARIANT 32953 32953 R -> H.
FT /FTId=VAR_040334.
FT VARIANT 32996 32996 R -> Q (in CMD1G).
FT /FTId=VAR_026693.
FT VARIANT 33213 33213 V -> L.
FT /FTId=VAR_040335.
FT VARIANT 33242 33242 R -> C (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040336.
FT VARIANT 33387 33387 T -> M.
FT /FTId=VAR_040337.
FT VARIANT 33419 33419 E -> D.
FT /FTId=VAR_040338.
FT VARIANT 33536 33536 V -> M.
FT /FTId=VAR_040339.
FT VARIANT 33568 33568 K -> Q.
FT /FTId=VAR_040340.
FT VARIANT 33616 33616 E -> K.
FT /FTId=VAR_040341.
FT VARIANT 33620 33620 P -> L.
FT /FTId=VAR_040342.
FT VARIANT 33886 33886 E -> V.
FT /FTId=VAR_040343.
FT VARIANT 33899 33899 I -> T.
FT /FTId=VAR_040344.
FT VARIANT 33904 33904 L -> P (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040345.
FT VARIANT 33955 33955 T -> I.
FT /FTId=VAR_040346.
FT VARIANT 34115 34115 V -> A.
FT /FTId=VAR_040347.
FT VARIANT 34306 34306 I -> N (in TMD).
FT /FTId=VAR_026694.
FT VARIANT 34315 34315 L -> P (in TMD).
FT /FTId=VAR_026695.
FT MUTAGEN 32207 32207 K->A: Disrupts catalytic activity.
FT MUTAGEN 32341 32341 Y->E: No phosphorylation on tyrosine.
FT CONFLICT 132 132 T -> N (in Ref. 1; CAA62188).
FT CONFLICT 255 255 P -> H (in Ref. 3; CAD12455/CAD12456/
FT CAD12457).
FT CONFLICT 1472 1474 QTA -> ANC (in Ref. 1; CAA62188).
FT CONFLICT 1730 1730 G -> S (in Ref. 1; CAA62188).
FT CONFLICT 3919 3919 P -> L (in Ref. 1; CAA62188).
FT CONFLICT 4525 4525 R -> K (in Ref. 3; CAD12456).
FT CONFLICT 6619 6619 R -> E (in Ref. 1; CAA62189 and 3;
FT CAD12456).
FT CONFLICT 7145 7145 D -> H (in Ref. 1; CAA62189).
FT CONFLICT 7441 7441 S -> N (in Ref. 1; CAA62189).
FT CONFLICT 8038 8038 A -> E (in Ref. 3; CAD12456).
FT CONFLICT 8225 8225 Q -> H (in Ref. 3; CAD12456).
FT CONFLICT 8850 8850 A -> P (in Ref. 1; CAA62189).
FT CONFLICT 9693 9693 C -> V (in Ref. 1; CAA62189).
FT CONFLICT 9892 9892 I -> V (in Ref. 1; CAA62189).
FT CONFLICT 10205 10205 I -> V (in Ref. 3; CAD12456 and 9;
FT AAP80791).
FT CONFLICT 10305 10305 G -> R (in Ref. 3; CAD12456).
FT CONFLICT 10566 10566 R -> K (in Ref. 1; CAA62189).
FT CONFLICT 10779 10779 R -> H (in Ref. 1; CAA62189).
FT CONFLICT 11424 11424 E -> D (in Ref. 3; CAD12456).
FT CONFLICT 11511 11511 A -> V (in Ref. 1; CAA62189).
FT CONFLICT 11626 11626 K -> N (in Ref. 1; CAA62189).
FT CONFLICT 11838 11838 K -> N (in Ref. 1; CAA62189).
FT CONFLICT 12994 12994 A -> T (in Ref. 1; CAA62188).
FT CONFLICT 13795 13797 YKF -> IQI (in Ref. 11).
FT CONFLICT 14590 14590 A -> T (in Ref. 1; CAA62188).
FT CONFLICT 14792 14792 V -> A (in Ref. 1; CAA62188).
FT CONFLICT 15974 15974 E -> K (in Ref. 1; CAA62188).
FT CONFLICT 16234 16235 TK -> QR (in Ref. 1; CAA62188).
FT CONFLICT 17238 17238 R -> H (in Ref. 1; CAA62188).
FT CONFLICT 17423 17423 R -> S (in Ref. 3; CAD12456).
FT CONFLICT 19734 19734 V -> A (in Ref. 1; CAA62188).
FT CONFLICT 20517 20517 G -> A (in Ref. 1; CAA62188 and 3;
FT CAD12455).
FT CONFLICT 20622 20622 L -> H (in Ref. 1; CAA62188).
FT CONFLICT 20775 20775 A -> P (in Ref. 1; CAA62188).
FT CONFLICT 21625 21625 Y -> I (in Ref. 13; CAA45939).
FT CONFLICT 21795 21800 PGPVLN -> ARPSPQ (in Ref. 13; CAA45939).
FT CONFLICT 22176 22176 C -> W (in Ref. 1; CAA62188).
FT CONFLICT 22816 22816 A -> D (in Ref. 1; CAA62188).
FT CONFLICT 22837 22837 T -> A (in Ref. 1; CAA62188).
FT CONFLICT 24176 24176 I -> M (in Ref. 1; CAA62188 and 13;
FT CAA45940).
FT CONFLICT 24181 24181 S -> F (in Ref. 13; CAA45940).
FT CONFLICT 25731 25731 P -> S (in Ref. 1; CAA62188).
FT CONFLICT 26573 26573 M -> V (in Ref. 1; CAA62188).
FT CONFLICT 26846 26848 IVE -> HRK (in Ref. 1; CAA62188).
FT CONFLICT 27879 27879 G -> A (in Ref. 1; CAA62188).
FT CONFLICT 28936 28936 D -> N (in Ref. 1; CAA62188).
FT CONFLICT 29222 29222 A -> T (in Ref. 1; CAA62188).
FT CONFLICT 29518 29518 F -> L (in Ref. 1; CAA62188).
FT CONFLICT 29701 29701 T -> P (in Ref. 14; CAA45938/CAA49245).
FT CONFLICT 29873 29873 E -> G (in Ref. 14; CAA45938/CAA49245).
FT CONFLICT 29878 29878 T -> Q (in Ref. 14; CAA45938/CAA49245).
FT CONFLICT 30209 30209 K -> E (in Ref. 1; CAA62188 and 14;
FT CAA45938/CAA49245).
FT CONFLICT 30256 30256 A -> R (in Ref. 1; CAA62188 and 14;
FT CAA45938/CAA49245).
FT CONFLICT 30496 30496 V -> I (in Ref. 1; CAA62188 and 14;
FT CAA45938/CAA49245).
FT CONFLICT 30534 30534 Y -> H (in Ref. 1; CAA62188 and 14;
FT CAA45938/CAA49245).
FT CONFLICT 30748 30748 S -> L (in Ref. 14; CAA45938/CAA49245).
FT CONFLICT 31303 31303 W -> V (in Ref. 1; CAA62188 and 14;
FT CAA45938/CAA49245).
FT CONFLICT 32060 32060 V -> A (in Ref. 1; CAA62188 and 14;
FT CAA45938/CAA49245).
FT CONFLICT 33084 33084 D -> N (in Ref. 1; CAA62188 and 14;
FT CAA49245).
FT CONFLICT 33120 33120 R -> W (in Ref. 15; CAD28458).
FT CONFLICT 33382 33382 A -> R (in Ref. 14; CAA49245).
FT CONFLICT 33424 33424 S -> P (in Ref. 1; CAA62188 and 14;
FT CAA49245).
FT CONFLICT 33526 33526 Q -> R (in Ref. 14; CAA49245).
FT CONFLICT 33633 33633 T -> I (in Ref. 1; CAA62188 and 14;
FT CAA49245).
FT CONFLICT 33716 33716 Y -> V (in Ref. 15; CAD28458).
FT CONFLICT 33995 33995 V -> A (in Ref. 15; CAD28458).
FT CONFLICT 34071 34071 N -> G (in Ref. 5; AAI07798).
FT CONFLICT 34082 34082 C -> R (in Ref. 14; CAA49245).
FT CONFLICT 34253 34253 G -> R (in Ref. 5; AAI07798).
FT STRAND 4 10
FT STRAND 15 18
FT STRAND 23 33
FT STRAND 36 45
FT TURN 48 50
FT STRAND 55 59
FT STRAND 62 69
FT HELIX 72 74
FT STRAND 76 84
FT STRAND 87 98
FT STRAND 102 108
FT STRAND 113 116
FT STRAND 119 131
FT STRAND 134 139
FT STRAND 142 144
FT STRAND 147 155
FT STRAND 158 166
FT HELIX 168 170
FT STRAND 172 180
FT STRAND 183 194
FT STRAND 2076 2082
FT STRAND 2087 2090
FT STRAND 2095 2105
FT STRAND 2108 2113
FT STRAND 2122 2130
FT STRAND 2133 2138
FT HELIX 2143 2145
FT STRAND 2147 2155
FT STRAND 2158 2169
FT STRAND 12680 12682
FT STRAND 12687 12690
FT STRAND 12691 12693
FT STRAND 12695 12705
FT STRAND 12709 12712
FT STRAND 12719 12722
FT STRAND 12723 12728
FT STRAND 12731 12736
FT HELIX 12741 12743
FT STRAND 12745 12751
FT STRAND 12754 12763
FT STRAND 22291 22296
FT STRAND 22299 22303
FT STRAND 22319 22324
FT STRAND 22340 22345
FT STRAND 22354 22361
FT STRAND 22367 22377
FT HELIX 22381 22384
FT STRAND 22883 22890
FT STRAND 22895 22900
FT STRAND 22912 22919
FT STRAND 22926 22932
FT STRAND 22934 22939
FT STRAND 22947 22956
FT STRAND 22970 22972
FT STRAND 22982 22987
FT STRAND 22992 22996
FT STRAND 23009 23016
FT STRAND 23023 23035
FT STRAND 23043 23052
FT STRAND 31458 31464
FT STRAND 31469 31472
FT STRAND 31475 31487
FT STRAND 31490 31495
FT STRAND 31498 31500
FT STRAND 31504 31520
FT HELIX 31524 31526
FT STRAND 31528 31535
FT STRAND 31540 31555
FT STRAND 31563 31568
FT STRAND 31573 31583
FT STRAND 31586 31591
FT STRAND 31600 31606
FT STRAND 31608 31617
FT HELIX 31620 31623
FT STRAND 31625 31632
FT STRAND 31637 31647
FT STRAND 31856 31859
FT STRAND 31864 31867
FT STRAND 31872 31879
FT STRAND 31885 31890
FT STRAND 31893 31895
FT STRAND 31899 31907
FT TURN 31908 31910
FT STRAND 31911 31916
FT HELIX 31921 31923
FT STRAND 31925 31933
FT STRAND 31936 31952
FT HELIX 31956 31959
FT STRAND 31961 31967
FT STRAND 31973 31982
FT STRAND 31985 31992
FT STRAND 31997 32000
FT STRAND 32002 32005
FT STRAND 32007 32013
FT HELIX 32020 32022
FT STRAND 32024 32032
FT STRAND 32035 32046
FT STRAND 32053 32059
FT STRAND 32065 32070
FT STRAND 32076 32078
FT STRAND 32080 32089
FT STRAND 32095 32108
FT STRAND 32116 32125
FT TURN 32175 32177
FT STRAND 32178 32186
FT STRAND 32188 32197
FT TURN 32198 32201
FT STRAND 32202 32209
FT HELIX 32214 32228
FT STRAND 32237 32243
FT STRAND 32246 32251
FT HELIX 32259 32263
FT STRAND 32265 32267
FT HELIX 32272 32291
FT HELIX 32301 32303
FT STRAND 32304 32310
FT STRAND 32314 32316
FT STRAND 32330 32336
FT HELIX 32338 32340
FT HELIX 32343 32346
FT HELIX 32353 32369
FT HELIX 32379 32388
FT HELIX 32395 32398
FT HELIX 32403 32410
FT HELIX 32417 32419
FT HELIX 32423 32428
FT HELIX 32430 32433
FT HELIX 32436 32438
FT HELIX 32447 32457
FT HELIX 32466 32472
FT STRAND 32474 32476
FT STRAND 32483 32489
FT STRAND 32504 32506
FT STRAND 32512 32520
FT STRAND 32526 32531
FT STRAND 32538 32547
FT STRAND 32550 32555
FT HELIX 32560 32562
FT STRAND 32564 32571
FT STRAND 32576 32585
FT TURN 32586 32588
FT TURN 33294 33297
FT STRAND 33299 33305
FT STRAND 33310 33313
FT STRAND 33318 33328
FT STRAND 33331 33336
FT STRAND 33345 33352
FT STRAND 33355 33360
FT HELIX 33365 33367
FT STRAND 33369 33377
FT STRAND 33380 33391
FT STRAND 33489 33492
FT STRAND 33497 33503
FT STRAND 33509 33512
FT STRAND 33514 33516
FT STRAND 33523 33526
FT STRAND 33532 33538
FT STRAND 33540 33547
FT STRAND 33556 33560
FT STRAND 33571 33577
FT STRAND 33777 33783
FT STRAND 33788 33794
FT STRAND 33796 33806
FT STRAND 33809 33814
FT STRAND 33821 33830
FT STRAND 33833 33838
FT HELIX 33843 33845
FT STRAND 33847 33855
FT STRAND 33858 33869
FT STRAND 34254 34258
FT STRAND 34263 34268
FT STRAND 34271 34283
FT STRAND 34286 34291
FT HELIX 34300 34302
FT STRAND 34304 34308
FT STRAND 34310 34319
FT HELIX 34322 34324
FT STRAND 34326 34334
FT STRAND 34337 34348
SQ SEQUENCE 34350 AA; 3816030 MW; DEB216410AD560D9 CRC64;
MTTQAPTFTQ PLQSVVVLEG STATFEAHIS GFPVPEVSWF RDGQVISTST LPGVQISFSD
GRAKLTIPAV TKANSGRYSL KATNGSGQAT STAELLVKAE TAPPNFVQRL QSMTVRQGSQ
VRLQVRVTGI PTPVVKFYRD GAEIQSSLDF QISQEGDLYS LLIAEAYPED SGTYSVNATN
SVGRATSTAE LLVQGEEEVP AKKTKTIVST AQISESRQTR IEKKIEAHFD ARSIATVEMV
IDGAAGQQLP HKTPPRIPPK PKSRSPTPPS IAAKAQLARQ QSPSPIRHSP SPVRHVRAPT
PSPVRSVSPA ARISTSPIRS VRSPLLMRKT QASTVATGPE VPPPWKQEGY VASSSEAEMR
ETTLTTSTQI RTEERWEGRY GVQEQVTISG AAGAAASVSA SASYAAEAVA TGAKEVKQDA
DKSAAVATVV AAVDMARVRE PVISAVEQTA QRTTTTAVHI QPAQEQVRKE AEKTAVTKVV
VAADKAKEQE LKSRTKEVIT TKQEQMHVTH EQIRKETEKT FVPKVVISAA KAKEQETRIS
EEITKKQKQV TQEAIRQETE ITAASMVVVA TAKSTKLETV PGAQEETTTQ QDQMHLSYEK
IMKETRKTVV PKVIVATPKV KEQDLVSRGR EGITTKREQV QITQEKMRKE AEKTALSTIA
VATAKAKEQE TILRTRETMA TRQEQIQVTH GKVDVGKKAE AVATVVAAVD QARVREPREP
GHLEESYAQQ TTLEYGYKER ISAAKVAEPP QRPASEPHVV PKAVKPRVIQ APSETHIKTT
DQKGMHISSQ IKKTTDLTTE RLVHVDKRPR TASPHFTVSK ISVPKTEHGY EASIAGSAIA
TLQKELSATS SAQKITKSVK APTVKPSETR VRAEPTPLPQ FPFADTPDTY KSEAGVEVKK
EVGVSITGTT VREERFEVLH GREAKVTETA RVPAPVEIPV TPPTLVSGLK NVTVIEGESV
TLECHISGYP SPTVTWYRED YQIESSIDFQ ITFQSGIARL MIREAFAEDS GRFTCSAVNE
AGTVSTSCYL AVQVSEEFEK ETTAVTEKFT TEEKRFVESR DVVMTDTSLT EEQAGPGEPA
APYFITKPVV QKLVEGGSVV FGCQVGGNPK PHVYWKKSGV PLTTGYRYKV SYNKQTGECK
LVISMTFADD AGEYTIVVRN KHGETSASAS LLEEADYELL MKSQQEMLYQ TQVTAFVQEP
KVGETAPGFV YSEYEKEYEK EQALIRKKMA KDTVVVRTYV EDQEFHISSF EERLIKEIEY
RIIKTTLEEL LEEDGEEKMA VDISESEAVE SGFDSRIKNY RILEGMGVTF HCKMSGYPLP
KIAWYKDGKR IKHGERYQMD FLQDGRASLR IPVVLPEDEG IYTAFASNIK GNAICSGKLY
VEPAAPLGAP TYIPTLEPVS RIRSLSPRSV SRSPIRMSPA RMSPARMSPA RMSPARMSPG
RRLEETDESQ LERLYKPVFV LKPVSFKCLE GQTARFDLKV VGRPMPETFW FHDGQQIVND
YTHKVVIKED GTQSLIIVPA TPSDSGEWTV VAQNRAGRSS ISVILTVEAV EHQVKPMFVE
KLKNVNIKEG SRLEMKVRAT GNPNPDIVWL KNSDIIVPHK YPKIRIEGTK GEAALKIDST
VSQDSAWYTA TAINKAGRDT TRCKVNVEVE FAEPEPERKL IIPRGTYRAK EIAAPELEPL
HLRYGQEQWE EGDLYDKEKQ QKPFFKKKLT SLRLKRFGPA HFECRLTPIG DPTMVVEWLH
DGKPLEAANR LRMINEFGYC SLDYGVAYSR DSGIITCRAT NKYGTDHTSA TLIVKDEKSL
VEESQLPEGR KGLQRIEELE RMAHEGALTG VTTDQKEKQK PDIVLYPEPV RVLEGETARF
RCRVTGYPQP KVNWYLNGQL IRKSKRFRVR YDGIHYLDIV DCKSYDTGEV KVTAENPEGV
IEHKVKLEIQ QREDFRSVLR RAPEPRPEFH VHEPGKLQFE VQKVDRPVDT TETKEVVKLK
RAERITHEKV PEESEELRSK FKRRTEEGYY EAITAVELKS RKKDESYEEL LRKTKDELLH
WTKELTEEEK KALAEEGKIT IPTFKPDKIE LSPSMEAPKI FERIQSQTVG QGSDAHFRVR
VVGKPDPECE WYKNGVKIER SDRIYWYWPE DNVCELVIRD VTAEDSASIM VKAINIAGET
SSHAFLLVQA KQLITFTQEL QDVVAKEKDT MATFECETSE PFVKVKWYKD GMEVHEGDKY
RMHSDRKVHF LSILTIDTSD AEDYSCVLVE DENVKTTAKL IVEGAVVEFV KELQDIEVPE
SYSGELECIV SPENIEGKWY HNDVELKSNG KYTITSRRGR QNLTVKDVTK EDQGEYSFVI
DGKKTTCKLK MKPRPIAILQ GLSDQKVCEG DIVQLEVKVS LESVEGVWMK DGQEVQPSDR
