Full text data of KRT8
KRT8
(CYK8)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Keratin, type II cytoskeletal 8 (Cytokeratin-8; CK-8; Keratin-8; K8; Type-II keratin Kb8)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Keratin, type II cytoskeletal 8 (Cytokeratin-8; CK-8; Keratin-8; K8; Type-II keratin Kb8)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00418411
IPI00418411 KRT8 protein Heterotetramer of two type I and two type II keratins. Keratin 8 associates with keratin 18, cytoskeletal keratins soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00418411 KRT8 protein Heterotetramer of two type I and two type II keratins. Keratin 8 associates with keratin 18, cytoskeletal keratins soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
P05787
ID K2C8_HUMAN Reviewed; 483 AA.
AC P05787; A8K4H3; B0AZN5; F8VXB4; Q14099; Q14716; Q14717; Q53GJ0;
read moreAC Q6DHW5; Q6GMY0; Q6P4C7; Q96J60;
DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 7.
DT 22-JAN-2014, entry version 172.
DE RecName: Full=Keratin, type II cytoskeletal 8;
DE AltName: Full=Cytokeratin-8;
DE Short=CK-8;
DE AltName: Full=Keratin-8;
DE Short=K8;
DE AltName: Full=Type-II keratin Kb8;
GN Name=KRT8; Synonyms=CYK8;
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 [GENOMIC DNA], AND VARIANT GLY-417.
RX PubMed=1691124; DOI=10.1016/0378-1119(90)90285-Y;
RA Krauss S., Franke W.W.;
RT "Organization and sequence of the human gene encoding cytokeratin 8.";
RL Gene 86:241-249(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1692965;
RA Yamamoto R., Kao L.C., McKnight C.E., Strauss J.F. III;
RT "Cloning and sequence of cDNA for human placental cytokeratin 8.
RT Regulation of the mRNA in trophoblastic cells by cAMP.";
RL Mol. Endocrinol. 4:370-374(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=1705144;
RA Waseem A., Alexander C.M., Steel J.B., Lane E.B.;
RT "Embryonic simple epithelial keratins 8 and 18: chromosomal location
RT emphasizes difference from other keratin pairs.";
RL New Biol. 2:464-478(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PHOSPHORYLATION AT SER-24
RP AND SER-432.
RX PubMed=9054461; DOI=10.1074/jbc.272.11.7556;
RA Ku N.-O., Omary M.B.;
RT "Phosphorylation of human keratin 8 in vivo at conserved head domain
RT serine 23 and at epidermal growth factor-stimulated tail domain serine
RT 431.";
RL J. Biol. Chem. 272:7556-7564(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP CYS-62.
RC TISSUE=Colon, Liver, Lung, and Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-231 (ISOFORM 1).
RX PubMed=2471065;
RA Kulesh D.A., Cecena G., Darmon Y.M., Vasseur M., Oshima R.G.;
RT "Posttranslational regulation of keratins: degradation of mouse and
RT human keratins 18 and 8.";
RL Mol. Cell. Biol. 9:1553-1565(1989).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 205-483 (ISOFORM 1), AND VARIANTS
RP GLY-417 AND ASP-429.
RX PubMed=2434381; DOI=10.1111/j.1432-0436.1986.tb00412.x;
RA Leube R.E., Bosch F.X., Romano V., Zimbelmann R., Hofler H.,
RA Franke W.W.;
RT "Cytokeratin expression in simple epithelia. III. Detection of mRNAs
RT encoding human cytokeratins nos. 8 and 18 in normal and tumor cells by
RT hybridization with cDNA sequences in vitro and in situ.";
RL Differentiation 33:69-85(1986).
RN [12]
RP PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Colon carcinoma;
RX PubMed=9150948; DOI=10.1002/elps.1150180344;
RA Ji H., Reid G.E., Moritz R.L., Eddes J.S., Burgess A.W., Simpson R.J.;
RT "A two-dimensional gel database of human colon carcinoma proteins.";
RL Electrophoresis 18:605-613(1997).
RN [13]
RP GLYCOSYLATION.
RX PubMed=1371281;
RA Chou C.F., Smith A.J., Omary M.B.;
RT "Characterization and dynamics of O-linked glycosylation of human
RT cytokeratin 8 and 18.";
RL J. Biol. Chem. 267:3901-3906(1992).