VHIVIDKQSH MLLIEDMTKE DAGNYSFTIP ALGLSTSGRV SVYSVDVITP LKDVNVIEGT
KAVLECKVSV PDVTSVKWYL NDEQIKPDDR VQAIVKGTKQ RLVINRTHAS DEGPYKLIVG
RVETNCNLSV EKIKIIRGLR DLTCTETQNV VFEVELSHSG IDVLWNFKDK EIKPSSKYKI
EAHGKIYKLT VLNMMKDDEG KYTFYAGENM TSGKLTVAGG AISKPLTDQT VAESQEAVFE
CEVANPDSKG EWLRDGKHLP LTNNIRSESD GHKRRLIIAA TKLDDIGEYT YKVATSKTSA
KLKVEAVKIK KTLKNLTVTE TQDAVFTVEL THPNVKGVQW IKNGVVLESN EKYAISVKGT
IYSLRIKNCA IVDESVYGFR LGRLGASARL HVETVKIIKK PKDVTALENA TVAFEVSVSH
DTVPVKWFHK SVEIKPSDKH RLVSERKVHK LMLQNISPSD AGEYTAVVGQ LECKAKLFVE
TLHITKTMKN IEVPETKTAS FECEVSHFNV PSMWLKNGVE IEMSEKFKIV VQGKLHQLII
MNTSTEDSAE YTFVCGNDQV SATLTVTPIM ITSMLKDINA EEKDTITFEV TVNYEGISYK
WLKNGVEIKS TDKCQMRTKK LTHSLNIRNV HFGDAADYTF VAGKATSTAT LYVEARHIEF
RKHIKDIKVL EKKRAMFECE VSEPDITVQW MKDDQELQIT DRIKIQKEKY VHRLLIPSTR
MSDAGKYTVV AGGNVSTAKL FVEGRDVRIR SIKKEVQVIE KQRAVVEFEV NEDDVDAHWY
KDGIEINFQV QERHKYVVER RIHRMFISET RQSDAGEYTF VAGRNRSSVT LYVNAPEPPQ
VLQELQPVTV QSGKPARFCA VISGRPQPKI SWYKEEQLLS TGFKCKFLHD GQEYTLLLIE
AFPEDAAVYT CEAKNDYGVA TTSASLSVEV PEVVSPDQEM PVYPPAIITP LQDTVTSEGQ
PARFQCRVSG TDLKVSWYSK DKKIKPSRFF RMTQFEDTYQ LEIAEAYPED EGTYTFVASN
AVGQVSSTAN LSLEAPESIL HERIEQEIEM EMKEFSSSFL SAEEEGLHSA ELQLSKINET
LELLSESPVY PTKFDSEKEG TGPIFIKEVS NADISMGDVA TLSVTVIGIP KPKIQWFFNG
VLLTPSADYK FVFDGDDHSL IILFTKLEDE GEYTCMASND YGKTICSAYL KINSKGEGHK
DTETESAVAK SLEKLGGPCP PHFLKELKPI RCAQGLPAIF EYTVVGEPAP TVTWFKENKQ
LCTSVYYTII HNPNGSGTFI VNDPQREDSG LYICKAENML GESTCAAELL VLLEDTDMTD
TPCKAKSTPE APEDFPQTPL KGPAVEALDS EQEIATFVKD TILKAALITE ENQQLSYEHI
AKANELSSQL PLGAQELQSI LEQDKLTPES TREFLCINGS IHFQPLKEPS PNLQLQIVQS
QKTFSKEGIL MPEEPETQAV LSDTEKIFPS AMSIEQINSL TVEPLKTLLA EPEGNYPQSS
IEPPMHSYLT SVAEEVLSPK EKTVSDTNRE QRVTLQKQEA QSALILSQSL AEGHVESLQS
PDVMISQVNY EPLVPSEHSC TEGGKILIES ANPLENAGQD SAVRIEEGKS LRFPLALEEK
QVLLKEEHSD NVVMPPDQII ESKREPVAIK KVQEVQGRDL LSKESLLSGI PEEQRLNLKI
QICRALQAAV ASEQPGLFSE WLRNIEKVEV EAVNITQEPR HIMCMYLVTS AKSVTEEVTI
IIEDVDPQMA NLKMELRDAL CAIIYEEIDI LTAEGPRIQQ GAKTSLQEEM DSFSGSQKVE
PITEPEVESK YLISTEEVSY FNVQSRVKYL DATPVTKGVA SAVVSDEKQD ESLKPSEEKE
ESSSESGTEE VATVKIQEAE GGLIKEDGPM IHTPLVDTVS EEGDIVHLTT SITNAKEVNW
YFENKLVPSD EKFKCLQDQN TYTLVIDKVN TEDHQGEYVC EALNDSGKTA TSAKLTVVKR
AAPVIKRKIE PLEVALGHLA KFTCEIQSAP NVRFQWFKAG REIYESDKCS IRSSKYISSL
EILRTQVVDC GEYTCKASNE YGSVSCTATL TVTEAYPPTF LSRPKSLTTF VGKAAKFICT
VTGTPVIETI WQKDGAALSP SPNWRISDAE NKHILELSNL TIQDRGVYSC KASNKFGADI
CQAELIIIDK PHFIKELEPV QSAINKKVHL ECQVDEDRKV TVTWSKDGQK LPPGKDYKIC
FEDKIATLEI PLAKLKDSGT YVCTASNEAG SSSCSATVTV REPPSFVKKV DPSYLMLPGE
SARLHCKLKG SPVIQVTWFK NNKELSESNT VRMYFVNSEA ILDITDVKVE DSGSYSCEAV
NDVGSDSCST EIVIKEPPSF IKTLEPADIV RGTNALLQCE VSGTGPFEIS WFKDKKQIRS
SKKYRLFSQK SLVCLEIFSF NSADVGEYEC VVANEVGKCG CMATHLLKEP PTFVKKVDDL
IALGGQTVTL QAAVRGSEPI SVTWMKGQEV IREDGKIKMS FSNGVAVLII PDVQISFGGK
YTCLAENEAG SQTSVGELIV KEPAKIIERA ELIQVTAGDP ATLEYTVAGT PELKPKWYKD
GRPLVASKKY RISFKNNVAQ LKFYSAELHD SGQYTFEISN EVGSSSCETT FTVLDRDIAP
FFTKPLRNVD SVVNGTCRLD CKIAGSLPMR VSWFKDGKEI AASDRYRIAF VEGTASLEII
RVDMNDAGNF TCRATNSVGS KDSSGALIVQ EPPSFVTKPG SKDVLPGSAV CLKSTFQGST
PLTIRWFKGN KELVSGGSCY ITKEALESSL ELYLVKTSDS GTYTCKVSNV AGGVECSANL
FVKEPATFVE KLEPSQLLKK GDATQLACKV TGTPPIKITW FANDREIKES SKHRMSFVES
TAVLRLTDVG IEDSGEYMCE AQNEAGSDHC SSIVIVKESP YFTKEFKPIE VLKEYDVMLL
AEVAGTPPFE ITWFKDNTIL RSGRKYKTFI QDHLVSLQIL KFVAADAGEY QCRVTNEVGS
SICSARVTLR EPPSFIKKIE STSSLRGGTA AFQATLKGSL PITVTWLKDS DEITEDDNIR
MTFENNVASL YLSGIEVKHD GKYVCQAKND AGIQRCSALL SVKEPATITE EAVSIDVTQG
DPATLQVKFS GTKEITAKWF KDGQELTLGS KYKISVTDTV SILKIISTEK KDSGEYTFEV
QNDVGRSSCK ARINVLDLII PPSFTKKLKK MDSIKGSFID LECIVAGSHP ISIQWFKDDQ
EISASEKYKF SFHDNTAFLE ISQLEGTDSG TYTCSATNKA GHNQCSGHLT VKEPPYFVEK
PQSQDVNPNT RVQLKALVGG TAPMTIKWFK DNKELHSGAA RSVWKDDTST SLELFAAKAT
DSGTYICQLS NDVGTATSKA TLFVKEPPQF IKKPSPVLVL RNGQSTTFEC QITGTPKIRV
SWYLDGNEIT AIQKHGISFI DGLATFQISG ARVENSGTYV CEARNDAGTA SCSIELKVKE
PPTFIRELKP VEVVKYSDVE LECEVTGTPP FEVTWLKNNR EIRSSKKYTL TDRVSVFNLH
ITKCDPSDTG EYQCIVSNEG GSCSCSTRVA LKEPPSFIKK IENTTTVLKS SATFQSTVAG
SPPISITWLK DDQILDEDDN VYISFVDSVA TLQIRSVDNG HSGRYTCQAK NESGVERCYA
FLLVQEPAQI VEKAKSVDVT EKDPMTLECV VAGTPELKVK WLKDGKQIVP SRYFSMSFEN
NVASFRIQSV MKQDSGQYTF KVENDFGSSS CDAYLRVLDQ NIPPSFTKKL TKMDKVLGSS
IHMECKVSGS LPISAQWFKD GKEISTSAKY RLVCHERSVS LEVNNLELED TANYTCKVSN
VAGDDACSGI LTVKEPPSFL VKPGRQQAIP DSTVEFKAIL KGTPPFKIKW FKDDVELVSG
PKCFIGLEGS TSFLNLYSVD ASKTGQYTCH VTNDVGSDSC TTMLLVTEPP KFVKKLEASK
IVKAGDSSRL ECKIAGSPEI RVVWFRNEHE LPASDKYRMT FIDSVAVIQM NNLSTEDSGD
FICEAQNPAG STSCSTKVIV KEPPVFSSFP PIVETLKNAE VSLECELSGT PPFEVVWYKD
KRQLRSSKKY KIASKNFHTS IHILNVDTSD IGEYHCKAQN EVGSDTCVCT VKLKEPPRFV
SKLNSLTVVA GEPAELQASI EGAQPIFVQW LKEKEEVIRE SENIRITFVE NVATLQFAKA
EPANAGKYIC QIKNDGGMRE NMATLMVLEP AVIVEKAGPM TVTVGETCTL ECKVAGTPEL
SVEWYKDGKL LTSSQKHKFS FYNKISSLRI LSVERQDAGT YTFQVQNNVG KSSCTAVVDV
SDRAVPPSFT RRLKNTGGVL GASCILECKV AGSSPISVAW FHEKTKIVSG AKYQTTFSDN
VCTLQLNSLD SSDMGNYTCV AANVAGSDEC RAVLTVQEPP SFVKEPEPLE VLPGKNVTFT
SVIRGTPPFK VNWFRGAREL VKGDRCNIYF EDTVAELELF NIDISQSGEY TCVVSNNAGQ
ASCTTRLFVK EPAAFLKRLS DHSVEPGKSI ILESTYTGTL PISVTWKKDG FNITTSEKCN
IVTTEKTCIL EILNSTKRDA GQYSCEIENE AGRDVCGALV STLEPPYFVT ELEPLEAAVG
DSVSLQCQVA GTPEITVSWY KGDTKLRPTP EYRTYFTNNV ATLVFNKVNI NDSGEYTCKA
ENSIGTASSK TVFRIQERQL PPSFARQLKD IEQTVGLPVT LTCRLNGSAP IQVCWYRDGV
LLRDDENLQT SFVDNVATLK ILQTDLSHSG QYSCSASNPL GTASSSARLT AREPKKSPFF
DIKPVSIDVI AGESADFECH VTGAQPMRIT WSKDNKEIRP GGNYTITCVG NTPHLRILKV
GKGDSGQYTC QATNDVGKDM CSAQLSVKEP PKFVKKLEAS KVAKQGESIQ LECKISGSPE
IKVSWFRNDS ELHESWKYNM SFINSVALLT INEASAEDSG DYICEAHNGV GDASCSTALT
VKAPPVFTQK PSPVGALKGS DVILQCEISG TPPFEVVWVK DRKQVRNSKK FKITSKHFDT
SLHILNLEAS DVGEYHCKAT NEVGSDTCSC SVKFKEPPRF VKKLSDTSTL IGDAVELRAI
VEGFQPISVV WLKDRGEVIR ESENTRISFI DNIATLQLGS PEASNSGKYI CQIKNDAGMR
ECSAVLTVLE PARIIEKPEP MTVTTGNPFA LECVVTGTPE LSAKWFKDGR ELSADSKHHI
TFINKVASLK IPCAEMSDKG LYSFEVKNSV GKSNCTVSVH VSDRIVPPSF IRKLKDVNAI
LGASVVLECR VSGSAPISVG WFQDGNEIVS GPKCQSSFSE NVCTLNLSLL EPSDTGIYTC
VAANVAGSDE CSAVLTVQEP PSFEQTPDSV EVLPGMSLTF TSVIRGTPPF KVKWFKGSRE
LVPGESCNIS LEDFVTELEL FEVQPLESGD YSCLVTNDAG SASCTTHLFV KEPATFVKRL
ADFSVETGSP IVLEATYTGT PPISVSWIKD EYLISQSERC SITMTEKSTI LEILESTIED
YAQYSCLIEN EAGQDICEAL VSVLEPPYFI EPLEHVEAVI GEPATLQCKV DGTPEIRISW
YKEHTKLRSA PAYKMQFKNN VASLVINKVD HSDVGEYSCK ADNSVGAVAS SAVLVIKARK
LPPFFARKLK DVHETLGFPV AFECRINGSE PLQVSWYKDG VLLKDDANLQ TSFVHNVATL
QILQTDQSHI GQYNCSASNP LGTASSSAKL ILSEHEVPPF FDLKPVSVDL ALGESGTFKC
HVTGTAPIKI TWAKDNREIR PGGNYKMTLV ENTATLTVLK VGKGDAGQYT CYASNIAGKD
SCSAQLGVQE PPRFIKKLEP SRIVKQDEFT RYECKIGGSP EIKVLWYKDE TEIQESSKFR
MSFVDSVAVL EMHNLSVEDS GDYTCEAHNA AGSASSSTSL KVKEPPIFRK KPHPIETLKG
ADVHLECELQ GTPPFHVSWY KDKRELRSGK KYKIMSENFL TSIHILNVDA ADIGEYQCKA
TNDVGSDTCV GSIALKAPPR FVKKLSDIST VVGKEVQLQT TIEGAEPISV VWFKDKGEIV
RESDNIWISY SENIATLQFS RVEPANAGKY TCQIKNDAGM QECFATLSVL EPATIVEKPE
SIKVTTGDTC TLECTVAGTP ELSTKWFKDG KELTSDNKYK ISFFNKVSGL KIINVAPSDS
GVYSFEVQNP VGKDSCTASL QVSDRTVPPS FTRKLKETNG LSGSSVVMEC KVYGSPPISV
SWFHEGNEIS SGRKYQTTLT DNTCALTVNM LEESDSGDYT CIATNMAGSD ECSAPLTVRE
PPSFVQKPDP MDVLTGTNVT FTSIVKGTPP FSVSWFKGSS ELVPGDRCNV SLEDSVAELE
LFDVDTSQSG EYTCIVSNEA GKASCTTHLY IKAPAKFVKR LNDYSIEKGK PLILEGTFTG
TPPISVTWKK NGINVTPSQR CNITTTEKSA ILEIPSSTVE DAGQYNCYIE NASGKDSCSA
QILILEPPYF VKQLEPVKVS VGDSASLQCQ LAGTPEIGVS WYKGDTKLRP TTTYKMHFRN
NVATLVFNQV DINDSGEYIC KAENSVGEVS ASTFLTVQEQ KLPPSFSRQL RDVQETVGLP
VVFDCAISGS EPISVSWYKD GKPLKDSPNV QTSFLDNTAT LNIFKTDRSL AGQYSCTATN
PIGSASSSAR LILTEGKNPP FFDIRLAPVD AVVGESADFE CHVTGTQPIK VSWAKDSREI
RSGGKYQISY LENSAHLTVL KVDKGDSGQY TCYAVNEVGK DSCTAQLNIK ERLIPPSFTK
RLSETVEETE GNSFKLEGRV AGSQPITVAW YKNNIEIQPT SNCEITFKNN TLVLQVRKAG
MNDAGLYTCK VSNDAGSALC TSSIVIKEPK KPPVFDQHLT PVTVSEGEYV QLSCHVQGSE
PIRIQWLKAG REIKPSDRCS FSFASGTAVL ELRDVAKADS GDYVCKASNV AGSDTTKSKV
TIKDKPAVAP ATKKAAVDGR LFFVSEPQSI RVVEKTTATF IAKVGGDPIP NVKWTKGKWR
QLNQGGRVFI HQKGDEAKLE IRDTTKTDSG LYRCVAFNEH GEIESNVNLQ VDERKKQEKI
EGDLRAMLKK TPILKKGAGE EEEIDIMELL KNVDPKEYEK YARMYGITDF RGLLQAFELL
KQSQEEETHR LEIEEIERSE RDEKEFEELV SFIQQRLSQT EPVTLIKDIE NQTVLKDNDA
VFEIDIKINY PEIKLSWYKG TEKLEPSDKF EISIDGDRHT LRVKNCQLKD QGNYRLVCGP
HIASAKLTVI EPAWERHLQD VTLKEGQTCT MTCQFSVPNV KSEWFRNGRI LKPQGRHKTE
VEHKVHKLTI ADVRAEDQGQ YTCKYEDLET SAELRIEAEP IQFTKRIQNI VVSEHQSATF
ECEVSFDDAI VTWYKGPTEL TESQKYNFRN DGRCHYMTIH NVTPDDEGVY SVIARLEPRG
EARSTAELYL TTKEIKLELK PPDIPDSRVP IPTMPIRAVP PEEIPPVVAP PIPLLLPTPE
EKKPPPKRIE VTKKAVKKDA KKVVAKPKEM TPREEIVKKP PPPTTLIPAK APEIIDVSSK
AEEVKIMTIT RKKEVQKEKE AVYEKKQAVH KEKRVFIESF EEPYDELEVE PYTEPFEQPY
YEEPDEDYEE IKVEAKKEVH EEWEEDFEEG QEYYEREEGY DEGEEEWEEA YQEREVIQVQ
KEVYEESHER KVPAKVPEKK APPPPKVIKK PVIEKIEKTS RRMEEEKVQV TKVPEVSKKI
VPQKPSRTPV QEEVIEVKVP AVHTKKMVIS EEKMFFASHT EEEVSVTVPE VQKEIVTEEK
IHVAISKRVE PPPKVPELPE KPAPEEVAPV PIPKKVEPPA PKVPEVPKKP VPEEKKPVPV
PKKEPAAPPK VPEVPKKPVP EEKIPVPVAK KKEAPPAKVP EVQKGVVTEE KITIVTQREE
SPPPAVPEIP KKKVPEERKP VPRKEEEVPP PPKVPALPKK PVPEEKVAVP VPVAKKAPPP
RAEVSKKTVV EEKRFVAEEK LSFAVPQRVE VTRHEVSAEE EWSYSEEEEG VSISVYREEE
REEEEEAEVT EYEVMEEPEE YVVEEKLHII SKRVEAEPAE VTERQEKKIV LKPKIPAKIE
EPPPAKVPEA PKKIVPEKKV PAPVPKKEKV PPPKVPEEPK KPVPEKKVPP KVIKMEEPLP
AKVTERHMQI TQEEKVLVAV TKKEAPPKAR VPEEPKRAVP EEKVLKLKPK REEEPPAKVT
EFRKRVVKEE KVSIEAPKRE PQPIKEVTIM EEKERAYTLE EEAVSVQREE EYEEYEEYDY
KEFEEYEPTE EYDQYEEYEE REYERYEEHE EYITEPEKPI PVKPVPEEPV PTKPKAPPAK
VLKKAVPEEK VPVPIPKKLK PPPPKVPEEP KKVFEEKIRI SITKREKEQV TEPAAKVPMK
PKRVVAEEKV PVPRKEVAPP VRVPEVPKEL EPEEVAFEEE VVTHVEEYLV EEEEEYIHEE
EEFITEEEVV PVIPVKVPEV PRKPVPEEKK PVPVPKKKEA PPAKVPEVPK KPEEKVPVLI
PKKEKPPPAK VPEVPKKPVP EEKVPVPVPK KVEAPPAKVP EVPKKPVPEK KVPVPAPKKV
EAPPAKVPEV PKKLIPEEKK PTPVPKKVEA PPPKVPKKRE PVPVPVALPQ EEEVLFEEEI
VPEEEVLPEE EEVLPEEEEV LPEEEEVLPE EEEIPPEEEE VPPEEEYVPE EEEFVPEEEV
LPEVKPKVPV PAPVPEIKKK VTEKKVVIPK KEEAPPAKVP EVPKKVEEKR IILPKEEEVL
PVEVTEEPEE EPISEEEIPE EPPSIEEVEE VAPPRVPEVI KKAVPEAPTP VPKKVEAPPA
KVSKKIPEEK VPVPVQKKEA PPAKVPEVPK KVPEKKVLVP KKEAVPPAKG RTVLEEKVSV
AFRQEVVVKE RLELEVVEAE VEEIPEEEEF HEVEEYFEEG EFHEVEEFIK LEQHRVEEEH
RVEKVHRVIE VFEAEEVEVF EKPKAPPKGP EISEKIIPPK KPPTKVVPRK EPPAKVPEVP
KKIVVEEKVR VPEEPRVPPT KVPEVLPPKE VVPEKKVPVP PAKKPEAPPP KVPEAPKEVV
PEKKVPVPPP KKPEVPPTKV PEVPKAAVPE KKVPEAIPPK PESPPPEVPE APKEVVPEKK
VPAAPPKKPE VTPVKVPEAP KEVVPEKKVP VPPPKKPEVP PTKVPEVPKV AVPEKKVPEA
IPPKPESPPP EVFEEPEEVA LEEPPAEVVE EPEPAAPPQV TVPPKKPVPE KKAPAVVAKK
PELPPVKVPE VPKEVVPEKK VPLVVPKKPE APPAKVPEVP KEVVPEKKVA VPKKPEVPPA
KVPEVPKKPV LEEKPAVPVP ERAESPPPEV YEEPEEIAPE EEIAPEEEKP VPVAEEEEPE
VPPPAVPEEP KKIIPEKKVP VIKKPEAPPP KEPEPEKVIE KPKLKPRPPP PPPAPPKEDV
KEKIFQLKAI PKKKVPEKPQ VPEKVELTPL KVPGGEKKVR KLLPERKPEP KEEVVLKSVL
RKRPEEEEPK VEPKKLEKVK KPAVPEPPPP KPVEEVEVPT VTKRERKIPE PTKVPEIKPA
IPLPAPEPKP KPEAEVKTIK PPPVEPEPTP IAAPVTVPVV GKKAEAKAPK EEAAKPKGPI
KGVPKKTPSP IEAERRKLRP GSGGEKPPDE APFTYQLKAV PLKFVKEIKD IILTESEFVG
SSAIFECLVS PSTAITTWMK DGSNIRESPK HRFIADGKDR KLHIIDVQLS DAGEYTCVLR
LGNKEKTSTA KLVVEELPVR FVKTLEEEVT VVKGQPLYLS CELNKERDVV WRKDGKIVVE
KPGRIVPGVI GLMRALTIND ADDTDAGTYT VTVENANNLE CSSCVKVVEV IRDWLVKPIR
DQHVKPKGTA IFACDIAKDT PNIKWFKGYD EIPAEPNDKT EILRDGNHLY LKIKNAMPED
IAEYAVEIEG KRYPAKLTLG EREVELLKPI EDVTIYEKES ASFDAEISEA DIPGQWKLKG
ELLRPSPTCE IKAEGGKRFL TLHKVKLDQA GEVLYQALNA ITTAILTVKE IELDFAVPLK
DVTVPERRQA RFECVLTREA NVIWSKGPDI IKSSDKFDII ADGKKHILVI NDSQFDDEGV
YTAEVEGKKT SARLFVTGIR LKFMSPLEDQ TVKEGETATF VCELSHEKMH VVWFKNDAKL
HTSRTVLISS EGKTHKLEMK EVTLDDISQI KAQVKELSST AQLKVLEADP YFTVKLHDKT
AVEKDEITLK CEVSKDVPVK WFKDGEEIVP SPKYSIKADG LRRILKIKKA DLKDKGEYVC
DCGTDKTKAN VTVEARLIKV EKPLYGVEVF VGETAHFEIE LSEPDVHGQW KLKGQPLTAS
PDCEIIEDGK KHILILHNCQ LGMTGEVSFQ AANAKSAANL KVKELPLIFI TPLSDVKVFE
KDEAKFECEV SREPKTFRWL KGTQEITGDD RFELIKDGTK HSMVIKSAAF EDEAKYMFEA
EDKHTSGKLI IEGIRLKFLT PLKDVTAKEK ESAVFTVELS HDNIRVKWFK NDQRLHTTRS
VSMQDEGKTH SITFKDLSID DTSQIRVEAM GMSSEAKLTV LEGDPYFTGK LQDYTGVEKD
EVILQCEISK ADAPVKWFKD GKEIKPSKNA VIKADGKKRM LILKKALKSD IGQYTCDCGT
DKTSGKLDIE DREIKLVRPL HSVEVMETET ARFETEISED DIHANWKLKG EALLQTPDCE
IKEEGKIHSL VLHNCRLDQT GGVDFQAANV KSSAHLRVKP RVIGLLRPLK DVTVTAGETA
TFDCELSYED IPVEWYLKGK KLEPSDKVVP RSEGKVHTLT LRDVKLEDAG EVQLTAKDFK
THANLFVKEP PVEFTKPLED QTVEEGATAV LECEVSRENA KVKWFKNGTE ILKSKKYEIV
ADGRVRKLVI HDCTPEDIKT YTCDAKDFKT SCNLNVVPPH VEFLRPLTDL QVREKEMARF
ECELSRENAK VKWFKDGAEI KKGKKYDIIS KGAVRILVIN KCLLDDEAEY SCEVRTARTS
GMLTVLEEEA VFTKNLANIE VSETDTIKLV CEVSKPGAEV IWYKGDEEII ETGRYEILTE
GRKRILVIQN AHLEDAGNYN CRLPSSRTDG KVKVHELAAE FISKPQNLEI LEGEKAEFVC
SISKESFPVQ WKRDDKTLES GDKYDVIADG KKRVLVVKDA TLQDMGTYVV MVGAARAAAH
LTVIEKLRIV VPLKDTRVKE QQEVVFNCEV NTEGAKAKWF RNEEAIFDSS KYIILQKDLV
YTLRIRDAHL DDQANYNVSL TNHRGENVKS AANLIVEEED LRIVEPLKDI ETMEKKSVTF
WCKVNRLNVT LKWTKNGEEV PFDNRVSYRV DKYKHMLTIK DCGFPDEGEY IVTAGQDKSV
AELLIIEAPT EFVEHLEDQT VTEFDDAVFS CQLSREKANV KWYRNGREIK EGKKYKFEKD
GSIHRLIIKD CRLDDECEYA CGVEDRKSRA RLFVEEIPVE IIRPPQDILE APGADVVFLA
ELNKDKVEVQ WLRNNMVVVQ GDKHQMMSEG KIHRLQICDI KPRDQGEYRF IAKDKEARAK
LELAAAPKIK TADQDLVVDV GKPLTMVVPY DAYPKAEAEW FKENEPLSTK TIDTTAEQTS
FRILEAKKGD KGRYKIVLQN KHGKAEGFIN LKVIDVPGPV RNLEVTETFD GEVSLAWEEP
LTDGGSKIIG YVVERRDIKR KTWVLATDRA ESCEFTVTGL QKGGVEYLFR VSARNRVGTG
EPVETDNPVE ARSKYDVPGP PLNVTITDVN RFGVSLTWEP PEYDGGAEIT NYVIELRDKT
SIRWDTAMTV RAEDLSATVT DVVEGQEYSF RVRAQNRIGV GKPSAATPFV KVADPIERPS
PPVNLTSSDQ TQSSVQLKWE PPLKDGGSPI LGYIIERCEE GKDNWIRCNM KLVPELTYKV
TGLEKGNKYL YRVSAENKAG VSDPSEILGP LTADDAFVEP TMDLSAFKDG LEVIVPNPIT
ILVPSTGYPR PTATWCFGDK VLETGDRVKM KTLSAYAELV ISPSERSDKG IYTLKLENRV
KTISGEIDVN VIARPSAPKE LKFGDITKDS VHLTWEPPDD DGGSPLTGYV VEKREVSRKT
WTKVMDFVTD LEFTVPDLVQ GKEYLFKVCA RNKCGPGEPA YVDEPVNMST PATVPDPPEN
VKWRDRTANS IFLTWDPPKN DGGSRIKGYI VERCPRGSDK WVACGEPVAE TKMEVTGLEE
GKWYAYRVKA LNRQGASKPS RPTEEIQAVD TQEAPEIFLD VKLLAGLTVK AGTKIELPAT
VTGKPEPKIT WTKADMILKQ DKRITIENVP KKSTVTIVDS KRSDTGTYII EAVNVCGRAT
AVVEVNVLDK PGPPAAFDIT DVTNESCLLT WNPPRDDGGS KITNYVVERR ATDSEVWHKL
SSTVKDTNFK ATKLIPNKEY IFRVAAENMY GVGEPVQASP ITAKYQFDPP GPPTRLEPSD
ITKDAVTLTW CEPDDDGGSP ITGYWVERLD PDTDKWVRCN KMPVKDTTYR VKGLTNKKKY
RFRVLAENLA GPGKPSKSTE PILIKDPIDP PWPPGKPTVK DVGKTSVRLN WTKPEHDGGA
KIESYVIEML KTGTDEWVRV AEGVPTTQHL LPGLMEGQEY SFRVRAVNKA GESEPSEPSD
PVLCREKLYP PSPPRWLEVI NITKNTADLK WTVPEKDGGS PITNYIVEKR DVRRKGWQTV
DTTVKDTKCT VTPLTEGSLY VFRVAAENAI GQSDYTEIED SVLAKDTFTT PGPPYALAVV
DVTKRHVDLK WEPPKNDGGR PIQRYVIEKK ERLGTRWVKA GKTAGPDCNF RVTDVIEGTE
VQFQVRAENE AGVGHPSEPT EILSIEDPTS PPSPPLDLHV TDAGRKHIAI AWKPPEKNGG
SPIIGYHVEM CPVGTEKWMR VNSRPIKDLK FKVEEGVVPD KEYVLRVRAV NAIGVSEPSE
ISENVVAKDP DCKPTIDLET HDIIVIEGEK LSIPVPFRAV PVPTVSWHKD GKEVKASDRL
TMKNDHISAH LEVPKSVRAD AGIYTITLEN KLGSATASIN VKVIGLPGPC KDIKASDITK
SSCKLTWEPP EFDGGTPILH YVLERREAGR RTYIPVMSGE NKLSWTVKDL IPNGEYFFRV
KAVNKVGGGE YIELKNPVIA QDPKQPPDPP VDVEVHNPTA EAMTITWKPP LYDGGSKIMG
YIIEKIAKGE ERWKRCNEHL VPILTYTAKG LEEGKEYQFR VRAENAAGIS EPSRATPPTK
AVDPIDAPKV ILRTSLEVKR GDEIALDASI SGSPYPTITW IKDENVIVPE EIKKRAAPLV
RRRKGEVQEE EPFVLPLTQR LSIDNSKKGE SQLRVRDSLR PDHGLYMIKV ENDHGIAKAP
CTVSVLDTPG PPINFVFEDI RKTSVLCKWE PPLDDGGSEI INYTLEKKDK TKPDSEWIVV
TSTLRHCKYS VTKLIEGKEY LFRVRAENRF GPGPPCVSKP LVAKDPFGPP DAPDKPIVED
VTSNSMLVKW NEPKDNGSPI LGYWLEKREV NSTHWSRVNK SLLNALKANV DGLLEGLTYV
FRVCAENAAG PGKFSPPSDP KTAHDPISPP GPPIPRVTDT SSTTIELEWE PPAFNGGGEI
VGYFVDKQLV GTNEWSRCTE KMIKVRQYTV KEIREGADYK LRVSAVNAAG EGPPGETQPV
TVAEPQEPPA VELDVSVKGG IQIMAGKTLR IPAVVTGRPV PTKVWTKEEG ELDKDRVVID
NVGTKSELII KDALRKDHGR YVITATNSCG SKFAAARVEV FDVPGPVLDL KPVVTNRKMC
LLNWSDPEDD GGSEITGFII ERKDAKMHTW RQPIETERSK CDITGLLEGQ EYKFRVIAKN
KFGCGPPVEI GPILAVDPLG PPTSPERLTY TERTKSTITL DWKEPRSNGG SPIQGYIIEK
RRHDKPDFER VNKRLCPTTS FLVENLDEHQ MYEFRVKAVN EIGESEPSLP LNVVIQDDEV
PPTIKLRLSV RGDTIKVKAG EPVHIPADVT GLPMPKIEWS KNETVIEKPT DALQITKEEV
SRSEAKTELS IPKAVREDKG TYTVTASNRL GSVFRNVHVE VYDRPSPPRN LAVTDIKAES
CYLTWDAPLD NGGSEITHYV IDKRDASRKK AEWEEVTNTA VEKRYGIWKL IPNGQYEFRV
RAVNKYGISD ECKSDKVVIQ DPYRLPGPPG KPKVLARTKG SMLVSWTPPL DNGGSPITGY
WLEKREEGSP YWSRVSRAPI TKVGLKGVEF NVPRLLEGVK YQFRAMAINA AGIGPPSEPS
DPEVAGDPIF PPGPPSCPEV KDKTKSSISL GWKPPAKDGG SPIKGYIVEM QEEGTTDWKR
VNEPDKLITT CECVVPNLKE LRKYRFRVKA VNEAGESEPS DTTGEIPATD IQEEPEVFID
IGAQDCLVCK AGSQIRIPAV IKGRPTPKSS WEFDGKAKKA MKDGVHDIPE DAQLETAENS
SVIIIPECKR SHTGKYSITA KNKAGQKTAN CRVKVMDVPG PPKDLKVSDI TRGSCRLSWK
MPDDDGGDRI KGYVIEKRTI DGKAWTKVNP DCGSTTFVVP DLLSEQQYFF RVRAENRFGI
GPPVETIQRT TARDPIYPPD PPIKLKIGLI TKNTVHLSWK PPKNDGGSPV THYIVECLAW
DPTGTKKEAW RQCNKRDVEE LQFTVEDLVE GGEYEFRVKA VNAAGVSKPS ATVGPVTVKD
QTCPPSIDLK EFMEVEEGTN VNIVAKIKGV PFPTLTWFKA PPKKPDNKEP VLYDTHVNKL
VVDDTCTLVI PQSRRSDTGL YTITAVNNLG TASKEMRLNV LGRPGPPVGP IKFESVSADQ
MTLSWFPPKD DGGSKITNYV IEKREANRKT WVHVSSEPKE CTYTIPKLLE GHEYVFRIMA
QNKYGIGEPL DSEPETARNL FSVPGAPDKP TVSSVTRNSM TVNWEEPEYD GGSPVTGYWL
EMKDTTSKRW KRVNRDPIKA MTLGVSYKVT GLIEGSDYQF RVYAINAAGV GPASLPSDPA
TARDPIAPPG PPFPKVTDWT KSSADLEWSP PLKDGGSKVT GYIVEYKEEG KEEWEKGKDK
EVRGTKLVVT GLKEGAFYKF RVRAVNIAGI GEPGEVTDVI EMKDRLVSPD LQLDASVRDR
IVVHAGGVIR IIAYVSGKPP PTVTWNMNER TLPQEATIET TAISSSMVIK NCQRSHQGVY
SLLAKNEAGE RKKTIIVDVL DVPGPVGTPF LAHNLTNESC KLTWFSPEDD GGSPITNYVI
EKRESDRRAW TPVTYTVTRQ NATVQGLIQG KAYFFRIAAE NSIGMGPFVE TSEALVIREP
ITVPERPEDL EVKEVTKNTV TLTWNPPKYD GGSEIINYVL ESRLIGTEKF HKVTNDNLLS
RKYTVKGLKE GDTYEYRVSA VNIVGQGKPS FCTKPITCKD ELAPPTLHLD FRDKLTIRVG
EAFALTGRYS GKPKPKVSWF KDEADVLEDD RTHIKTTPAT LALEKIKAKR SDSGKYCVVV
ENSTGSRKGF CQVNVVDRPG PPVGPVSFDE VTKDYMVISW KPPLDDGGSK ITNYIIEKKE
VGKDVWMPVT SASAKTTCKV SKLLEGKDYI FRIHAENLYG ISDPLVSDSM KAKDRFRVPD
APDQPIVTEV TKDSALVTWN KPHDGGKPIT NYILEKRETM SKRWARVTKD PIHPYTKFRV
PDLLEGCQYE FRVSAENEIG IGDPSPPSKP VFAKDPIAKP SPPVNPEAID TTCNSVDLTW
QPPRHDGGSK ILGYIVEYQK VGDEEWRRAN HTPESCPETK YKVTGLRDGQ TYKFRVLAVN
AAGESDPAHV PEPVLVKDRL EPPELILDAN MAREQHIKVG DTLRLSAIIK GVPFPKVTWK
KEDRDAPTKA RIDVTPVGSK LEIRNAAHED GGIYSLTVEN PAGSKTVSVK VLVLDKPGPP
RDLEVSEIRK DSCYLTWKEP LDDGGSVITN YVVERRDVAS AQWSPLSATS KKKSHFAKHL
NEGNQYLFRV AAENQYGRGP FVETPKPIKA LDPLHPPGPP KDLHHVDVDK TEVSLVWNKP
DRDGGSPITG YLVEYQEEGT QDWIKFKTVT NLECVVTGLQ QGKTYRFRVK AENIVGLGLP
DTTIPIECQE KLVPPSVELD VKLIEGLVVK AGTTVRFPAI IRGVPVPTAK WTTDGSEIKT
DEHYTVETDN FSSVLTIKNC LRRDTGEYQI TVSNAAGSKT VAVHLTVLDV PGPPTGPINI
LDVTPEHMTI SWQPPKDDGG SPVINYIVEK QDTRKDTWGV VSSGSSKTKL KIPHLQKGCE
YVFRVRAENK IGVGPPLDST PTVAKHKFSP PSPPGKPVVT DITENAATVS WTLPKSDGGS
PITGYYMERR EVTGKWVRVN KTPIADLKFR VTGLYEGNTY EFRVFAENLA GLSKPSPSSD
PIKACRPIKP PGPPINPKLK DKSRETADLV WTKPLSDGGS PILGYVVECQ KPGTAQWNRI
NKDELIRQCA FRVPGLIEGN EYRFRIKAAN IVGEGEPREL AESVIAKDIL HPPEVELDVT
CRDVITVRVG QTIRILARVK GRPEPDITWT KEGKVLVREK RVDLIQDLPR VELQIKEAVR
ADHGKYIISA KNSSGHAQGS AIVNVLDRPG PCQNLKVTNV TKENCTISWE NPLDNGGSEI
TNFIVEYRKP NQKGWSIVAS DVTKRLIKAN LLANNEYYFR VCAENKVGVG PTIETKTPIL
AINPIDRPGE PENLHIADKG KTFVYLKWRR PDYDGGSPNL SYHVERRLKG SDDWERVHKG
SIKETHYMVD RCVENQIYEF RVQTKNEGGE SDWVKTEEVV VKEDLQKPVL DLKLSGVLTV
KAGDTIRLEA GVRGKPFPEV AWTKDKDATD LTRSPRVKID TRADSSKFSL TKAKRSDGGK
YVVTATNTAG SFVAYATVNV LDKPGPVRNL KIVDVSSDRC TVCWDPPEDD GGCEIQNYIL
EKCETKRMVW STYSATVLTP GTTVTRLIEG NEYIFRVRAE NKIGTGPPTE SKPVIAKTKY
DKPGRPDPPE VTKVSKEEMT VVWNPPEYDG GKSITGYFLE KKEKHSTRWV PVNKSAIPER
RMKVQNLLPD HEYQFRVKAE NEIGIGEPSL PSRPVVAKDP IEPPGPPTNF RVVDTTKHSI
TLGWGKPVYD GGAPIIGYVV EMRPKIADAS PDEGWKRCNA AAQLVRKEFT VTSLDENQEY
EFRVCAQNQV GIGRPAELKE AIKPKEILEP PEIDLDASMR KLVIVRAGCP IRLFAIVRGR
PAPKVTWRKV GIDNVVRKGQ VDLVDTMAFL VIPNSTRDDS GKYSLTLVNP AGEKAVFVNV
RVLDTPGPVS DLKVSDVTKT SCHVSWAPPE NDGGSQVTHY IVEKREADRK TWSTVTPEVK
KTSFHVTNLV PGNEYYFRVT AVNEYGPGVP TDVPKPVLAS DPLSEPDPPR KLEVTEMTKN
SATLAWLPPL RDGGAKIDGY ITSYREEEQP ADRWTEYSVV KDLSLVVTGL KEGKKYKFRV
AARNAVGVSL PREAEGVYEA KEQLLPPKIL MPEQITIKAG KKLRIEAHVY GKPHPTCKWK
KGEDEVVTSS HLAVHKADSS SILIIKDVTR KDSGYYSLTA ENSSGTDTQK IKVVVMDAPG
PPQPPFDISD IDADACSLSW HIPLEDGGSN ITNYIVEKCD VSRGDWVTAL ASVTKTSCRV
GKLIPGQEYI FRVRAENRFG ISEPLTSPKM VAQFPFGVPS EPKNARVTKV NKDCIFVAWD
RPDSDGGSPI IGYLIERKER NSLLWVKAND TLVRSTEYPC AGLVEGLEYS FRIYALNKAG
SSPPSKPTEY VTARMPVDPP GKPEVIDVTK STVSLIWARP KHDGGSKIIG YFVEACKLPG
DKWVRCNTAP HQIPQEEYTA TGLEEKAQYQ FRAIARTAVN ISPPSEPSDP VTILAENVPP
RIDLSVAMKS LLTVKAGTNV CLDATVFGKP MPTVSWKKDG TLLKPAEGIK MAMQRNLCTL
ELFSVNRKDS GDYTITAENS SGSKSATIKL KVLDKPGPPA SVKINKMYSD RAMLSWEPPL
EDGGSEITNY IVDKRETSRP NWAQVSATVP ITSCSVEKLI EGHEYQFRIC AENKYGVGDP
VFTEPAIAKN PYDPPGRCDP PVISNITKDH MTVSWKPPAD DGGSPITGYL LEKRETQAVN
WTKVNRKPII ERTLKATGLQ EGTEYEFRVT AINKAGPGKP SDASKAAYAR DPQYPPGPPA
FPKVYDTTRS SVSLSWGKPA YDGGSPIIGY LVEVKRADSD NWVRCNLPQN LQKTRFEVTG
LMEDTQYQFR VYAVNKIGYS DPSDVPDKHY PKDILIPPEG ELDADLRKTL ILRAGVTMRL
YVPVKGRPPP KITWSKPNVN LRDRIGLDIK STDFDTFLRC ENVNKYDAGK YILTLENSCG
KKEYTIVVKV LDTPGPPVNV TVKEISKDSA YVTWEPPIID GGSPIINYVV QKRDAERKSW
STVTTECSKT SFRVANLEEG KSYFFRVFAE NEYGIGDPGE TRDAVKASQT PGPVVDLKVR
SVSKSSCSIG WKKPHSDGGS RIIGYVVDFL TEENKWQRVM KSLSLQYSAK DLTEGKEYTF
RVSAENENGE GTPSEITVVA RDDVVAPDLD LKGLPDLCYL AKENSNFRLK IPIKGKPAPS
VSWKKGEDPL ATDTRVSVES SAVNTTLIVY DCQKSDAGKY TITLKNVAGT KEGTISIKVV
GKPGIPTGPI KFDEVTAEAM TLKWAPPKDD GGSEITNYIL EKRDSVNNKW VTCASAVQKT
TFRVTRLHEG MEYTFRVSAE NKYGVGEGLK SEPIVARHPF DVPDAPPPPN IVDVRHDSVS
LTWTDPKKTG GSPITGYHLE FKERNSLLWK RANKTPIRMR DFKVTGLTEG LEYEFRVMAI
NLAGVGKPSL PSEPVVALDP IDPPGKPEVI NITRNSVTLI WTEPKYDGGH KLTGYIVEKR
DLPSKSWMKA NHVNVPECAF TVTDLVEGGK YEFRIRAKNT AGAISAPSES TETIICKDEY
EAPTIVLDPT IKDGLTIKAG DTIVLNAISI LGKPLPKSSW SKAGKDIRPS DITQITSTPT
SSMLTIKYAT RKDAGEYTIT ATNPFGTKVE HVKVTVLDVP GPPGPVEISN VSAEKATLTW
TPPLEDGGSP IKSYILEKRE TSRLLWTVVS EDIQSCRHVA TKLIQGNEYI FRVSAVNHYG
KGEPVQSEPV KMVDRFGPPG PPEKPEVSNV TKNTATVSWK RPVDDGGSEI TGYHVERREK
KSLRWVRAIK TPVSDLRCKV TGLQEGSTYE FRVSAENRAG IGPPSEASDS VLMKDAAYPP
GPPSNPHVTD TTKKSASLAW GKPHYDGGLE ITGYVVEHQK VGDEAWIKDT TGTALRITQF
VVPDLQTKEK YNFRISAIND AGVGEPAVIP DVEIVEREMA PDFELDAELR RTLVVRAGLS
IRIFVPIKGR PAPEVTWTKD NINLKNRANI ENTESFTLLI IPECNRYDTG KFVMTIENPA
GKKSGFVNVR VLDTPGPVLN LRPTDITKDS VTLHWDLPLI DGGSRITNYI VEKREATRKS
YSTATTKCHK CTYKVTGLSE GCEYFFRVMA ENEYGIGEPT ETTEPVKASE APSPPDSLNI
MDITKSTVSL AWPKPKHDGG SKITGYVIEA QRKGSDQWTH ITTVKGLECV VRNLTEGEEY
TFQVMAVNSA GRSAPRESRP VIVKEQTMLP ELDLRGIYQK LVIAKAGDNI KVEIPVLGRP
KPTVTWKKGD QILKQTQRVN FETTATSTIL NINECVRSDS GPYPLTARNI VGEVGDVITI
QVHDIPGPPT GPIKFDEVSS DFVTFSWDPP ENDGGVPISN YVVEMRQTDS TTWVELATTV
IRTTYKATRL TTGLEYQFRV KAQNRYGVGP GITSACIVAN YPFKVPGPPG TPQVTAVTKD
SMTISWHEPL SDGGSPILGY HVERKERNGI LWQTVSKALV PGNIFKSSGL TDGIAYEFRV
IAENMAGKSK PSKPSEPMLA LDPIDPPGKP VPLNITRHTV TLKWAKPEYT GGFKITSYIV
EKRDLPNGRW LKANFSNILE NEFTVSGLTE DAAYEFRVIA KNAAGAISPP SEPSDAITCR
DDVEAPKIKV DVKFKDTVIL KAGEAFRLEA DVSGRPPPTM EWSKDGKELE GTAKLEIKIA
DFSTNLVNKD STRRDSGAYT LTATNPGGFA KHIFNVKVLD RPGPPEGPLA VTEVTSEKCV
LSWFPPLDDG GAKIDHYIVQ KRETSRLAWT NVASEVQVTK LKVTKLLKGN EYIFRVMAVN
KYGVGEPLES EPVLAVNPYG PPDPPKNPEV TTITKDSMVV CWGHPDSDGG SEIINYIVER
RDKAGQRWIK CNKKTLTDLR YKVSGLTEGH EYEFRIMAEN AAGISAPSPT SPFYKACDTV
FKPGPPGNPR VLDTSRSSIS IAWNKPIYDG GSEITGYMVE IALPEEDEWQ IVTPPAGLKA
TSYTITGLTE NQEYKIRIYA MNSEGLGEPA LVPGTPKAED RMLPPEIELD ADLRKVVTIR
ACCTLRLFVP IKGRPAPEVK WARDHGESLD KASIESTSSY TLLIVGNVNR FDSGKYILTV
ENSSGSKSAF VNVRVLDTPG PPQDLKVKEV TKTSVTLTWD PPLLDGGSKI KNYIVEKRES
TRKAYSTVAT NCHKTSWKVD QLQEGCSYYF RVLAENEYGI GLPAETAESV KASERPLPPG
KITLMDVTRN SVSLSWEKPE HDGGSRILGY IVEMQTKGSD KWATCATVKV TEATITGLIQ
GEEYSFRVSA QNEKGISDPR QLSVPVIAKD LVIPPAFKLL FNTFTVLAGE DLKVDVPFIG
RPTPAVTWHK DNVPLKQTTR VNAESTENNS LLTIKDACRE DVGHYVVKLT NSAGEAIETL
NVIVLDKPGP PTGPVKMDEV TADSITLSWG PPKYDGGSSI NNYIVEKRDT STTTWQIVSA
TVARTTIKAC RLKTGCEYQF RIAAENRYGK STYLNSEPTV AQYPFKVPGP PGTPVVTLSS
RDSMEVQWNE PISDGGSRVI GYHLERKERN SILWVKLNKT PIPQTKFKTT GLEEGVEYEF
RVSAENIVGI GKPSKVSECY VARDPCDPPG RPEAIIVTRN SVTLQWKKPT YDGGSKITGY
IVEKKELPEG RWMKASFTNI IDTHFEVTGL VEDHRYEFRV IARNAAGVFS EPSESTGAIT
ARDEVDPPRI SMDPKYKDTI VVHAGESFKV DADIYGKPIP TIQWIKGDQE LSNTARLEIK
STDFATSLSV KDAVRVDSGN YILKAKNVAG ERSVTVNVKV LDRPGPPEGP VVISGVTAEK
CTLAWKPPLQ DGGSDIINYI VERRETSRLV WTVVDANVQT LSCKVTKLLE GNEYTFRIMA
VNKYGVGEPL ESEPVVAKNP FVVPDAPKAP EVTTVTKDSM IVVWERPASD GGSEILGYVL