RN [14]
RP PHOSPHORYLATION AT SER-9 AND SER-24.
RX PubMed=1374067; DOI=10.1083/jcb.117.3.583;
RA Omary M.B., Baxter G.T., Chou C.F., Riopel C.L., Lin W.Y.,
RA Strulovici B.;
RT "PKC epsilon-related kinase associates with and phosphorylates
RT cytokeratin 8 and 18.";
RL J. Cell Biol. 117:583-593(1992).
RN [15]
RP INTERACTION WITH KRT20, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=10973561; DOI=10.1016/S0003-9969(00)00050-9;
RA Barrett A.W., Cort E.M., Patel P., Berkovitz B.K.B.;
RT "An immunohistological study of cytokeratin 20 in human and mammalian
RT oral epithelium.";
RL Arch. Oral Biol. 45:879-887(2000).
RN [16]
RP INTERACTION WITH PNN.
RX PubMed=10809736; DOI=10.1074/jbc.275.20.14910;
RA Shi J., Sugrue S.P.;
RT "Dissection of protein linkage between keratins and pinin, a protein
RT with dual location at desmosome-intermediate filament complex and in
RT the nucleus.";
RL J. Biol. Chem. 275:14910-14915(2000).
RN [17]
RP PHOSPHORYLATION AT SER-74.
RX PubMed=11781324; DOI=10.1074/jbc.M111436200;
RA He T., Stepulak A., Holmstrom T.H., Omary M.B., Eriksson J.E.;
RT "The intermediate filament protein keratin 8 is a novel cytoplasmic
RT substrate for c-Jun N-terminal kinase.";
RL J. Biol. Chem. 277:10767-10774(2002).
RN [18]
RP PHOSPHORYLATION AT SER-74, AND MUTAGENESIS OF LEU-72 AND SER-74.
RX PubMed=11788583; DOI=10.1074/jbc.M107623200;
RA Ku N.O., Azhar S., Omary M.B.;
RT "Keratin 8 phosphorylation by p38 kinase regulates cellular keratin
RT filament reorganization: modulation by a keratin 1-like disease
RT causing mutation.";
RL J. Biol. Chem. 277:10775-10782(2002).
RN [19]
RP INTERACTION WITH TCHP.
RX PubMed=15731013; DOI=10.1242/jcs.01667;
RA Nishizawa M., Izawa I., Inoko A., Hayashi Y., Nagata K., Yokoyama T.,
RA Usukura J., Inagaki M.;
RT "Identification of trichoplein, a novel keratin filament-binding
RT protein.";
RL J. Cell Sci. 118:1081-1090(2005).
RN [20]
RP FUNCTION, SUBUNIT, AND TISSUE SPECIFICITY.
RX PubMed=16000376; DOI=10.1091/mbc.E05-02-0112;
RA Stone M.R., O'Neill A., Catino D., Bloch R.J.;
RT "Specific interaction of the actin-binding domain of dystrophin with
RT intermediate filaments containing keratin 19.";
RL Mol. Biol. Cell 16:4280-4293(2005).
RN [21]
RP INTERACTION WITH HCV CORE PROTEIN.
RX PubMed=15846844; DOI=10.1002/pmic.200401093;
RA Kang S.-M., Shin M.-J., Kim J.-H., Oh J.-W.;
RT "Proteomic profiling of cellular proteins interacting with the
RT hepatitis C virus core protein.";
RL Proteomics 5:2227-2237(2005).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-253 AND SER-330, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [23]
RP INTERACTION WITH KRT20.
RX PubMed=16608857; DOI=10.1074/jbc.M512284200;
RA Zhou Q., Cadrin M., Herrmann H., Chen C.-H., Chalkley R.J.,
RA Burlingame A.L., Omary M.B.;
RT "Keratin 20 serine 13 phosphorylation is a stress and intestinal
RT goblet cell marker.";
RL J. Biol. Chem. 281:16453-16461(2006).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-253 AND SER-258, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21; SER-24; SER-27;
RP SER-34; SER-36; SER-37; SER-43; SER-253; SER-258; SER-400; SER-410;
RP SER-432; SER-475 AND SER-478, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [27]
RP INTERACTION WITH APEX1, MASS SPECTROMETRY, AND SUBCELLULAR LOCATION.