EKRDKEGIRW TRCHKRLIGE LRLRVTGLIE NHDYEFRVSA ENAAGLSEPS PPSAYQKACD
PIYKPGPPNN PKVIDITRSS VFLSWSKPIY DGGCEIQGYI VEKCDVSVGE WTMCTPPTGI
NKTNIEVEKL LEKHEYNFRI CAINKAGVGE HADVPGPIIV EEKLEAPDID LDLELRKIIN
IRAGGSLRLF VPIKGRPTPE VKWGKVDGEI RDAAIIDVTS SFTSLVLDNV NRYDSGKYTL
TLENSSGTKS AFVTVRVLDT PSPPVNLKVT EITKDSVSIT WEPPLLDGGS KIKNYIVEKR
EATRKSYAAV VTNCHKNSWK IDQLQEGCSY YFRVTAENEY GIGLPAQTAD PIKVAEVPQP
PGKITVDDVT RNSVSLSWTK PEHDGGSKII QYIVEMQAKH SEKWSECARV KSLQAVITNL
TQGEEYLFRV VAVNEKGRSD PRSLAVPIVA KDLVIEPDVK PAFSSYSVQV GQDLKIEVPI
SGRPKPTITW TKDGLPLKQT TRINVTDSLD LTTLSIKETH KDDGGQYGIT VANVVGQKTA
SIEIVTLDKP DPPKGPVKFD DVSAESITLS WNPPLYTGGC QITNYIVQKR DTTTTVWDVV
SATVARTTLK VTKLKTGTEY QFRIFAENRY GQSFALESDP IVAQYPYKEP GPPGTPFATA
ISKDSMVIQW HEPVNNGGSP VIGYHLERKE RNSILWTKVN KTIIHDTQFK AQNLEEGIEY
EFRVYAENIV GVGKASKNSE CYVARDPCDP PGTPEPIMVK RNEITLQWTK PVYDGGSMIT
GYIVEKRDLP DGRWMKASFT NVIETQFTVS GLTEDQRYEF RVIAKNAAGA ISKPSDSTGP
ITAKDEVELP RISMDPKFRD TIVVNAGETF RLEADVHGKP LPTIEWLRGD KEIEESARCE
IKNTDFKALL IVKDAIRIDG GQYILRASNV AGSKSFPVNV KVLDRPGPPE GPVQVTGVTS
EKCSLTWSPP LQDGGSDISH YVVEKRETSR LAWTVVASEV VTNSLKVTKL LEGNEYVFRI
MAVNKYGVGE PLESAPVLMK NPFVLPGPPK SLEVTNIAKD SMTVCWNRPD SDGGSEIIGY
IVEKRDRSGI RWIKCNKRRI TDLRLRVTGL TEDHEYEFRV SAENAAGVGE PSPATVYYKA
CDPVFKPGPP TNAHIVDTTK NSITLAWGKP IYDGGSEILG YVVEICKADE EEWQIVTPQT
GLRVTRFEIS KLTEHQEYKI RVCALNKVGL GEATSVPGTV KPEDKLEAPE LDLDSELRKG
IVVRAGGSAR IHIPFKGRPT PEITWSREEG EFTDKVQIEK GVNYTQLSID NCDRNDAGKY
ILKLENSSGS KSAFVTVKVL DTPGPPQNLA VKEVRKDSAF LVWEPPIIDG GAKVKNYVID
KRESTRKAYA NVSSKCSKTS FKVENLTEGA IYYFRVMAEN EFGVGVPVET VDAVKAAEPP
SPPGKVTLTD VSQTSASLMW EKPEHDGGSR VLGYVVEMQP KGTEKWSIVA ESKVCNAVVT
GLSSGQEYQF RVKAYNEKGK SDPRVLGVPV IAKDLTIQPS LKLPFNTYSI QAGEDLKIEI
PVIGRPRPNI SWVKDGEPLK QTTRVNVEET ATSTVLHIKE GNKDDFGKYT VTATNSAGTA
TENLSVIVLE KPGPPVGPVR FDEVSADFVV ISWEPPAYTG GCQISNYIVE KRDTTTTTWH
MVSATVARTT IKITKLKTGT EYQFRIFAEN RYGKSAPLDS KAVIVQYPFK EPGPPGTPFV
TSISKDQMLV QWHEPVNDGG TKIIGYHLEQ KEKNSILWVK LNKTPIQDTK FKTTGLDEGL
EYEFKVSAEN IVGIGKPSKV SECFVARDPC DPPGRPEAIV ITRNNVTLKW KKPAYDGGSK
ITGYIVEKKD LPDGRWMKAS FTNVLETEFT VSGLVEDQRY EFRVIARNAA GNFSEPSDSS
GAITARDEID APNASLDPKY KDVIVVHAGE TFVLEADIRG KPIPDVVWSK DGKELEETAA
RMEIKSTIQK TTLVVKDCIR TDGGQYILKL SNVGGTKSIP ITVKVLDRPG PPEGPLKVTG
VTAEKCYLAW NPPLQDGGAN ISHYIIEKRE TSRLSWTQVS TEVQALNYKV TKLLPGNEYI
FRVMAVNKYG IGEPLESGPV TACNPYKPPG PPSTPEVSAI TKDSMVVTWA RPVDDGGTEI
EGYILEKRDK EGVRWTKCNK KTLTDLRLRV TGLTEGHSYE FRVAAENAAG VGEPSEPSVF
YRACDALYPP GPPSNPKVTD TSRSSVSLAW SKPIYDGGAP VKGYVVEVKE AAADEWTTCT
PPTGLQGKQF TVTKLKENTE YNFRICAINS EGVGEPATLP GSVVAQERIE PPEIELDADL
RKVVVLRASA TLRLFVTIKG RPEPEVKWEK AEGILTDRAQ IEVTSSFTML VIDNVTRFDS
GRYNLTLENN SGSKTAFVNV RVLDSPSAPV NLTIREVKKD SVTLSWEPPL IDGGAKITNY
IVEKRETTRK AYATITNNCT KTTFRIENLQ EGCSYYFRVL ASNEYGIGLP AETTEPVKVS
EPPLPPGRVT LVDVTRNTAT IKWEKPESDG GSKITGYVVE MQTKGSEKWS TCTQVKTLEA
TISGLTAGEE YVFRVAAVNE KGRSDPRQLG VPVIARDIEI KPSVELPFHT FNVKAREQLK
IDVPFKGRPQ ATVNWRKDGQ TLKETTRVNV SSSKTVTSLS IKEASKEDVG TYELCVSNSA
GSITVPITII VLDRPGPPGP IRIDEVSCDS ITISWNPPEY DGGCQISNYI VEKKETTSTT
WHIVSQAVAR TSIKIVRLTT GSEYQFRVCA ENRYGKSSYS ESSAVVAEYP FSPPGPPGTP
KVVHATKSTM LVTWQVPVND GGSRVIGYHL EYKERSSILW SKANKILIAD TQMKVSGLDE
GLMYEYRVYA ENIAGIGKCS KSCEPVPARD PCDPPGQPEV TNITRKSVSL KWSKPHYDGG
AKITGYIVER RELPDGRWLK CNYTNIQETY FEVTELTEDQ RYEFRVFARN AADSVSEPSE
STGPIIVKDD VEPPRVMMDV KFRDVIVVKA GEVLKINADI AGRPLPVISW AKDGIEIEER
ARTEIISTDN HTLLTVKDCI RRDTGQYVLT LKNVAGTRSV AVNCKVLDKP GPPAGPLEIN
GLTAEKCSLS WGRPQEDGGA DIDYYIVEKR ETSHLAWTIC EGELQMTSCK VTKLLKGNEY
IFRVTGVNKY GVGEPLESVA IKALDPFTVP SPPTSLEITS VTKESMTLCW SRPESDGGSE
ISGYIIERRE KNSLRWVRVN KKPVYDLRVK STGLREGCEY EYRVYAENAA GLSLPSETSP
LIRAEDPVFL PSPPSKPKIV DSGKTTITIA WVKPLFDGGA PITGYTVEYK KSDDTDWKTS
IQSLRGTEYT ISGLTTGAEY VFRVKSVNKV GASDPSDSSD PQIAKEREEE PLFDIDSEMR
KTLIVKAGAS FTMTVPFRGR PVPNVLWSKP DTDLRTRAYV DTTDSRTSLT IENANRNDSG
KYTLTIQNVL SAASLTLVVK VLDTPGPPTN ITVQDVTKES AVLSWDVPEN DGGAPVKNYH
IEKREASKKA WVSVTNNCNR LSYKVTNLQE GAIYYFRVSG ENEFGVGIPA ETKEGVKITE
KPSPPEKLGV TSISKDSVSL TWLKPEHDGG SRIVHYVVEA LEKGQKNWVK CAVAKSTHHV
VSGLRENSEY FFRVFAENQA GLSDPRELLL PVLIKEQLEP PEIDMKNFPS HTVYVRAGSN
LKVDIPISGK PLPKVTLSRD GVPLKATMRF NTEITAENLT INLKESVTAD AGRYEITAAN
SSGTTKAFIN IVVLDRPGPP TGPVVISDIT EESVTLKWEP PKYDGGSQVT NYILLKRETS
TAVWTEVSAT VARTMMKVMK LTTGEEYQFR IKAENRFGIS DHIDSACVTV KLPYTTPGPP
STPWVTNVTR ESITVGWHEP VSNGGSAVVG YHLEMKDRNS ILWQKANKLV IRTTHFKVTT
ISAGLIYEFR VYAENAAGVG KPSHPSEPVL AIDACEPPRN VRITDISKNS VSLSWQQPAF
DGGSKITGYI VERRDLPDGR WTKASFTNVT ETQFIISGLT QNSQYEFRVF ARNAVGSISN
PSEVVGPITC IDSYGGPVID LPLEYTEVVK YRAGTSVKLR AGISGKPAPT IEWYKDDKEL
QTNALVCVEN TTDLASILIK DADRLNSGCY ELKLRNAMGS ASATIRVQIL DKPGPPGGPI
EFKTVTAEKI TLLWRPPADD GGAKITHYIV EKRETSRVVW SMVSEHLEEC IITTTKIIKG
NEYIFRVRAV NKYGIGEPLE SDSVVAKNAF VTPGPPGIPE VTKITKNSMT VVWSRPIADG
GSDISGYFLE KRDKKSLGWF KVLKETIRDT RQKVTGLTEN SDYQYRVCAV NAAGQGPFSE
PSEFYKAADP IDPPGPPAKI RIADSTKSSI TLGWSKPVYD GGSAVTGYVV EIRQGEEEEW
TTVSTKGEVR TTEYVVSNLK PGVNYYFRVS AVNCAGQGEP IEMNEPVQAK DILEAPEIDL
DVALRTSVIA KAGEDVQVLI PFKGRPPPTV TWRKDEKNLG SDARYSIENT DSSSLLTIPQ
VTRNDTGKYI LTIENGVGEP KSSTVSVKVL DTPAACQKLQ VKHVSRGTVT LLWDPPLIDG
GSPIINYVIE KRDATKRTWS VVSHKCSSTS FKLIDLSEKT PFFFRVLAEN EIGIGEPCET
TEPVKAAEVP APIRDLSMKD STKTSVILSW TKPDFDGGSV ITEYVVERKG KGEQTWSHAG
ISKTCEIEVS QLKEQSVLEF RVFAKNEKGL SDPVTIGPIT VKELIITPEV DLSDIPGAQV
TVRIGHNVHL ELPYKGKPKP SISWLKDGLP LKESEFVRFS KTENKITLSI KNAKKEHGGK
YTVILDNAVC RIAVPITVIT LGPPSKPKGP IRFDEIKADS VILSWDVPED NGGGEITCYS
IEKRETSQTN WKMVCSSVAR TTFKVPNLVK DAEYQFRVRA ENRYGVSQPL VSSIIVAKHQ
FRIPGPPGKP VIYNVTSDGM SLTWDAPVYD GGSEVTGFHV EKKERNSILW QKVNTSPISG
REYRATGLVE GLDYQFRVYA ENSAGLSSPS DPSKFTLAVS PVDPPGTPDY IDVTRETITL
KWNPPLRDGG SKIVGYSIEK RQGNERWVRC NFTDVSECQY TVTGLSPGDR YEFRIIARNA
VGTISPPSQS SGIIMTRDEN VPPIVEFGPE YFDGLIIKSG ESLRIKALVQ GRPVPRVTWF
KDGVEIEKRM NMEITDVLGS TSLFVRDATR DHRGVYTVEA KNASGSAKAE IKVKVQDTPG
KVVGPIRFTN ITGEKMTLWW DAPLNDGCAP ITHYIIEKRE TSRLAWALIE DKCEAQSYTA
IKLINGNEYQ FRVSAVNKFG VGRPLDSDPV VAQIQYTVPD APGIPEPSNI TGNSITLTWA
RPESDGGSEI QQYILERREK KSTRWVKVIS KRPISETRFK VTGLTEGNEY EFHVMAENAA
GVGPASGISR LIKCREPVNP PGPPTVVKVT DTSKTTVSLE WSKPVFDGGM EIIGYIIEMC
KADLGDWHKV NAEACVKTRY TVTDLQAGEE YKFRVSAING AGKGDSCEVT GTIKAVDRLT
APELDIDANF KQTHVVRAGA SIRLFIAYQG RPTPTAVWSK PDSNLSLRAD IHTTDSFSTL
TVENCNRNDA GKYTLTVENN SGSKSITFTV KVLDTPGPPG PITFKDVTRG SATLMWDAPL
LDGGARIHHY VVEKREASRR SWQVISEKCT RQIFKVNDLA EGVPYYFRVS AVNEYGVGEP
YEMPEPIVAT EQPAPPRRLD VVDTSKSSAV LAWLKPDHDG GSRITGYLLE MRQKGSDFWV
EAGHTKQLTF TVERLVEKTE YEFRVKAKND AGYSEPREAF SSVIIKEPQI EPTADLTGIT
NQLITCKAGS PFTIDVPISG RPAPKVTWKL EEMRLKETDR VSITTTKDRT TLTVKDSMRG
DSGRYFLTLE NTAGVKTFSV TVVVIGRPGP VTGPIEVSSV SAESCVLSWG EPKDGGGTEI
TNYIVEKRES GTTAWQLVNS SVKRTQIKVT HLTKYMEYSF RVSSENRFGV SKPLESAPII
AEHPFVPPSA PTRPEVYHVS ANAMSIRWEE PYHDGGSKII GYWVEKKERN TILWVKENKV
PCLECNYKVT GLVEGLEYQF RTYALNAAGV SKASEASRPI MAQNPVDAPG RPEVTDVTRS
TVSLIWSAPA YDGGSKVVGY IIERKPVSEV GDGRWLKCNY TIVSDNFFTV TALSEGDTYE
FRVLAKNAAG VISKGSESTG PVTCRDEYAP PKAELDARLH GDLVTIRAGS DLVLDAAVGG
KPEPKIIWTK GDKELDLCEK VSLQYTGKRA TAVIKFCDRS DSGKYTLTVK NASGTKAVSV
MVKVLDSPGP CGKLTVSRVT QEKCTLAWSL PQEDGGAEIT HYIVERRETS RLNWVIVEGE
CPTLSYVVTR LIKNNEYIFR VRAVNKYGPG VPVESEPIVA RNSFTIPSPP GIPEEVGTGK
EHIIIQWTKP ESDGGNEISN YLVDKREKKS LRWTRVNKDY VVYDTRLKVT SLMEGCDYQF
RVTAVNAAGN SEPSEASNFI SCREPSYTPG PPSAPRVVDT TKHSISLAWT KPMYDGGTDI
VGYVLEMQEK DTDQWYRVHT NATIRNTEFT VPDLKMGQKY SFRVAAVNVK GMSEYSESIA
EIEPVERIEI PDLELADDLK KTVTIRAGAS LRLMVSVSGR PPPVITWSKQ GIDLASRAII
DTTESYSLLI VDKVNRYDAG KYTIEAENQS GKKSATVLVK VYDTPGPCPS VKVKEVSRDS
VTITWEIPTI DGGAPVNNYI VEKREAAMRA FKTVTTKCSK TLYRISGLVE GTMYYFRVLP
ENIYGIGEPC ETSDAVLVSE VPLVPAKLEV VDVTKSTVTL AWEKPLYDGG SRLTGYVLEA
CKAGTERWMK VVTLKPTVLE HTVTSLNEGE QYLFRIRAQN EKGVSEPRET VTAVTVQDLR
VLPTIDLSTM PQKTIHVPAG RPVELVIPIA GRPPPAASWF FAGSKLRESE RVTVETHTKV
AKLTIRETTI RDTGEYTLEL KNVTGTTSET IKVIILDKPG PPTGPIKIDE IDATSITISW
EPPELDGGAP LSGYVVEQRD AHRPGWLPVS ESVTRSTFKF TRLTEGNEYV FRVAATNRFG
IGSYLQSEVI ECRSSIRIPG PPETLQIFDV SRDGMTLTWY PPEDDGGSQV TGYIVERKEV
RADRWVRVNK VPVTMTRYRS TGLTEGLEYE HRVTAINARG SGKPSRPSKP IVAMDPIAPP
GKPQNPRVTD TTRTSVSLAW SVPEDEGGSK VTGYLIEMQK VDQHEWTKCN TTPTKIREYT
LTHLPQGAEY RFRVLACNAG GPGEPAEVPG TVKVTEMLEY PDYELDERYQ EGIFVRQGGV
IRLTIPIKGK PFPICKWTKE GQDISKRAMI ATSETHTELV IKEADRGDSG TYDLVLENKC
GKKAVYIKVR VIGSPNSPEG PLEYDDIQVR SVRVSWRPPA DDGGADILGY ILERREVPKA
AWYTIDSRVR GTSLVVKGLK ENVEYHFRVS AENQFGISKP LKSEEPVTPK TPLNPPEPPS
NPPEVLDVTK SSVSLSWSRP KDDGGSRVTG YYIERKETST DKWVRHNKTQ ITTTMYTVTG
LVPDAEYQFR IIAQNDVGLS ETSPASEPVV CKDPFDKPSQ PGELEILSIS KDSVTLQWEK
PECDGGKEIL GYWVEYRQSG DSAWKKSNKE RIKDKQFTIG GLLEATEYEF RVFAENETGL
SRPRRTAMSI KTKLTSGEAP GIRKEMKDVT TKLGEAAQLS CQIVGRPLPD IKWYRFGKEL
IQSRKYKMSS DGRTHTLTVM TEEQEDEGVY TCIATNEVGE VETSSKLLLQ ATPQFHPGYP
LKEKYYGAVG STLRLHVMYI GRPVPAMTWF HGQKLLQNSE NITIENTEHY THLVMKNVQR
KTHAGKYKVQ LSNVFGTVDA ILDVEIQDKP DKPTGPIVIE ALLKNSAVIS WKPPADDGGS
WITNYVVEKC EAKEGAEWQL VSSAISVTTC RIVNLTENAG YYFRVSAQNT FGISDPLEVS
SVVIIKSPFE KPGAPGKPTI TAVTKDSCVV AWKPPASDGG AKIRNYYLEK REKKQNKWIS
VTTEEIRETV FSVKNLIEGL EYEFRVKCEN LGGESEWSEI SEPITPKSDV PIQAPHFKEE
LRNLNVRYQS NATLVCKVTG HPKPIVKWYR QGKEIIADGL KYRIQEFKGG YHQLIIASVT
DDDATVYQVR ATNQGGSVSG TASLEVEVPA KIHLPKTLEG MGAVHALRGE VVSIKIPFSG
KPDPVITWQK GQDLIDNNGH YQVIVTRSFT SLVFPNGVER KDAGFYVVCA KNRFGIDQKT
VELDVADVPD PPRGVKVSDV SRDSVNLTWT EPASDGGSKI TNYIVEKCAT TAERWLRVGQ
ARETRYTVIN LFGKTSYQFR VIAENKFGLS KPSEPSEPTI TKEDKTRAMN YDEEVDETRE
VSMTKASHSS TKELYEKYMI AEDLGRGEFG IVHRCVETSS KKTYMAKFVK VKGTDQVLVK
KEISILNIAR HRNILHLHES FESMEELVMI FEFISGLDIF ERINTSAFEL NEREIVSYVH
QVCEALQFLH SHNIGHFDIR PENIIYQTRR SSTIKIIEFG QARQLKPGDN FRLLFTAPEY
YAPEVHQHDV VSTATDMWSL GTLVYVLLSG INPFLAETNQ QIIENIMNAE YTFDEEAFKE
ISIEAMDFVD RLLVKERKSR MTASEALQHP WLKQKIERVS TKVIRTLKHR RYYHTLIKKD
LNMVVSAARI SCGGAIRSQK GVSVAKVKVA SIEIGPVSGQ IMHAVGEEGG HVKYVCKIEN
YDQSTQVTWY FGVRQLENSE KYEITYEDGV AILYVKDITK LDDGTYRCKV VNDYGEDSSY
AELFVKGVRE VYDYYCRRTM KKIKRRTDTM RLLERPPEFT LPLYNKTAYV GENVRFGVTI
TVHPEPHVTW YKSGQKIKPG DNDKKYTFES DKGLYQLTIN SVTTDDDAEY TVVARNKYGE
DSCKAKLTVT LHPPPTDSTL RPMFKRLLAN AECQEGQSVC FEIRVSGIPP PTLKWEKDGQ
PLSLGPNIEI IHEGLDYYAL HIRDTLPEDT GYYRVTATNT AGSTSCQAHL QVERLRYKKQ
EFKSKEEHER HVQKQIDKTL RMAEILSGTE SVPLTQVAKE ALREAAVLYK PAVSTKTVKG
EFRLEIEEKK EERKLRMPYD VPEPRKYKQT TIEEDQRIKQ FVPMSDMKWY KKIRDQYEMP
GKLDRVVQKR PKRIRLSRWE QFYVMPLPRI TDQYRPKWRI PKLSQDDLEI VRPARRRTPS
PDYDFYYRPR RRSLGDISDE ELLLPIDDYL AMKRTEEERL RLEEELELGF SASPPSRSPP
HFELSSLRYS SPQAHVKVEE TRKDFRYSTY HIPTKAEAST SYAELRERHA QAAYRQPKQR
QRIMAEREDE ELLRPVTTTQ HLSEYKSELD FMSKEEKSRK KSRRQREVTE ITEIEEEYEI
SKHAQRESSS SASRLLRRRR SLSPTYIELM RPVSELIRSR PQPAEEYEDD TERRSPTPER
TRPRSPSPVS SERSLSRFER SARFDIFSRY ESMKAALKTQ KTSERKYEVL SQQPFTLDHA
PRITLRMRSH RVPCGQNTRF ILNVQSKPTA EVKWYHNGVE LQESSKIHYT NTSGVLTLEI
LDCHTDDSGT YRAVCTNYKG EASDYATLDV TGGDYTTYAS QRRDEEVPRS VFPELTRTEA
YAVSSFKKTS EMEASSSVRE VKSQMTETRE SLSSYEHSAS AEMKSAALEE KSLEEKSTTR
KIKTTLAARI LTKPRSMTVY EGESARFSCD TDGEPVPTVT WLRKGQVLST SARHQVTTTK
YKSTFEISSV QASDEGNYSV VVENSEGKQE AEFTLTIQKA RVTEKAVTSP PRVKSPEPRV
KSPEAVKSPK RVKSPEPSHP KAVSPTETKP TPTEKVQHLP VSAPPKITQF LKAEASKEIA
KLTCVVESSV LRAKEVTWYK DGKKLKENGH FQFHYSADGT YELKINNLTE SDQGEYVCEI
SGEGGTSKTN LQFMGQAFKS IHEKVSKISE TKKSDQKTTE STVTRKTEPK APEPISSKPV
IVTGLQDTTV SSDSVAKFAV KATGEPRPTA IWTKDGKAIT QGGKYKLSED KGGFFLEIHK
TDTSDSGLYT CTVKNSAGSV SSSCKLTIKA IKDTEAQKVS TQKTSEITPQ KKAVVQEEIS
QKALRSEEIK MSEAKSQEKL ALKEEASKVL ISEEVKKSAA TSLEKSIVHE EITKTSQASE
EVRTHAEIKA FSTQMSINEG QRLVLKANIA GATDVKWVLN GVELTNSEEY RYGVSGSDQT
LTIKQASHRD EGILTCISKT KEGIVKCQYD LTLSKELSDA PAFISQPRSQ NINEGQNVLF
TCEISGEPSP EIEWFKNNLP ISISSNVSIS RSRNVYSLEI RNASVSDSGK YTIKAKNFRG
QCSATASLMV LPLVEEPSRE VVLRTSGDTS LQGSFSSQSV QMSASKQEAS FSSFSSSSAS
SMTEMKFASM SAQSMSSMQE SFVEMSSSSF MGISNMTQLE SSTSKMLKAG IRGIPPKIEA
LPSDISIDEG KVLTVACAFT GEPTPEVTWS CGGRKIHSQE QGRFHIENTD DLTTLIIMDV
QKQDGGLYTL SLGNEFGSDS ATVNIHIRSI
//

MIM 188840
*RECORD*
*FIELD* NO
188840
*FIELD* TI
*188840 TITIN; TTN
;;CONNECTIN
*FIELD* TX

DESCRIPTION

Titin, or connectin, is a giant muscle protein expressed in the cardiac
read moreand skeletal muscles that spans half of the sarcomere from Z line to M
line. Titin plays a key role in muscle assembly, force transmission at
the Z line, and maintenance of resting tension in the I band region
(Itoh-Satoh et al., 2002).

CLONING

Labeit et al. (1990) showed that partial titin cDNAs encode a regular
pattern of 2 types of 100-residue motif, each of which probably folds
into a separate domain type. Such motifs are present in several
evolutionarily divergent proteins, all of which are likely to interact
with myosin.

Labeit and Kolmerer (1995) determined the cDNA sequence of human cardiac
titin. The 82-kb cDNA predicted a 26,926-amino acid protein with a
molecular mass of 2,993 kD. Ninety percent of the mass is contained in a
repetitive structure composed of 244 copies of 100-residue repeats that
encode 112 immunoglobulin-like and 132 fibronectin type III domains.
Alternative splicing accounts for tissue-specific titin isoforms. In the
central part of I band titin, cardiac and skeletal titins branch into
distinct isoforms; in heart, differential splicing includes about 3.5 kb
of cDNA within the I band region of titin, whereas in skeletal muscle,
22.5 kb of cDNA is included. In addition, a sequence element rich in
proline (P), glutamic acid (E), lysine (K), and valine (V) residues,
referred to as the PEVK domain, comprises 163 residues in cardiac titin
and 2,174 residues in skeletal titin.

Bang et al. (2001) determined that the complete sequence of human titin
encodes a 38,138-amino acid protein with a molecular mass of 4,200 kD.

GENE STRUCTURE

Bang et al. (2001) determined that titin has 363 exons.

Titin contains 6 M band-encoding exons at the C terminus, exons 358 to
363, referred to as Mex1 to Mex6. These exons are constitutively
expressed in both skeletal and cardiac muscle (Carmignac et al., 2007).

GENE FUNCTION

Labeit et al. (1990) suggested that the I band of titin makes elastic
connections between the thick filament and the Z line within the
sarcomere. The A band of titin appears to bind to the thick filament,
where it may regulate filament length and assembly. The architecture of
sequences in the A band region of titin suggested to Labeit and Kolmerer
(1995) why thick filament structure is conserved among vertebrates. In
the I band region, comparison of titin sequences from muscles of
different passive tension identified 2 elements that correlate with
tissue stiffness, suggesting that titin may act as 2 springs in series.
The differential expression of the springs provides a molecular
explanation for the diversity of sarcomere length and resting tension in
vertebrate striated muscles.

Ma and Wang (2002) presented evidence that the PEVK segment of titin,
which contains numerous SH3-binding motifs, and the Z line protein
myopalladin (MYPN; 608517) may play signaling roles in targeting and
orienting nebulin (NEB; 161650) to the Z line during sarcomere assembly.

The I band region of titin contains tandem arrays of immunoglobulin
domains. Immunoglobulin domain-27 (I27) unfolds through an intermediate
under force in which the A-strand is detached. The lengthening of I27
without unfolding forms a stable intermediate that is believed to be an
important component of titin elasticity (Marszalek et al., 1999).
Williams et al. (2003) used mutant titins to study the role of the
partly unfolded intermediate of titin. Under physiologic forces, the
partly unfolded intermediate of immunoglobulin domain-27 does not
contribute to mechanical strength. Williams et al. (2003) also proposed
a unified forced unfolding model of all I27 analogs studied, and
concluded that I27 can withstand higher forces in muscle than had
previously been predicted.

Titin interacts with many sarcomeric proteins: telethonin (TCAP; 604488)
and alpha-actinin (e.g., 102575) at the Z line region; calpain-3 (CAPN3;
114240) and obscurin (OBSCN; 608616) at the I band region; and
myosin-binding protein C (MYBPC3; 600958), calmodulin (CALM1; 114180),
and CAPN3 at the M line region (Bang et al., 2001). In a review, Hackman
et al. (2003) noted that titin has at least 2 different CAPN3-binding
sites: one is in region N2A in I band titin and the other is in the Mex5
exon of M line titin. Obscurin (608616) interacts with both the
NH2-terminal of Z disc titin and the M line titin during different
phases of myofibrillogenesis, and MURF1 (606131) binds titin close to
the kinase domain at the periphery of the M line titin.

Lange et al. (2005) identified a signaling complex where the titin
protein kinase domain (TK) interacts with the zinc finger protein NBR1
(166945) through a mechanically inducible conformation. NBR1 targets the
ubiquitin-associated p62/SQSTM1 (601530) to sarcomeres, and p62 in turn
interacts with MURF2 (606469), a muscle-specific RING-B-box E3 ligase
and ligand of the transactivation domain of the serum response
transcription factor (SRF; 600589). Nuclear translocation of MURF2 was
induced by mechanical inactivity and caused reduction of nuclear SRF and
repression of transcription.

Sarparanta et al. (2010) observed that M-band-localized myospryn (CMYA5;
612193) was in close proximity (less than 40 nm) to the
M-band-associated titin C terminus in mouse muscle sections. Yeast
2-hybrid analysis of human fetal and adult skeletal muscle cDNA
libraries showed that C-terminal domains of titin interacted with a
C-terminal fragment of myospryn. Reciprocal coimmunoprecipitation
analysis confirmed the interaction between the titin and myospryn
fragments.

BIOCHEMICAL FEATURES

Li et al. (2002) used protein engineering and single-molecule atomic
force microscopy to examine the mechanical components that form the
elastic region of human cardiac titin. They showed that when these
mechanical elements are combined, they explain the macroscopic behavior
of titin in intact muscle.

Using x-ray crystallography, Zou et al. (2006) showed how the amino
terminus of the longest filament component in the Z disc of muscle, the
giant muscle protein titin, is assembled into an antiparallel (2:1)
sandwich complex by the Z disc ligand telethonin. The pseudosymmetric
structure of telethonin mediates a unique palindromic arrangement of 2
titin filaments, a type of molecular assembly previously found only in
protein-DNA complexes. Zou et al. (2006) confirmed its unique
architecture in vivo by protein complementation assays, and in vitro by
experiments using fluorescence resonance energy transfer. Zou et al.
(2006) proposed a model that provides a molecular paradigm of how major
sarcomeric filaments are crosslinked, anchored, and aligned within
complex cytoskeletal networks.

MAPPING

By studies of DNA from a panel of Chinese hamster/human hybrid cell
lines, Labeit et al. (1990) assigned the TTN locus to 2q13-q33. Another
myofibrillar protein, nebulin, maps to 2q31-q32. The fact that the 2
genes are close together suggests that their regulation may be
coordinated, possibly to control the ratio of the proteins. In the
mouse, the titin gene was also mapped to chromosome 2. Muller-Seitz et
al. (1993) showed that the murine equivalents of the human TTN, NEB, and
CHRNA1 (100690) genes are all on mouse chromosome 2.

Using radiation hybrid mapping, Pelin et al. (1997) reassigned the titin
gene to the vicinity of the markers D2S384 and D2S364 on 2q24.3. They
concluded that the TTN gene lies outside the candidate region for NEM2
(256030), the autosomal recessive form of nemaline myopathy.

Carmignac et al. (2007) noted that the TTN gene maps to chromosome
2q31.2.

MOLECULAR GENETICS

- Cardiomyopathy

In 1 of 82 patients with hypertrophic cardiomyopathy (CMH) who had no
mutation in known disease genes, Satoh et al. (1999) identified a
mutation in the TTN gene (188840.0001) that was not found in more than
500 normal chromosomes and increased the binding affinity of titin to
alpha-actinin (see 102575) in the yeast 2-hybrid assay. The form of
hypertrophic cardiomyopathy due to mutation in the TTN gene has been
designated CMH9 (613765).

In 2 unrelated families with autosomal dominant dilated cardiomyopathy
(CMD) linked to 2q31 (CMD1G; 604145), Gerull et al. (2002) identified 2
different heterozygous mutations in the TTN gene (188840.0002;
188840.0003).

In 4 patients with dilated cardiomyopathy, Itoh-Satoh et al. (2002)
identified 4 different mutations in the TTN gene
(188840.0007-188840.0010). Two of the cases were familial.