RX PubMed=19188445; DOI=10.1128/MCB.01337-08;
RA Vascotto C., Fantini D., Romanello M., Cesaratto L., Deganuto M.,
RA Leonardi A., Radicella J.P., Kelley M.R., D'Ambrosio C., Scaloni A.,
RA Quadrifoglio F., Tell G.;
RT "APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in
RT the rRNA quality control process.";
RL Mol. Cell. Biol. 29:1834-1854(2009).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-253, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [29]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-117; LYS-207; LYS-295;
RP LYS-325 AND LYS-347, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [30]
RP GLYCOSYLATION.
RX PubMed=20729549; DOI=10.1074/jbc.M109.098996;
RA Srikanth B., Vaidya M.M., Kalraiya R.D.;
RT "O-GlcNAcylation determines the solubility, filament organization, and
RT stability of keratins 8 and 18.";
RL J. Biol. Chem. 285:34062-34071(2010).
RN [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-475 AND SER-478, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [32]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [33]
RP MALONYLATION AT LYS-101.
RX PubMed=21908771; DOI=10.1074/mcp.M111.012658;
RA Peng C., Lu Z., Xie Z., Cheng Z., Chen Y., Tan M., Luo H., Zhang Y.,
RA He W., Yang K., Zwaans B.M., Tishkoff D., Ho L., Lombard D., He T.C.,
RA Dai J., Verdin E., Ye Y., Zhao Y.;
RT "The first identification of lysine malonylation substrates and its
RT regulatory enzyme.";
RL Mol. Cell. Proteomics 10:M111.012658.01-M111.012658.12(2011).
RN [34]
RP INTERACTION WITH GPER1.
RX PubMed=21149639; DOI=10.1124/mol.110.069500;
RA Sanden C., Broselid S., Cornmark L., Andersson K.,
RA Daszkiewicz-Nilsson J., Martensson U.E., Olde B., Leeb-Lundberg L.M.;
RT "G protein-coupled estrogen receptor 1/G protein-coupled receptor 30
RT localizes in the plasma membrane and traffics intracellularly on
RT cytokeratin intermediate filaments.";
RL Mol. Pharmacol. 79:400-410(2011).
RN [35]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-24; SER-34; SER-37;
RP SER-43; SER-253 AND SER-258, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [36]
RP GLYCOSYLATION.
RX PubMed=22967762; DOI=10.1016/j.bbagen.2012.08.024;
RA Drougat L., Olivier-Van Stichelen S., Mortuaire M., Foulquier F.,
RA Lacoste A.S., Michalski J.C., Lefebvre T., Vercoutter-Edouart A.S.;
RT "Characterization of O-GlcNAc cycling and proteomic identification of
RT differentially O-GlcNAcylated proteins during G1/S transition.";
RL Biochim. Biophys. Acta 1820:1839-1848(2012).
RN [37]
RP VARIANTS CIRRH VAL-53; CYS-54 AND CYS-62, AND VARIANT VAL-63.
RX PubMed=12724528; DOI=10.1073/pnas.0936165100;
RA Ku N.-O., Darling J.M., Krams S.M., Esquivel C.O., Keeffe E.B.,
RA Sibley R.K., Lee Y.M., Wright T.L., Omary M.B.;
RT "Keratin 8 and 18 mutations are risk factors for developing liver
RT disease of multiple etiologies.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:6063-6068(2003).
CC -!- FUNCTION: Together with KRT19, helps to link the contractile
CC apparatus to dystrophin at the costameres of striated muscle.
CC -!- SUBUNIT: Heterotetramer of two type I and two type II keratins.
CC KRT8 associates with KRT18. Associates with KRT20. Interacts with
CC HCV core protein and PNN. When associated with KRT19, interacts
CC with DMD. Interacts with TCHP. Interacts with APEX1. Interacts
CC with GPER1.