Herman et al. (2012) used next-generation sequencing to analyze the TTN
gene in 203 individuals with dilated cardiomyopathy, 231 with
hypertrophic cardiomyopathy, and 249 controls. The frequency of TTN
mutations was significantly higher among individuals with CMD (27%) than
among those with CMH (1%) or controls (3%). In the 3 patients with CMH
in whom TTN truncating or splicing mutations were identified, concurrent
analyses revealed a pathogenic mutation in the known CMH genes MYH7
(160760) or MYBPC3 (600958). In CMD families, TTN mutations cosegregated
with dilated cardiomyopathy, with highly observed penetrance after the
age of 40 years. Mutations associated with CMD were overrepresented in
the titin A-band but were absent from the Z-disc and M-band regions of
titin. Herman et al. (2012) concluded that TTN truncating mutations are
a common cause of dilated cardiomyopathy, occurring in approximately 25%
of familial CMD cases and in 18% of sporadic cases, and suggested that
TTN truncations rarely, if ever, cause hypertrophic cardiomyopathy.

Lopes et al. (2013) analyzed the coding, intronic, and regulatory
regions of 41 cardiovascular genes in 223 unrelated patients with CMH
using high-throughput sequencing technology. They found 219 rare
variants in 142 (63.6%) of the patients: 30 patients (13%) had titin
candidate variants in isolation, 22 (10%) had titin variants only in
association with desmosomal gene candidate variants or ion channel
disease-associated variants, and 171 (77%) carried a TTN candidate
variant in association with sarcomere, Z-disc, or calcium-handling gene
variants. Lopes et al. (2013) noted that titin has been difficult to
sequence and study due to its size, large number of isoforms, and
unsolved tertiary structure. All of the individual variants present in
this cohort occurred with a frequency of less than 0.5% in the 1000
Genomes Project, suggesting that a proportion of them might be, at the
very least, modulators of the phenotype. However, the overall frequency
of variants in the CMH cohort was actually lower than that seen in the
control exome population. Lopes et al. (2013) concluded that further
work on understanding the role of titin in CMH was necessary.

- Muscular Dystrophy

Tibial muscular dystrophy (TMD; 600334) is an autosomal dominant
late-onset distal myopathy characterized by weakness and atrophy usually
confined to the anterior compartment of the lower leg. Cardiomyopathy
has not been diagnosed in patients with TMD. In 81 Finnish patients with
TMD from 12 unrelated families, Hackman et al. (2002) identified an
11-bp deletion (188840.0004) in Mex6, the last exon (exon 363) of the
TTN gene. Mex6 encodes an Ig domain that, in situ, is localized at the
periphery of the M line lattice. Mex6 and Mex5 are in the region
determining the calpain-3 binding site of M line titin. Three patients
with a more severe phenotype, limb-girdle muscular dystrophy type 2J
(LGMD2J; 608807), were homozygous for the 11-bp deletion. In a French
family with TMD, a leu34315-to-pro mutation in Mex6 (188840.0005) was
discovered.

Lange et al. (2005) found a mutation in the titin protein kinase domain
that results in Edstrom myopathy (603689).

Carmignac et al. (2007) identified 2 different homozygous deletions in
the TTN gene (188840.0012; 188840.0013, respectively) in affected
members of 2 unrelated families with early-onset myopathy and fatal
cardiomyopathy (611705). The deletions occurred in Mex1 and Mex3,
truncating the C-terminal region of the protein; the kinase portion was
preserved.

ANIMAL MODEL

The zebrafish embryo is transparent and can tolerate absence of blood
flow because its oxygen is delivered by diffusion rather than by the
cardiovascular system. It is, therefore, possible to attribute cardiac
failure directly to particular genes by ruling out the possibility that
it is due to a secondary effect of hypoxia. Xu et al. (2002) studied a
recessive lethal mutation, called 'pickwick' (pik), discovered in a
large-scale genetic screen. The heart of the pik mutant develops
normally but is poorly contractile from the first beat. Aside from the
edema that inevitably accompanies cardiac dysfunction, development is
normal during the first 3 days. Xu et al. (2002) showed by positional
cloning that the 'causative' mutation is in an alternatively spliced
exon of the titin gene. Titin is the biggest known protein and spans the
half-sarcomere from the Z disc to M line in heart and skeletal muscle.
It appears to provide a scaffold for the assembly of thick and thin
filaments and to provide elastic recoil engendered by stretch during
diastole. Xu et al. (2002) found that nascent myofibrils form in pik
mutants, but normal sarcomeres are absent. Mutant cells transplanted to
wildtype hearts remained thin and bulged outwards as individual cell
aneurysms without affecting nearby wildtype cardiomyocytes, indicating
that the contractile deficiency is cell-autonomous. Absence of titin
function thus results in blockage of sarcomere assembly and causes a
functional disorder resembling human dilated cardiomyopathies, one form
of which was shown to be caused in the human by mutations in the TTN
gene (Gerull et al., 2002).

Muscular dystrophy with myositis (mdm) is a recessive mouse mutation
that causes severe and progressive muscular degeneration. Garvey et al.
(2002) identified the mdm mutation as a complex rearrangement that
includes a deletion and LINE insertion in the titin gene. Mutant
allele-specific splicing results in the deletion of 83 amino acids from
the N2A region of TTN, a domain thought to bind CAPN3. Western blot
analysis detected a 50 to 60% reduction in the amount of CAPN3 in
affected muscles. Garvey et al. (2002) concluded that the mdm mouse is a
model for tibial muscular dystrophy.

The giant protein titin serves a primary role as a scaffold for
sarcomere assembly; one potential mediator of this process is calpain-3
(CAPN3; 114240). To test the hypothesis that calpain-3 mediates
remodeling during myofibrillogenesis, Kramerova et al. (2004) generated
CAPN3 knockout (C3KO) mice. The mice were atrophic, with small foci of
muscular necrosis. Myogenic cells fused normally in vitro, but lacked
well-organized sarcomeres, as visualized by electron microscopy. Titin
distribution was normal in longitudinal sections from the C3KO mice;
however, electron microscopy of muscle fibers showed misaligned A bands.
In vitro studies revealed that calpain-3 can bind and cleave titin and
that some mutations that are pathogenic in human muscular dystrophy
result in reduced affinity of calpain-3 for titin. The authors suggested
a role for calpain-3 in myofibrillogenesis and sarcomere remodeling.

Huebsch et al. (2005) generated CAPN3 overexpressing transgenic (C3Tg)
and C3KO mice and showed that overexpression of CAPN3 exacerbated mdm
disease, leading to a shorter life span and more severe muscular
dystrophy. However, C3KO/mdm double-mutant mice showed no change in the
progression or severity of disease, indicating that aberrant CAPN3
activity is not a primary mechanism in this disease. The authors
examined the treadmill locomotion of heterozygous +/mdm mice and
detected a significant increase in stride time with a concomitant
increase in stance time. These altered gait parameters were completely
corrected by CAPN3 overexpression in C3Tg/+/mdm mice, suggesting a
CAPN3-dependent role for the N2A domain of TTN in the dynamics of muscle
contraction.

The N2B region of cardiac titin is thought to modulate elasticity of the
titin filament and may be important for hypertrophy signaling and
ischemic stress response through its binding to FHL2 (602633) and
alpha-B crystallin (CRYAB; 123590), respectively. Radke et al. (2007)
deleted the N2B-encoding exon 49 of the titin gene in mice, leaving the
remainder of the gene intact. Mutant mice survived to adulthood and were
fertile. Although mutant hearts were small, they produced normal
ejection volumes because of an increased ejection fraction. Mutant mice
has significantly reduced Fhl2 protein levels, consistent with the
reduced size of mutant hearts. Ultrastructural analysis revealed
increased extension of the remaining spring elements of titin (tandem Ig
segments and the PEVK region), resulting in reduced sarcomere length and
increased passive tension in skinned cardiomyocytes and diastolic
dysfunction. Radke et al. (2007) concluded that the titin N2B region is
dispensable for cardiac development and systolic properties, but it is
important to integrate trophic and elastic functions of the heart.

*FIELD* AV
.0001
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 9
TTN, ARG740LEU

In a patient with hypertrophic cardiomyopathy (CMH9; 613765) and no
mutations in any of the 8 genes associated with this disorder, Satoh et
al. (1999) identified a heterozygous 740G-T transversion in the TTN
gene, resulting in an arg740-to-leu (R740L) substitution. The parents
were deceased, and the few relatives available were unaffected.
Functional expression studies showed that the mutation resulted in
increased titin binding affinity for alpha-actinin (102575). See
188840.0007 for a nearby mutation (A743V) that causes decreased titin
binding affinity to alpha-actinin, resulting in dilated cardiomyopathy
(604145).

.0002
CARDIOMYOPATHY, DILATED, 1G
TTN, 2-BP INS, 43628AT

In a large family with autosomal dominant dilated cardiomyopathy and
linkage to 2q31 (604145), Gerull et al. (2002) found a 2-bp insertion
mutation (43628AT) in exon 326 of the TTN gene, causing a frameshift
that truncated A band titin. The premature stop codon occurred after the
addition of 4 novel amino acid residues. Puzzling was the absence of any
clinically detectable phenotype in skeletal muscle. The 2 exons found to
be affected in dilated cardiomyopathy by Gerull et al. (2002), namely
exons 18 and 326, are both expressed in cardiac and noncardiac muscle
isoforms. The truncated protein of approximately 2 mD was expressed in
skeletal muscle, but Western blot studies with epitope-specific
anti-titin antibodies suggested that the mutant protein was truncated to
a 1.14-mD subfragment by site-specific cleavage. Clinical
characteristics were described by Siu et al. (1999).

.0003
CARDIOMYOPATHY, DILATED, 1G
TTN, TRP930ARG

In a large family with autosomal dominant dilated cardiomyopathy mapping
to 2q31 (Siu et al., 1999; CMD1G, 604145), Gerull et al. (2002) found a
TTN missense mutation, trp930-to-arg (W930R), predicted to disrupt a
highly conserved hydrophobic core sequence of an immunoglobulin fold
located in the Z disc/I band transition zone. In this kindred, reduced
penetrance of the mutation was observed, as was the case also in the
family with the 2-bp insertion mutation (188840.0002).

.0004
TIBIAL MUSCULAR DYSTROPHY, TARDIVE
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2J, INCLUDED
TTN, 11-BP DEL/INS

In 81 Finnish patients with TMD (600334) from 12 unrelated families,
Hackman et al. (2002) found a heterozygous 11-bp deletion/insertion
mutation located at position 293269-293279 in the TTN sequence. The
mutation changed 4 amino acids close to the C-terminal end of the titin
protein but did not cause a frameshift or a stop codon. Each of the 4
amino acids was changed to an amino acid of another charge, and the
overall charge was changed from acidic to basic. The mutation was not
found in 216 Finnish control samples.

In 3 patients with limb-girdle muscular dystrophy type 2J (608807) from
a large consanguineous Finnish family, Hackman et al. (2002) identified
homozygosity for the TTN 11-bp deletion. Other members in the same
family who were heterozygous for the 11-bp deletion manifested the less
severe TMD phenotype.

Using yeast 2-hybrid analysis, Sarparanta et al. (2010) found that titin
containing this mutation failed to interact with myospryn (CMYA5;
612193).

.0005
TIBIAL MUSCULAR DYSTROPHY, TARDIVE
TTN, LEU34315PRO

In a French family in which TMD (600334) was shown to be linked to 2q31,
Hackman et al. (2002) identified a 293357T-C transition in the TTN
sequence, resulting in a leu34315-to-pro change in the last exon.

.0006
TIBIAL MUSCULAR DYSTROPHY, TARDIVE
TTN, 293329T-A

In affected members of a Belgian family with tibial muscular dystrophy
(600334), Van den Bergh et al. (2003) identified a heterozygous
293329T-A change in the Mex6 exon of the TTN gene, resulting in an
ile-to-asn substitution. The family showed incomplete disease
penetrance.

.0007
CARDIOMYOPATHY, DILATED, 1G
TTN, ALA743VAL

In a father and daughter with dilated cardiomyopathy (604145),
Itoh-Satoh et al. (2002) identified a heterozygous C-to-T transition in
the TTN gene, resulting in an ala743-to-val (A743V) substitution. Both
patients had a history of cardiac arrhythmias (premature atrial or
ventricular contraction and atrioventricular conduction block) before
they developed dilated cardiomyopathy or congestive heart failure. The
A743V mutation is located in the alpha-actinin (102575)-binding domain
of titin, and functional studies showed that the mutation decreased the
affinity of titin Z-repeats to alpha-actinin by about 40% compared to
normal. The authors noted that the A743V mutation is located near the
R740L (188840.0001) mutation, which was found in a patient with
hypertrophic cardiomyopathy and results in increased titin-binding
affinity to alpha-actinin.

.0008
CARDIOMYOPATHY, DILATED, 1G
TTN, VAL54MET

In a 19-year-old woman with dilated cardiomyopathy (604145) whose father
had died from the same disorder, Itoh-Satoh et al. (2002) identified a
heterozygous G-to-A transition in the TTN gene, resulting in a
val54-to-met (V54M) substitution at a well-conserved residue in the Z1
domain. The V54M mutation is located in the telethonin (604488)-binding
domain of titin, and functional studies showed that the V54M mutation
decreased the affinity of titin for telethonin to about 60% of normal.

.0009
CARDIOMYOPATHY, DILATED, 1G
TTN, GLN4053TER

In a 45-year-old man with severe heart failure and cardiac dilatation
(604145) without signs of muscle disease, Itoh-Satoh et al. (2002)
identified a heterozygous C-to-T transition in the TTN gene, resulting
in a gln4053-to-ter (Q4053X) nonsense mutation. The mutation occurred in
the N2-B domain of the titin protein, which is known to be expressed
only in cardiac muscle.

.0010
CARDIOMYOPATHY, DILATED, 1G
TTN, SER4465ASN

In a 51-year-old man with dilated cardiomyopathy (604145), Itoh-Satoh et
al. (2002) identified a heterozygous G-to-A transition in the TTN gene,
resulting in a ser4465-to-asn (S4465N) substitution. The mutation
occurred in the N2-B domain of the titin protein, which is known to be
expressed only in cardiac muscle.

.0011
HEREDITARY MYOPATHY WITH EARLY RESPIRATORY FAILURE
TTN, ARG279TRP

In 2 large unrelated Swedish families described by Nicolao et al. (1999)
segregating Edstrom myopathy as an autosomal dominant, also known as
hereditary myopathy with early respiratory failure (HMERF; 603689),
Lange et al. (2005) identified a C-to-T transition in the TTN gene
resulting in an arg-to-trp substitution at codon 279 (R279W) in the
alpha-R1 region of the protein kinase regulatory tail of titin. This
mutation showed complete segregation with the disease in the 2 families.
The mutation was not reported in single-nucleotide polymorphism (SNP)
databases and was not found in 200 normal Swedish controls. An
additional Swedish patient with an identical phenotype but without known
genealogic relation to anyone in the 2 original families was found to
have the same mutation on the same haplotype, indicating a common
ancestry. The R279W mutant protein kinase domain (TK) showed no
difference in calmodulin (114180)-stimulated catalytic activity when
compared with wildtype TK. However, the interaction of TK with NBR1
(166945) was dramatically reduced. In patient biopsies, NBR1 was
localized abnormally diffusely in diseased muscle instead of being M
band- and Z disc-associated, although in HMERF 50% of TK was expected to
be wildtype. This suggested a dominant-negative mechanism of action for
this mutation.

.0012
MYOPATHY, EARLY-ONSET, WITH FATAL CARDIOMYOPATHY
TTN, 1-BP DEL, 291394A

In 3 sibs with early-onset myopathy with fatal cardiomyopathy (611705),
born of consanguineous Moroccan parents, Carmignac et al. (2007)
analyzed genomic DNA and identified a homozygous 1-bp deletion
(291394delA) in exon 380 (Mex3) of the TTN gene, resulting in the loss
of 447 C-terminal residues and disruption of the sarcomeric M line
protein complex. Absence of this part of titin had been expected to be
lethal. The heterozygous parents were clinically unaffected. (The
original article erroneously labeled the mutation 291297delA.)

.0013
MYOPATHY, EARLY-ONSET, WITH FATAL CARDIOMYOPATHY
TTN, 8-BP DEL, NT289385

In 2 sibs, born of consanguineous Sudanese parents, with early-onset
myopathy with fatal cardiomyopathy (611705), Carmignac et al. (2007)
analyzed genomic DNA and identified a homozygous 8-bp deletion
(289385delACCAAGTG) in exon 358 (Mex1) of the TTN gene, resulting in the
loss of 808 C-terminal residues and disruption of the sarcomeric M line
protein complex. Absence of this part of titin had been expected to be
lethal. The heterozygous parents were clinically unaffected.

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limb-girdle muscular dystrophies. J. Biol. Chem. 39: 30304-30315,
2010.

23. Satoh, M.; Takahashi, M.; Sakamoto, T.; Hiroe, M.; Marumo, F.;
Kimura, A.: Structural analysis of the titin gene in hypertrophic
cardiomyopathy: identification of a novel disease gene. Biochem.
Biophys. Res. Commun. 262: 411-417, 1999.

24. Siu, B. L.; Niimura, H.; Osborne, J. A.; Fatkin, D.; MacRae, C.;
Solomon, S.; Benson, D. W.; Seidman, J. G.; Seidman, C. E.: Familial
dilated cardiomyopathy locus maps to chromosome 2q31. Circulation 99:
1022-1026, 1999.

25. Van den Bergh, P. Y. K.; Bouquiaux, O.; Verellen, C.; Marchand,
S.; Richard, I.; Hackman, P.; Udd, B.: Tibial muscular dystrophy
in a Belgian family. Ann. Neurol. 54: 248-251, 2003.

26. Williams, P. M.; Fowler, S. B.; Best, R. B.; Toca-Herrera, J.
L.; Scott, K. A.; Steward, A.; Clarke, J.: Hidden complexity in the
mechanical properties of titin. Nature 422: 446-449, 2003.

27. Xu, X.; Meiler, S. E.; Zhong, T. P.; Mohideen, M.; Crossley, D.
A.; Burggren, W. W.; Fishman, M. C.: Cardiomyopathy in zebrafish
due to mutation in an alternatively spliced exon of titin. Nature
Genet. 30: 205-209, 2002.

28. Zou, P.; Pinotsis, N.; Lange, S.; Song, Y.-H.; Popov, A.; Mavridis,
I.; Mayans, O. M.; Gautel, M.; Wilmanns, M.: Palindromic assembly
of the giant muscle protein titin in the sarcomeric Z-disk. Nature 439:
229-233, 2006.

*FIELD* CN
Marla J. F. O'Neill - updated: 5/8/2013
Marla J. F. O'Neill - updated: 2/23/2012
Patricia A. Hartz - updated: 2/14/2012
George E. Tiller - updated: 4/22/2009
Cassandra L. Kniffin - updated: 12/28/2007
Patricia A. Hartz - updated: 4/13/2007
George E. Tiller - updated: 9/11/2006
Ada Hamosh - updated: 5/1/2006
Ada Hamosh - updated: 2/3/2006
Cassandra L. Kniffin - reorganized: 7/28/2004
Cassandra L. Kniffin - updated: 7/23/2004
Patricia A. Hartz - updated: 3/9/2004
Cassandra L. Kniffin - updated: 12/24/2003
Ada Hamosh - updated: 4/2/2003
Ada Hamosh - updated: 9/20/2002
Victor A. McKusick - updated: 9/17/2002
Victor A. McKusick - updated: 1/18/2002
Victor A. McKusick - updated: 11/18/1999
Victor A. McKusick - updated: 10/30/1997

*FIELD* CD
Victor A. McKusick: 8/20/1991

*FIELD* ED
carol: 08/05/2013
carol: 5/8/2013
carol: 10/4/2012
carol: 2/23/2012
terry: 2/23/2012
mgross: 2/17/2012
terry: 2/14/2012
alopez: 2/3/2012
carol: 2/23/2011
wwang: 5/7/2009
terry: 4/22/2009
terry: 7/3/2008
wwang: 1/15/2008
ckniffin: 12/28/2007
mgross: 4/18/2007
terry: 4/13/2007
alopez: 9/11/2006
alopez: 5/3/2006
terry: 5/1/2006
alopez: 2/6/2006
terry: 2/3/2006
terry: 11/2/2004
carol: 7/28/2004
ckniffin: 7/28/2004
ckniffin: 7/23/2004
alopez: 3/17/2004
mgross: 3/9/2004
carol: 12/29/2003
ckniffin: 12/24/2003
alopez: 4/4/2003
terry: 4/2/2003
cwells: 3/12/2003
terry: 3/7/2003
alopez: 9/20/2002
alopez: 9/18/2002
carol: 9/17/2002
alopez: 2/5/2002
alopez: 1/23/2002
terry: 1/18/2002
mgross: 12/6/1999
terry: 11/18/1999
alopez: 2/10/1999
jenny: 11/5/1997
terry: 10/30/1997
mark: 1/17/1996
carol: 7/9/1995
supermim: 3/16/1992
carol: 9/4/1991
carol: 8/21/1991
carol: 8/20/1991

MIM 600334
*RECORD*
*FIELD* NO
600334
*FIELD* TI
#600334 TIBIAL MUSCULAR DYSTROPHY, TARDIVE
;;TMD;;
TARDIVE TIBIAL MUSCULAR DYSTROPHY;;
read moreUDD MYOPATHY
*FIELD* TX
A number sign (#) is used with this entry because tibial muscular
dystrophy (TMD) is caused by heterozygous mutation in the gene encoding
the giant skeletal muscle protein titin (TTN; 188840).

Homozygous mutation in the titin gene causes the more severe limb-girdle
muscular dystrophy type 2J (LGMD2J; 608807).

CLINICAL FEATURES

Markesbery et al. (1974) reported a late adult-onset, autosomal dominant
form of distal myopathy with onset in the anterior compartment of the
legs rather than in the hands, which is the presenting feature of
Welander myopathy (604454). In addition, they reported the occurrence of
cardiomyopathy. Edstrom et al. (1980) thought that the family of
Markesbery et al. (1974) had a distinct disorder because the affected
members showed cardiomyopathy (which was never found in Welander
myopathy) and had different histopathologic findings (compare Edstrom,
1975 and Markesbery et al., 1977).

Udd (1992) reported a large consanguineous Finnish pedigree with 2
separate muscle disease phenotypes: mild late-onset distal myopathy
inherited in an autosomal dominant pattern and severe limb-girdle
muscular dystrophy (see LGMD2J) inherited in an autosomal recessive
pattern. Segregation analysis showed that the corrected proportion of
affected persons with the severe proximal type was 0.246 and the
proportion of affected persons with the distal myopathy was 0.58. The
findings were compatible with the hypothesis that the severe LGMD
phenotype was the homozygous manifestation of a dominant gene that in
the heterozygous state caused the milder distal myopathy. Udd et al.
(1992), who referred to the distal myopathy as 'tibial muscular
dystrophy,' reported follow-up on the large affected Finnish pedigree.

Partanen et al. (1994) studied a family with very late-onset (fifth or
sixth decade) or asymptomatic hereditary myopathy of the anterior tibial
muscle. The muscles of the upper extremity were spared. The anterior
tibial muscles had a characteristic myopathic alteration with rimmed
vacuoles. Twelve persons, both male and female, were affected, and
male-to-male transmission was demonstrated. Partanen et al. (1994) noted
the similarity of their cases to those of Markesbery et al. (1974) in
that there was late adult onset in the anterior compartment of the legs.
However, Partanen et al. (1994) thought that the patients reported by
Markesbery et al. (1974) had a far wider involvement and earlier onset
of disease.

Partanen et al. (1994) distinguished 6 types of distal myopathy: (1)
Welander myopathy; (2) a late-onset autosomal dominant form with onset
in the anterior compartment of the legs; (3) an early adult-onset
recessive or sporadic form with onset in the anterior compartment of the
legs with vacuolar myopathy on biopsy (Sunohara et al., 1989); (4) an
early adult-onset recessive distal myopathy of the posterior compartment
of the legs (Miyoshi et al., 1986; 254130); (5) an autosomal recessive
vacuolar myopathy sparing the quadriceps (Sadeh et al., 1993; 600737);
and (6) a late-onset autosomal dominant tibial dystrophy as described by
Udd et al. (1991, 1992) and Udd (1992).

Udd et al. (1993) investigated 66 Finnish patients with late adult-onset
tibial muscular dystrophy. Symptoms appeared after the age of 35 years
with reduced ankle dorsiflexion, and progression was slow without marked
disability. Facial muscles, upper extremities, and proximal muscles were
usually spared. Pedigree data suggested autosomal dominant inheritance.
The clinical studies suggested homogeneity in the various families
affected with this rather frequent disorder in Finns.

Van den Bergh et al. (2003) reported a Belgian family with tibial
muscular dystrophy. The proband had onset of gait difficulties in his
late 40s, and clinical examination showed steppage gait and weakness and
atrophy of the anterior compartment muscles of the lower legs without
proximal weakness or sensory loss. CT scan of the lower leg muscles
showed marked atrophy and low density, suggestive of fatty degeneration.
Family investigation revealed that the proband's father, a paternal
uncle, and one of his daughters had mild tibialis anterior weakness and
atrophy, although all were asymptomatic. In affected members of the
family, Van den Bergh et al. (2003) identified a heterozygous mutation
in the Mex6 exon of the titin gene (188840.0006). The authors noted that
the family showed incomplete disease penetrance.

- Pathologic Findings

In 12 affected members of a large Finnish pedigree with distal myopathy,
Udd et al. (1992) found that muscle biopsy did not show vacuolar
degeneration, which was in contrast to most adult-onset distal
myopathies. Histopathologic changes correlating with the muscular
dystrophy were extensive in tibial anterior muscles in patients with
distal myopathy and in all muscles of those family members who had a
severe limb-girdle muscular dystrophy phenotype.

Among 66 Finnish patients with TMD, Udd et al. (1993) found that muscle
biopsies showed nonspecific dystrophic changes in clinically affected
muscles and severe adipose replacement in the anterior tibial muscles.
Asymptomatic muscles had mild myopathic changes only. Vacuolar
degeneration was detected in a minority of patients. Electromyography
showed profound myopathic changes in the anterior tibial muscle, but
extensor brevis muscles were well preserved. Computed tomography or
magnetic resonance imaging of muscles disclosed marked involvement of
tibial extensor muscles and focal patches of fatty degeneration in
various asymptomatic muscles.

In tibial muscular dystrophy, some biopsies showed rimmed vacuoles and
others did not. Udd (1997) concluded that the presence or absence of
rimmed vacuoles was not indicative of heterogeneity because there was
intrafamilial variation and families with or without rimmed vacuoles
were shown to be genealogically linked.

MAPPING

In a Finnish tibial muscular dystrophy family with 11 affected
individuals, Haravuori et al. (1997, 1998) found a region of interest on
2q by a genomewide scan with microsatellite markers. Further analyses
with additional family members and additional families, 1 of whom was
the large Finnish family reported by Udd et al. (1992), yielded a
maximum 2-point lod score of 10.14 at theta = 0.05 with marker D2S364.
Multipoint likelihood calculations assigned the TMD locus to the
proximity of marker D2S324 with a maximum multipoint lod score of 12.4
at theta = 0.0. Haplotype analysis revealed the same core haplotype in
all analyzed families, thus providing evidence for an ancestral mutation
and further restricting the critical chromosomal region to about 1 cM.
The location of the locus was determined to be 2q31 (Udd, 1997;
Haravuori et al., 1998).

De Seze et al. (1998) described a French family with TMD and confirmed
the linkage to 2q31 with a different haplotype for linked markers.

HETEROGENEITY

- Genetic Heterogeneity

Felice et al. (1999) reported a family with autosomal dominant distal
myopathy spanning 4 generations in whom linkage to Nonaka distal
myopathy (605820) on 9p, MPD1 (160500) on 14q, Miyoshi myopathy on 2p13,
and TMD on 2q31 was excluded. Clinical features included onset in the
second to third decade of foot drop, difficulty in stair climbing, and
progressive leg weakness. Some had later involvement of proximal lower
limb muscles and distal upper limb muscles. Laboratory studies showed
increased serum creatine kinase and nonspecific myopathic changes
without rimmed vacuoles.

MOLECULAR GENETICS

Because of the map location of TMD on 2q31, the gene encoding the giant
skeletal muscle protein titin (188840) was a strong positional as well
as functional candidate for the site of causative mutations. Hackman et
al. (2002) demonstrated a heterozygous 11-bp deletion/insertion in the
last exon (exon 363) of the TTN gene (188840.0004) as the cause of TMD
in 81 Finnish patients from 12 unrelated families. One of the families
with the 11-bp deletion was the large Finnish family reported by Udd et
al. (1992). A different mutation in the TTN gene, a missense mutation
that was also located in the last exon (188840.0005), was identified in
an affected French family.

*FIELD* RF
1. de Seze, J.; Udd, B.; Haravuori, H.; Sablonniere, B.; Maurage,
C. A.; Hurtevent, J. F.; Boutry, N.; Stojkovic, T.; Schraen, S.; Petit,
H.; Vermersch, P.: The first European family with tibial muscular
dystrophy outside the Finnish population. Neurology 51: 1746-1748,
1998.

2. Edstrom, L.: Histochemical and histopathological changes in skeletal
muscle in late onset hereditary distal myopathy (Welander). J. Neurol.
Sci. 26: 147-157, 1975.

3. Edstrom, L.; Thornell, L.-E.; Eriksson, A.: A new type of hereditary
distal myopathy with characteristic sarcoplasmic bodies and intermediate
(skeletin) filaments. J. Neurol. Sci. 47: 171-190, 1980.

4. Felice, K. J.; Meredith, C.; Binz, N.; Butler, A.; Jacob, R.; Akkari,
P.; Hallmayer, J.; Laing, N.: Autosomal dominant distal myopathy
not linked to the known distal myopathy loci. Neuromusc. Disord. 9:
59-65, 1999.

5. Hackman, P.; Vihola, A.; Haravuori, H.; Marchand, S.; Sarparanta,
J.; de Seze, J.; Labeit, S.; Witt, C.; Peltonen, L.; Richard, I.;
Udd, B.: Tibial muscular dystrophy is a titinopathy caused by mutations
in TTN, the gene encoding the giant skeletal-muscle protein titin. Am.
J. Hum. Genet. 71: 492-500, 2002.

6. Haravuori, H.; Makela-Bengs, P.; Udd, B.; Partanen, J.; Pulkkinen,
L.; Somer, H.; Peltonen, L.: Assignment of the tibial muscular dystrophy
locus to chromosome 2q31. Am. J. Hum. Genet. 62: 620-626, 1998.

7. Haravuori, H.; Makela-Bengs, P.; Udd, B.; Pulkkinen, L.; Partanen,
J.; Somer, H.; Peltonen, L.: Assignment of the tibial muscular dystrophy
(TMD) locus on chromosome 2q31. (Abstract) Am. J. Hum. Genet. 61
(suppl.): A29 only, 1997.

8. Markesbery, W. R.; Griggs, R. C.; Herr, B.: Distal myopathy--electron
microscopic and histochemical studies. Neurology 27: 727-735, 1977.

9. Markesbery, W. R.; Griggs, R. C.; Leach, R. P.; Lapham, L. W.:
Late onset hereditary distal myopathy. Neurology 24: 127-134, 1974.

10. Miyoshi, K.; Kawai, H.; Isawa, M.; Kusaka, K.; Nishino, H.: Autosomal
recessive distal muscular dystrophy as a new type of progressive muscular
dystrophy: seventeen cases in eight families including an autopsied
case. Brain 109: 31-54, 1986.

11. Partanen, J.; Laulumaa, V.; Paljarvi, L.; Partanen, K.; Naukkarinen,
A.: Late onset foot-drop muscular dystrophy with rimmed vacuoles. J.
Neurol. Sci. 125: 158-167, 1994.

12. Sadeh, M.; Gadoth, N.; Hadar, H.; Ben-David, E.: Vacuolar myopathy
sparing the quadriceps. Brain 116: 217-232, 1993.

13. Sunohara, N.; Nonaka, I.; Kamei, N.; Satoyoshi, E.: Distal myopathy
with rimmed vacuole formation: a follow-up study. Brain 112: 65-83,
1989.

14. Udd, B.: Personal Communication. Vasa, Finland 10/31/1997.

15. Udd, B.: Limb-girdle type muscular dystrophy in a large family
with distal myopathy: homozygous manifestation of a dominant gene? J.
Med. Genet. 29: 383-389, 1992.

16. Udd, B.; Kaarianen, H.; Somer, H.: Muscular dystrophy with separate
clinical phenotypes in a large family. Muscle Nerve 14: 1050-1058,
1991.

17. Udd, B.; Partanen, J.; Halonen, P.; Falck, B.; Hakamies, L.; Heikkila,
H.; Ingo, S.; Kalimo, H.; Kaariainen, H.; Laulumaa, V.; Paljarvi,
L.; Rapola, J.; Reunanen, M.; Sonninen, V.; Somer, H.: Tibial muscular
dystrophy: late adult-onset distal myopathy in 66 Finnish patients. Arch.
Neurol. 50: 604-608, 1993.

18. Udd, B.; Rapola, J.; Nokelainen, P.; Arikawa, E.; Somer, H.:
Nonvacuolar myopathy in a large family with both late adult onset
distal myopathy and severe proximal muscular dystrophy. J. Neurol.
Sci. 113: 214-221, 1992.

19. Van den Bergh, P. Y. K.; Bouquiaux, O.; Verellen, C.; Marchand,
S.; Richard, I.; Hackman, P.; Udd, B.: Tibial muscular dystrophy
in a Belgian family. Ann. Neurol. 54: 248-251, 2003.

*FIELD* CS
INHERITANCE:
Autosomal dominant

MUSCLE, SOFT TISSUE:
Weakness of the muscles in the anterior compartment of the lower leg
(particularly the tibialis anterior muscle);
Atrophy of the muscles in the anterior compartment of the lower leg;
'Steppage' gait;
Reduced ankle dorsiflexion;
Replacement of affected muscle tissue with fatty tissue;
Biopsy shows rimmed vacuoles, central nuclei, and variation in fiber
size;
EMG shows myopathy;
Cardiomyopathy is not a feature

MISCELLANEOUS:
Adult onset (after age 35 years);
Slow progression without marked disability;
Incomplete penetrance;
Allelic disorder to a form of dilated cardiomyopathy (CMD1G, 604145)

MOLECULAR BASIS:
Caused by mutation in the titin gene (TTN, 188840.0004)

*FIELD* CN
Cassandra L. Kniffin - revised: 12/24/2003

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
ckniffin: 12/24/2003

*FIELD* CN
Victor A. McKusick - updated: 9/17/2002
Victor A. McKusick - updated: 6/3/1999
Victor A. McKusick - updated: 5/7/1998
Victor A. McKusick - updated: 11/13/1997
Victor A. McKusick - updated: 10/22/1997

*FIELD* CD
Victor A. McKusick: 1/23/1995

*FIELD* ED
carol: 07/28/2004
ckniffin: 7/20/2004
carol: 12/29/2003
ckniffin: 12/24/2003
alopez: 9/18/2002
carol: 9/17/2002
mgross: 4/5/2001
mgross: 1/24/2000
kayiaros: 7/13/1999
carol: 6/15/1999
jlewis: 6/15/1999
jlewis: 6/14/1999
terry: 6/3/1999
terry: 8/5/1998
terry: 5/7/1998
jenny: 11/18/1997
terry: 11/13/1997
terry: 10/28/1997
jenny: 10/28/1997
jenny: 10/27/1997
terry: 10/22/1997
mimadm: 9/23/1995
carol: 1/31/1995
carol: 1/27/1995
carol: 1/24/1995
carol: 1/23/1995

MIM 603689
*RECORD*
*FIELD* NO
603689
*FIELD* TI
#603689 HEREDITARY MYOPATHY WITH EARLY RESPIRATORY FAILURE; HMERF
;;MYOPATHY, PROXIMAL, WITH EARLY RESPIRATORY MUSCLE INVOLVEMENT; MPRM;;
read moreEDSTROM MYOPATHY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
mutation in the protein kinase domain of titin (188840) can cause
hereditary myopathy with early respiratory failure (HMERF).

CLINICAL FEATURES

Edstrom et al. (1990) described 16 individuals, from 7 families, who had
autosomal dominant, adult-onset myopathy with early respiratory muscle
involvement. All patients showed proximal weakness of the upper and
lower extremities. In many patients, the respiratory muscles, especially
the diaphragm, were involved. Neck flexors were typically affected, and
foot extensor weakness was also present in some patients. The age at
onset of significant symptoms varied from the second to the fifth
decade, with an average age of approximately 35 years. The creatine
kinase (CK) levels were normal or slightly elevated in all cases.
Typical muscle biopsy samples showed, at the light microscopic level,
cytoplasmic bodies that were highly positive for rhodamine-conjugated
phalloidin. Rhodamine-conjugated phalloidin selectively binds to
F-actin. At the ultrastructural level, these bodies were seen to be
composed of thin filaments and dense material related to the Z discs.

MAPPING

In 2 Swedish families with this disorder, Nicolao et al. (1999)
established linkage of the phenotype to the chromosomal region 2q24-q31.
A maximum combined 2-point lod score of 4.87 at a recombination fraction
of 0.0 was obtained with marker D2S1245. Haplotype analysis indicated
that the gene responsible for the disease is likely to be located in the
17-cM region between markers D2S2384 and D2S364. The affected
individuals from these 2 families shared an identical haplotype, which
suggested a common origin.

Xiang et al. (1999) performed linkage analysis in a French family with
similar clinical phenotype and findings on muscle biopsy to those in the
Swedish families reported by Nicolao et al. (1999), and excluded linkage
to the 2q24-q33 region. They conducted a genomewide scan in the French
family using polymorphic microsatellite markers and obtained a maximum
2-point lod score of 2.11 (the highest lod score that could be achieved
in this family) for markers in the 2q21 region. They suggested that
there may be a second locus for this disorder in that region.

MOLECULAR GENETICS

Nicolao et al. (1999) considered the titin gene (TTN; 188840) to be a
strong candidate. Titin, or connectin, is the largest polypeptide known
and forms filaments that span from the Z discs to the M lines. The
entire coding region of the gene (approximately 300 kb) maps within the
candidate region demonstrated by Nicolao et al. (1999) for Edstrom
myopathy.

In the 2 Swedish families described by Nicolao et al. (1999) as well as
in 1 additional Swedish patient with an identical phenotype, Lange et
al. (2005) identified a C-to-T transition resulting in an
arginine-to-tryptophan substitution at codon 279 of the titin gene
(R279W; 188840.0011), which lies within alpha helix R1 (alpha-R1) of the
protein kinase domain. The single patient had no known genealogic
relationship to any of the 2 original families but had the same mutation
on the same haplotype, indicating a common ancestry.

Lange et al. (2005) found no difference in calmodulin
(114180)-stimulated catalytic activity between recombinant R279W mutant
titin kinase domain (TK) and wildtype. Because the R279W mutation in
alpha-R1 results in a drastic change of a surface-exposed basic to a
nonpolar, bulky amino acid in the NBR1 (166945) binding site, Lange et
al. (2005) tested the interaction of TK with NBR1, which was
dramatically reduced in the mutant protein kinase domain. In patient
biopsies, NBR1 was localized abnormally diffusely in diseased muscle
instead of being M band- and Z disc-associated, although in HMERF 50% of
TK was expected to be wildtype. P62 (601530) accumulated in many
diseased muscle fibers of HMERF patients. MURF2 (606469) showed unusual
nuclear localization in centralized nuclei of patient muscle fibers not
observed in peripheral nuclei of normal muscle or in 3 other myopathies
with centralized nuclei (DMD, 310200; tibial muscular dystrophy, 600334;
and myotubular myopathy, 310400). Furthermore, MURF1 (606131), a close
homolog of MURF2, did not show nuclear localization in HMERF patients or
in the other myopathies tested with centralized nuclei.

*FIELD* RF
1. Edstrom, L.; Thornell, L. E.; Albo, J.; Landin, S.; Samuelsson,
M.: Myopathy with respiratory failure and typical myofibrillar lesions. J.
Neurol. Sci. 96: 211-228, 1990.

2. Lange, S.; Xiang, F.; Yakovenko, A.; Vihola, A.; Hackman, P.; Rostkova,
E.; Kristensen, J.; Brandmeier, B.; Franzen, G.; Hedberg, B.; Gunnarsson,
L. G.; Hughes, S. M.; Marchand, S.; Sejersen, T.; Richard, I.; Edstrom,
L.; Ehler, E.; Udd, B.; Gautel, M.: The kinase domain of titin controls
muscle gene expression and protein turnover. Science 308: 1599-1603,
2005.

3. Nicolao, P.; Xiang, F.; Gunnarsson, L.-G.; Giometto, B.; Edstrom,
L.; Anvret, M.; Zhang, Z.: Autosomal dominant myopathy with proximal
weakness and early respiratory muscle involvement maps to chromosome
2q. Am. J. Hum. Genet. 64: 788-792, 1999.