CC -!- INTERACTION:
CC P13569:CFTR; NbExp=7; IntAct=EBI-297852, EBI-349854;
CC P62993:GRB2; NbExp=3; IntAct=EBI-297852, EBI-401755;
CC Q9Y6K9:IKBKG; NbExp=2; IntAct=EBI-297852, EBI-81279;
CC P05783:KRT18; NbExp=8; IntAct=EBI-297852, EBI-297888;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus, nucleoplasm (By
CC similarity). Nucleus matrix (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P05787-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P05787-2; Sequence=VSP_046000;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Observed in muscle fibers accumulating in the
CC costameres of myoplasm at the sarcolemma membrane in structures
CC that contain dystrophin and spectrin. Expressed in gingival mucosa
CC and hard palate of the oral cavity.
CC -!- PTM: Phosphorylation on serine residues is enhanced during EGF
CC stimulation and mitosis. Ser-74 phosphorylation plays an important
CC role in keratin filament reorganization.
CC -!- PTM: O-glycosylated. O-GlcNAcylation at multiple sites increases
CC solubility, and decreases stability by inducing proteasomal
CC degradation.
CC -!- PTM: O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent
CC manner.
CC -!- DISEASE: Cirrhosis (CIRRH) [MIM:215600]: A liver disease
CC characterized by severe panlobular liver-cell swelling with
CC Mallory body formation, prominent pericellular fibrosis, and
CC marked deposits of copper. Clinical features include abdomen
CC swelling, jaundice and pulmonary hypertension. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: There are two types of cytoskeletal and
CC microfibrillar keratin: I (acidic; 40-55 kDa) and II (neutral to
CC basic; 56-70 kDa).
CC -!- SIMILARITY: Belongs to the intermediate filament family.
CC -!- WEB RESOURCE: Name=Human Intermediate Filament Mutation Database;
CC URL="http://www.interfil.org";
CC -----------------------------------------------------------------------
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DR EMBL; M34482; AAA35763.1; -; Genomic_DNA.
DR EMBL; M34225; AAA35748.1; -; mRNA.
DR EMBL; X74929; CAA52882.1; -; mRNA.
DR EMBL; X74981; CAA52916.1; -; Genomic_DNA.
DR EMBL; U76549; AAB18966.1; -; mRNA.
DR EMBL; AK290938; BAF83627.1; -; mRNA.
DR EMBL; AK310257; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AK315826; BAF98717.1; -; mRNA.
DR EMBL; AK222941; BAD96661.1; -; mRNA.
DR EMBL; AC107016; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471054; EAW96653.1; -; Genomic_DNA.
DR EMBL; BC000654; AAH00654.3; -; mRNA.
DR EMBL; BC063513; AAH63513.2; -; mRNA.
DR EMBL; BC073760; AAH73760.1; -; mRNA.
DR EMBL; BC075839; AAH75839.1; -; mRNA.
DR EMBL; M26512; AAA51542.1; -; mRNA.
DR EMBL; X12882; CAA31376.1; -; mRNA.
DR EMBL; X98614; CAA67203.1; -; mRNA.
DR PIR; A34720; A34720.
DR RefSeq; NP_001243222.1; NM_001256293.1.
DR RefSeq; NP_002264.1; NM_002273.3.
DR UniGene; Hs.533782; -.
DR UniGene; Hs.708445; -.
DR ProteinModelPortal; P05787; -.
DR SMR; P05787; 88-239, 303-397.
DR DIP; DIP-424N; -.
DR IntAct; P05787; 21.
DR MINT; MINT-256526; -.
DR DrugBank; DB00009; Alteplase.
DR DrugBank; DB00029; Anistreplase.
DR DrugBank; DB00015; Reteplase.
DR DrugBank; DB00031; Tenecteplase.
DR PhosphoSite; P05787; -.
DR UniCarbKB; P05787; -.
DR DMDM; 90110027; -.
DR SWISS-2DPAGE; P05787; -.
DR PaxDb; P05787; -.
DR PeptideAtlas; P05787; -.
DR PRIDE; P05787; -.
DR DNASU; 3856; -.
DR Ensembl; ENST00000293308; ENSP00000293308; ENSG00000170421.
DR Ensembl; ENST00000546897; ENSP00000447402; ENSG00000170421.
DR Ensembl; ENST00000552150; ENSP00000449404; ENSG00000170421.
DR Ensembl; ENST00000552551; ENSP00000447566; ENSG00000170421.
DR GeneID; 3856; -.
DR KEGG; hsa:3856; -.
DR UCSC; uc009zmk.1; human.
DR CTD; 3856; -.
DR GeneCards; GC12M053290; -.
DR H-InvDB; HIX0026255; -.
DR H-InvDB; HIX0034365; -.
DR H-InvDB; HIX0168895; -.
DR HGNC; HGNC:6446; KRT8.
DR HPA; CAB000131; -.
DR HPA; CAB001696; -.
DR HPA; HPA049866; -.
DR MIM; 148060; gene.
DR MIM; 215600; phenotype.
DR neXtProt; NX_P05787; -.
DR PharmGKB; PA30234; -.
DR eggNOG; NOG146769; -.
DR HOVERGEN; HBG013015; -.
DR InParanoid; P05787; -.
DR KO; K07605; -.
DR OMA; XRASLEA; -.
DR OrthoDB; EOG7FV3Q8; -.
DR PhylomeDB; P05787; -.
DR SignaLink; P05787; -.
DR GeneWiki; Keratin_8; -.
DR GenomeRNAi; 3856; -.
DR NextBio; 15173; -.
DR PMAP-CutDB; P05787; -.
DR PRO; PR:P05787; -.
DR ArrayExpress; P05787; -.
DR Bgee; P05787; -.
DR Genevestigator; P05787; -.
DR GO; GO:0043034; C:costamere; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0016010; C:dystrophin-associated glycoprotein complex; IEA:Ensembl.
DR GO; GO:0005882; C:intermediate filament; NAS:UniProtKB.
DR GO; GO:0045095; C:keratin filament; IEA:Ensembl.
DR GO; GO:0016363; C:nuclear matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl.
DR GO; GO:0030018; C:Z disc; IEA:Ensembl.
DR GO; GO:0005198; F:structural molecule activity; NAS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:Ensembl.
DR GO; GO:0060706; P:cell differentiation involved in embryonic placenta development; IEA:Ensembl.
DR GO; GO:0007010; P:cytoskeleton organization; NAS:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0051599; P:response to hydrostatic pressure; IEA:Ensembl.
DR GO; GO:0051707; P:response to other organism; IEA:Ensembl.
DR GO; GO:0045214; P:sarcomere organization; IEA:Ensembl.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IEA:Ensembl.
DR InterPro; IPR001664; IF.
DR InterPro; IPR018039; Intermediate_filament_CS.
DR InterPro; IPR003054; Keratin_II.
DR InterPro; IPR009053; Prefoldin.
DR PANTHER; PTHR23239; PTHR23239; 1.
DR Pfam; PF00038; Filament; 1.
DR PRINTS; PR01276; TYPE2KERATIN.
DR SUPFAM; SSF46579; SSF46579; 1.
DR PROSITE; PS00226; IF; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Coiled coil; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Disease mutation; Glycoprotein;
KW Host-virus interaction; Intermediate filament; Keratin; Nucleus;
KW Phosphoprotein; Polymorphism; Reference proteome.
FT CHAIN 1 483 Keratin, type II cytoskeletal 8.
FT /FTId=PRO_0000063740.
FT REGION 1 90 Head.
FT REGION 91 398 Rod.
FT REGION 91 126 Coil 1A.
FT REGION 127 143 Linker 1.
FT REGION 144 235 Coil 1B.
FT REGION 236 259 Linker 12.
FT REGION 260 398 Coil 2.
FT REGION 261 382 Necessary for interaction with PNN.
FT REGION 399 483 Tail.
FT COMPBIAS 9 49 Ser-rich.
FT SITE 342 342 Stutter.
FT MOD_RES 9 9 Phosphoserine; by PKC/PRKCE.
FT MOD_RES 13 13 Phosphoserine (By similarity).
FT MOD_RES 21 21 Phosphoserine.
FT MOD_RES 24 24 Phosphoserine; by PKC/PRKCE.
FT MOD_RES 27 27 Phosphoserine.
FT MOD_RES 34 34 Phosphoserine.
FT MOD_RES 36 36 Phosphoserine.
FT MOD_RES 37 37 Phosphoserine.
FT MOD_RES 43 43 Phosphoserine.
FT MOD_RES 74 74 Phosphoserine; by MAPK.
FT MOD_RES 101 101 N6-malonyllysine.
FT MOD_RES 117 117 N6-acetyllysine.