4. Xiang, F.; Nicolao, P.; Chapon, F.; Edstrom, L.; Anvret, M.; Zhang,
Z.: A second locus for autosomal dominant myopathy with proximal
muscle weakness and early respiratory muscle involvement: a likely
chromosomal locus on 2q21. Neuromusc. Disord. 9: 308-312, 1999.

*FIELD* CN
Ada Hamosh - updated: 2/3/2006
Victor A. McKusick - updated: 10/25/1999

*FIELD* CD
Victor A. McKusick: 3/31/1999

*FIELD* ED
terry: 10/12/2010
terry: 7/3/2008
alopez: 2/6/2006
terry: 2/3/2006
mgross: 3/18/2004
carol: 10/25/1999
carol: 3/31/1999

MIM 604145
*RECORD*
*FIELD* NO
604145
*FIELD* TI
#604145 CARDIOMYOPATHY, DILATED, 1G; CMD1G
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreautosomal dominant dilated cardiomyopathy-1G (CMD1G) is caused by
heterozygous mutation in the titin gene (TTN; 188840) on chromosome
2q31.

For a general phenotypic description and a discussion of genetic
heterogeneity of dilated cardiomyopathy (CMD), see CMD1A (115200).

MAPPING

Siu et al. (1999) clinically evaluated 3 generations of a Native
American kindred with autosomal dominant transmission of dilated
cardiomyopathy. Nine surviving affected individuals had early-onset
disease (ventricular chamber dilatation during the teenage years and
congestive heart failure during the third decade of life). The disease
was nonpenetrant in 2 obligate carriers. By linkage analysis, Siu et al.
(1999) identified a novel disease locus at marker D2S1244 on 2q31
(maximum lod = 4.06 at theta = 0.0) between the glucagon gene (138030)
and marker D2S72; they designated this locus CMD1G. Because the massive
gene encoding titin, a cytoskeletal muscle protein, resides in this
disease interval, the authors analyzed sequences encoding 900-amino acid
residues of the cardiac-specific (N2-B) domain of the gene. Although 5
sequence variants were identified, none segregated with the disease in
this family.

MOLECULAR GENETICS

In 2 unrelated families with autosomal dominant dilated cardiomyopathy,
Gerull et al. (2002) identified 2 different heterozygous mutations in
the titin gene (188840.0002; 188840.0003). Both families showed reduced
penetrance and no involvement of noncardiac muscle. The latter was
surprising since exons of TTN that contain the 2 CMD-causing mutations
are both expressed in cardiac and noncardiac muscle isoforms.

In 4 patients with dilated cardiomyopathy, Itoh-Satoh et al. (2002)
identified 4 different mutations in the TTN gene
(188840.0007-188840.0010). Two of the cases were familial.

Herman et al. (2012) used next-generation sequencing to analyze the TTN
gene in 203 individuals with dilated cardiomyopathy, 231 with
hypertrophic cardiomyopathy (CMH), and 249 controls. The frequency of
TTN mutations was significantly higher among individuals with CMD (27%)
than among those with CMH (1%) or controls (3%). In CMD families, TTN
mutations cosegregated with dilated cardiomyopathy, with highly observed
penetrance (greater than 95%) after the age of 40 years. Mutations
associated with CMD were overrepresented in the titin A-band but were
absent from the Z-disc and M-band regions of titin. Overall, rates of
cardiac outcomes were similar in individuals with or without TTN
mutations, but adverse events occurred earlier in male mutation carriers
than in female carriers. Herman et al. (2012) concluded that TTN
truncating mutations are the most common known genetic cause of dilated
cardiomyopathy, occurring in approximately 25% of familial CMD cases and
in 18% of sporadic cases.

*FIELD* RF
1. Gerull, B.; Gramlich, M.; Atherton, J.; McNabb, M.; Trombitas,
K.; Sasse-Klaassen, S.; Seidman, J. G.; Seidman, C.; Granzier, H.;
Labeit, S.; Frenneaux, M.; Thierfelder, L.: Mutations of TTN, encoding
the giant muscle filament titin, cause familial dilated cardiomyopathy. Nature
Genet. 30: 201-204, 2002.

2. Herman, D. S.; Lam, L.; Taylor, M. R. G.; Wang, L.; Teekakirikul,
P.; Christodoulou, D.; Conner, L.; DePalma, S. R.; McDonough, B.;
Sparks, E.; Teodorescu, D. L.; Cirino, A. L.; and 17 others: Truncations
of titin causing dilated cardiomyopathy. New Eng. J. Med. 366: 619-628,
2012.

3. Itoh-Satoh, M.; Hayashi, T.; Nishi, H.; Koga, Y.; Arimura, T.;
Koyanagi, T.; Takahashi, M.; Hohda, S.; Ueda, K.; Nouchi, T.; Hiroe,
M.; Marumo, F.; Imaizumi, T.; Yasunami, M.; Kimura, A.: Titin mutations
as the molecular basis for dilated cardiomyopathy. Biochem. Biophys.
Res. Commun. 291: 385-393, 2002.

4. Siu, B. L.; Niimura, H.; Osborne, J. A.; Fatkin, D.; MacRae, C.;
Solomon, S.; Benson, D. W.; Seidman, J. G.; Seidman, C. E.: Familial
dilated cardiomyopathy locus maps to chromosome 2q31. Circulation 99:
1022-1026, 1999.

*FIELD* CN
Marla J. F. O'Neill - updated: 2/23/2012
Cassandra L. Kniffin - updated: 7/23/2004
Victor A. McKusick - updated: 1/18/2002
Victor A. McKusick - updated: 9/10/1999

*FIELD* CD
Paul Brennan: 8/31/1999

*FIELD* ED
alopez: 05/18/2013
terry: 5/10/2012
carol: 2/23/2012
terry: 2/23/2012
carol: 7/28/2004
ckniffin: 7/23/2004
alopez: 2/5/2002
alopez: 1/23/2002
terry: 1/18/2002
mgross: 9/13/1999
mgross: 9/10/1999
mgross: 8/31/1999

MIM 608807
*RECORD*
*FIELD* NO
608807
*FIELD* TI
#608807 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2J; LGMD2J
*FIELD* TX
A number sign (#) is used with this entry because limb-girdle muscular
read moredystrophy type 2J (LGMD2J) is caused by homozygous mutation in the titin
gene (TTN; 188840). Heterozygous mutation in the titin gene causes
tardive tibial muscular dystrophy (TMD; 600334). Mutation in the titin
gene also causes dilated cardiomyopathy type 1G (CMD1G; 604145).

For a general description and a discussion of genetic heterogeneity of
autosomal recessive limb-girdle muscular dystrophy, see LGMD2A (253600).

CLINICAL FEATURES

Udd et al. (1991, 1992) reported a large consanguineous Finnish pedigree
in which 12 members had mild late-onset distal tibial myopathy (see TMD)
inherited in an autosomal dominant pattern and 8 members had a severe
limb-girdle muscular dystrophy inherited in an autosomal recessive
pattern. Both groups had nonspecific myopathic changes on muscle biopsy
and progressive fatty infiltration of involved muscles. Onset of the
severe LGMD phenotype was in the first to third decades and involved
weakness of all proximal muscles. Severe disability with loss of
ambulation occurred within 20 years (third to sixth decades). There was
no facial muscle involvement or cardiomyopathy. Some patients later
developed distal muscle involvement. Segregation analysis showed that
the corrected proportion of affected persons with the severe proximal
type was 0.246 and the proportion of affected persons with the distal
myopathy was 0.58. The findings were compatible with the hypothesis that
the severe LGMD phenotype was the homozygous manifestation of a dominant
gene that in the heterozygous state caused the milder distal myopathy
(Udd, 1992).

In muscle biopsies from a patient with limb-girdle muscular dystrophy
who was homozygous for a TMD haplotype, Haravuori et al. (2001) found
almost complete loss of calpain-3 (CAPN3; 114240), a ligand of titin.
The authors concluded that the loss of calpain-3 is a secondary
downstream effect of deficiency of the TMD gene protein and results in
phenotypic overlap with LGMD2A, which is caused by mutation in the
calpain-3 gene.

MAPPING

By genomewide scan of the large Finnish family with LGMD and TMD
reported by Udd et al. (1992), Haravuori et al. (1997, 1998) found a
region of interest on 2q. Further analyses with additional family
members and additional families with TMD, yielded a maximum multipoint
lod score of 12.4 with marker D2S324. Haplotype analysis revealed the
same core haplotype in all analyzed families, providing evidence for an
ancestral mutation, further restricting the critical chromosomal region
to about 1 cM, and mapping the disease locus to chromosome 2q31. Three
patients with the more severe LGMD phenotype were homozygous for the
haplotype, whereas those with the milder TMD phenotype were
heterozygous.

MOLECULAR GENETICS

In patients with LGMD2J from the large Finnish family reported by Udd et
al. (1992), Hackman et al. (2002) identified homozygosity for an 11-bp
deletion/insertion in the last exon (exon 363) of the TTN gene
(188840.0004). Family members affected with the milder adult-onset TMD
phenotype were heterozygous for the TTN deletion.

NOMENCLATURE

According to the report of the 105th ENMC workshop, the phenotype of the
homozygous TTN gene mutation is termed 'LGMD2J' (Bushby and Beckmann,
2003).

*FIELD* RF
1. Bushby, K. M.; Beckmann, J. S.: The 105th ENMC sponsored workshop:
pathogenesis in the non-sarcoglycan limb-girdle muscular dystrophies,
Naarden, April 12-14, 2002. Neuromusc. Disord. 13: 80-90, 2003.

2. Hackman, P.; Vihola, A.; Haravuori, H.; Marchand, S.; Sarparanta,
J.; de Seze, J.; Labeit, S.; Witt, C.; Peltonen, L.; Richard, I.;
Udd, B.: Tibial muscular dystrophy is a titinopathy caused by mutations
in TTN, the gene encoding the giant skeletal-muscle protein titin. Am.
J. Hum. Genet. 71: 492-500, 2002.

3. Haravuori, H.; Makela-Bengs, P.; Udd, B.; Partanen, J.; Pulkkinen,
L.; Somer, H.; Peltonen, L.: Assignment of the tibial muscular dystrophy
locus to chromosome 2q31. Am. J. Hum. Genet. 62: 620-626, 1998.

4. Haravuori, H.; Makela-Bengs, P.; Udd, B.; Pulkkinen, L.; Partanen,
J.; Somer, H.; Peltonen, L.: Assignment of the tibial muscular dystrophy
(TMD) locus on chromosome 2q31. (Abstract) Am. J. Hum. Genet. 61
(suppl.): A29 only, 1997.

5. Haravuori, H.; Vihola, A.; Straub, V.; Auranen, M.; Richard, I.;
Marchand, S.; Voit, T.; Labeit, S.; Somer, H.; Peltonen, L.; Beckmann,
J. S.; Udd, B.: Secondary calpain3 deficiency in 2q-linked muscular
dystrophy: titin is the candidate gene. Neurology 56: 869-877, 2001.

6. Udd, B.: Limb-girdle type muscular dystrophy in a large family
with distal myopathy: homozygous manifestation of a dominant gene? J.
Med. Genet. 29: 383-389, 1992.

7. Udd, B.; Kaarianen, H.; Somer, H.: Muscular dystrophy with separate
clinical phenotypes in a large family. Muscle Nerve 14: 1050-1058,
1991.

8. Udd, B.; Rapola, J.; Nokelainen, P.; Arikawa, E.; Somer, H.: Nonvacuolar
myopathy in a large family with both late adult onset distal myopathy
and severe proximal muscular dystrophy. J. Neurol. Sci. 113: 214-221,
1992.

*FIELD* CS
INHERITANCE:
Autosomal recessive

CARDIOVASCULAR:
[Heart];
No cardiomyopathy

MUSCLE, SOFT TISSUE:
Proximal muscle weakness;
Distal muscle weakness, mild;
Severe disability within 20 years of onset;
Loss of ambulation between third and sixth decade;
No facial muscle involvement;
EMG shows myopathic changes;
Muscle biopsy shows dystrophic changes;
Fatty infiltration of affected muscles;
Secondary decrease of calpain-3 (CAPN3, 114240) protein expression
in muscle

LABORATORY ABNORMALITIES:
Normal or increased serum creatine kinase

MISCELLANEOUS:
Childhood-onset;
Heterozygous titin mutation causes the less-severe tardive tibial
muscular dystrophy (600334);
Allelic disorder to a form of dilated cardiomyopathy (CMD1G, 604145)

MOLECULAR BASIS:
Caused by mutation in the titin gene (TTN, 188840.0004)

*FIELD* CD
Cassandra L. Kniffin: 7/23/2004

*FIELD* ED
ckniffin: 07/23/2004

*FIELD* CD
Cassandra L. Kniffin: 7/19/2004

*FIELD* ED
carol: 07/28/2004
ckniffin: 7/23/2004
ckniffin: 7/20/2004

MIM 611705
*RECORD*
*FIELD* NO
611705
*FIELD* TI
#611705 MYOPATHY, EARLY-ONSET, WITH FATAL CARDIOMYOPATHY
;;EOMFC
*FIELD* TX
A number sign (#) is used with this entry because early-onset myopathy
read morewith fatal cardiomyopathy (EOMFC) can be caused by homozygous mutation
in the gene encoding titin (TTN; 188840) on chromosome 2q31.

CLINICAL FEATURES

Carmignac et al. (2007) reported 5 patients from 2 consanguineous
families of Moroccan and Sudanese origin, respectively, with congenital
myopathy and fatal dilated cardiomyopathy. All patients showed delayed
motor development with symmetric, generalized muscle weakness
predominantly of proximal and distal lower limbs. The 3 male sibs of the
Moroccan family showed onset in infancy, whereas the 2 sibs of the
Sudanese family had onset at birth with neonatal hypotonia. Other
features included facial muscle weakness, ptosis, and relative calf
hypertrophy. Progressive dilated cardiomyopathy with rhythm disturbances
developed between ages 5 and 12 years. Death from cardiomyopathy
occurred in all 5 patients; 4 survived into their teenage years.
Skeletal muscle biopsies showed minicore-like lesions with mitochondrial
depletion and sarcomere disorganization, centralized nuclei, and type 1
fiber predominance. Dystrophic changes were more apparent in the second
decade. Cardiac muscle biopsies showed disruption of myocardial
architecture, nuclear hypertrophy, and endomysial fibrosis. All parents
were clinically unaffected.

MOLECULAR GENETICS

By linkage analysis, followed by candidate gene sequencing, Carmignac et
al. (2007) identified 2 different homozygous deletions in the TTN gene
(188840.0012 and 188840.0013, respectively) in affected members of 2
unrelated families with early-onset myopathy and fatal cardiomyopathy.
The deletions resulted in truncation of the C terminus of the protein,
absence of which had been expected to be lethal, and disruption of the
sarcomeric M-line protein complex. The consanguineous parents of each
family were heterozygous for the respective deletions and were
clinically unaffected.

*FIELD* RF
1. Carmignac, V.; Salih, M. A. M.; Quijano-Roy, S.; Marchand, S.;
Al Rayess, M. M.; Mukhtar, M. M.; Urtizberea, J. A.; Labeit, S.; Guicheney,
P.; Leturcq, F.; Gautel, M.; Fardeau, M.; Campbell, K. P.; Richard,
I.; Estournet, B.; Ferreiro, A.: C-terminal titin deletions cause
a novel early-onset myopathy with fatal cardiomyopathy. Ann. Neurol. 61:
340-351, 2007. Note: Erratum: Ann. Neurol. 71: 728 only, 2012.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Face];
Facial muscle weakness;
[Eyes];
Ptosis

CARDIOVASCULAR:
[Heart];
Dilated cardiomyopathy;
Arrhythmia

MUSCLE, SOFT TISSUE:
Delayed motor development;
Muscle weakness, generalized, proximal and distal;
Calf hypertrophy;
Muscle biopsy shows centralized nuclei;
Type 1 fiber predominance;
Minicore-like lesions with mitochondrial depletion and sarcomeric
disorganization;
Disruption of the M-line;
Dystrophic changes occur later

LABORATORY ABNORMALITIES:
Serum creatine kinase may be increased

MISCELLANEOUS:
Muscle involvement shows onset at birth or in infancy;
Cardiac involvement occurs between 5 and 12 years;
Sudden death due to cardiomyopathy

MOLECULAR BASIS:
Caused by mutation in the titin gene (TTN, 188840.0012)

*FIELD* CD
Cassandra L. Kniffin: 12/27/2007

*FIELD* ED
ckniffin: 12/28/2007

*FIELD* CD
Cassandra L. Kniffin: 12/27/2007

*FIELD* ED
alopez: 02/04/2013
carol: 10/4/2012
terry: 4/28/2011
wwang: 1/15/2008
ckniffin: 12/28/2007

MIM 613765
*RECORD*
*FIELD* NO
613765
*FIELD* TI
#613765 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 9; CMH9
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morefamilial hypertrophic cardiomyopathy-9 (CMH9) is caused by heterozygous
mutation in the TTN gene (188840) on chromosome 2q31.

For a phenotypic description and a discussion of genetic heterogeneity
of familial hypertrophic cardiomyopathy (CMH), see CMH1 (192600).

MOLECULAR GENETICS

In 1 of 82 patients with hypertrophic cardiomyopathy who had no mutation
in known disease genes, Satoh et al. (1999) identified a mutation in the
TTN gene (188840.0001) that was not found in more than 500 normal
chromosomes and increased the binding affinity of titin to alpha-actinin
(see 102575) in the yeast 2-hybrid assay.

Herman et al. (2012) used next-generation sequencing to analyze the TTN
gene in 203 individuals with dilated cardiomyopathy (CMD; see CMD1G,
604145), 231 with CMH, and 249 controls. The frequency of TTN mutations
was significantly higher among individuals with CMD (27%) than among
those with CMH (1%) or controls (3%). In the 3 patients with CMH in whom
TTN truncating or splicing mutations were identified, concurrent
analyses revealed a pathogenic mutation in the known CMH genes MYH7
(160760) or MYBPC3 (600958). Herman et al. (2012) suggested that TTN
truncations rarely, if ever, cause hypertrophic cardiomyopathy.

Lopes et al. (2013) analyzed the coding, intronic, and regulatory
regions of 41 cardiovascular genes in 223 unrelated patients with CMH
using high-throughput sequencing technology. They found 219 rare
variants in 142 (63.6%) of the patients: 30 patients (13%) had titin
candidate variants in isolation, 22 (10%) had titin variants only in
association with desmosomal gene candidate variants or ion channel
disease-associated variants, and 171 (77%) carried a TTN candidate
variant in association with sarcomere, Z-disc, or calcium-handling gene
variants. Lopes et al. (2013) noted that titin has been difficult to
sequence and study due to its size, large number of isoforms, and
unsolved tertiary structure. All of the individual variants present in
this cohort occurred with a frequency of less than 0.5% in the 1000
Genomes Project, suggesting that a proportion of them might be, at the
very least, modulators of the phenotype. However, the overall frequency
of variants in the CMH cohort was actually lower than that seen in the
control exome population. Lopes et al. (2013) concluded that further
work on understanding the role of titin in CMH was necessary.

*FIELD* RF
1. Herman, D. S.; Lam, L.; Taylor, M. R. G.; Wang, L.; Teekakirikul,
P.; Christodoulou, D.; Conner, L.; DePalma, S. R.; McDonough, B.;
Sparks, E.; Teodorescu, D. L.; Cirino, A. L.; and 17 others: Truncations
of titin causing dilated cardiomyopathy. New Eng. J. Med. 366: 619-628,
2012.

2. Lopes, L. R.; Zekavati, A.; Syrris, P.; Hubank, M.; Giambartolomei,
C.; Dalageorgou, C.; Jenkins, S.; McKenna, W.; Uk10k Consortium;
Plagnol, V.; Elliott, P. M.: Genetic complexity in hypertrophic cardiomyopathy
revealed by high-throughput sequencing. J. Med. Genet. 50: 228-239,
2013.

3. Satoh, M.; Takahashi, M.; Sakamoto, T.; Hiroe, M.; Marumo, F.;
Kimura, A.: Structural analysis of the titin gene in hypertrophic
cardiomyopathy: identification of a novel disease gene. Biochem.
Biophys. Res. Commun. 262: 411-417, 1999.

*FIELD* CN
Marla J. F. O'Neill - updated: 05/08/2013
Marla J. F. O'Neill - updated: 2/23/2012

*FIELD* CD
Carol A. Bocchini: 2/23/2011

*FIELD* ED
carol: 05/08/2013
carol: 2/23/2012
terry: 2/23/2012
carol: 2/23/2011