FT MOD_RES 207 207 N6-acetyllysine.
FT MOD_RES 253 253 Phosphoserine.
FT MOD_RES 258 258 Phosphoserine.
FT MOD_RES 295 295 N6-acetyllysine.
FT MOD_RES 325 325 N6-acetyllysine.
FT MOD_RES 330 330 Phosphoserine.
FT MOD_RES 347 347 N6-acetyllysine.
FT MOD_RES 400 400 Phosphoserine.
FT MOD_RES 410 410 Phosphoserine.
FT MOD_RES 417 417 Phosphoserine (By similarity).
FT MOD_RES 424 424 Phosphoserine (By similarity).
FT MOD_RES 432 432 Phosphoserine; by CaMK2 and MAPK.
FT MOD_RES 475 475 Phosphoserine.
FT MOD_RES 478 478 Phosphoserine.
FT VAR_SEQ 1 1 M -> MNGVSWSQDLQEGISAWFGPPASTPASTM (in
FT isoform 2).
FT /FTId=VSP_046000.
FT VARIANT 53 53 G -> V (in CIRRH; dbSNP:rs61710484).
FT /FTId=VAR_023058.
FT VARIANT 54 54 Y -> C (in CIRRH).
FT /FTId=VAR_023059.
FT VARIANT 62 62 G -> C (in CIRRH; dbSNP:rs11554495).
FT /FTId=VAR_023060.
FT VARIANT 63 63 I -> V (in dbSNP:rs59536457).
FT /FTId=VAR_023061.
FT VARIANT 401 401 R -> W (in dbSNP:rs2277330).
FT /FTId=VAR_049805.
FT VARIANT 417 417 S -> G (in dbSNP:rs1065591).
FT /FTId=VAR_069106.
FT VARIANT 429 429 G -> D (in dbSNP:rs1065648).
FT /FTId=VAR_069107.
FT MUTAGEN 72 72 L->P: Increases phosphorylation.
FT MUTAGEN 74 74 S->A: Generates normal-appearing
FT filaments, that remain stable after
FT okadaic acid treatment.
FT MUTAGEN 74 74 S->D: Generates normal-appearing
FT filaments, that are destabilized by
FT okadaic acid.
FT CONFLICT 56 56 G -> V (in Ref. 5; BAF83627).
FT CONFLICT 77 77 V -> S (in Ref. 2; AAA35748).
FT CONFLICT 201 201 D -> DVD (in Ref. 3; CAA52882).
FT CONFLICT 232 232 I -> L (in Ref. 11; CAA67203).
FT CONFLICT 257 257 D -> E (in Ref. 2; AAA35748).
FT CONFLICT 310 310 M -> I (in Ref. 11; CAA31376).
FT CONFLICT 324 324 L -> F (in Ref. 6; BAD96661).
FT CONFLICT 384 384 L -> M (in Ref. 11; CAA67203).
FT CONFLICT 387 387 E -> D (in Ref. 2; AAA35748).
FT CONFLICT 401 401 R -> P (in Ref. 2; AAA35748).
FT CONFLICT 430 433 LTSP -> SQA (in Ref. 1; AAA35763).
FT CONFLICT 431 431 T -> A (in Ref. 11; CAA67203).
FT CONFLICT 432 432 S -> D (in Ref. 2; AAA35748 and 11;
FT CAA67203/CAA31376).
SQ SEQUENCE 483 AA; 53704 MW; B0BC730B65929D37 CRC64;
MSIRVTQKSY KVSTSGPRAF SSRSYTSGPG SRISSSSFSR VGSSNFRGGL GGGYGGASGM
GGITAVTVNQ SLLSPLVLEV DPNIQAVRTQ EKEQIKTLNN KFASFIDKVR FLEQQNKMLE
TKWSLLQQQK TARSNMDNMF ESYINNLRRQ LETLGQEKLK LEAELGNMQG LVEDFKNKYE
DEINKRTEME NEFVLIKKDV DEAYMNKVEL ESRLEGLTDE INFLRQLYEE EIRELQSQIS
DTSVVLSMDN SRSLDMDSII AEVKAQYEDI ANRSRAEAES MYQIKYEELQ SLAGKHGDDL
RRTKTEISEM NRNISRLQAE IEGLKGQRAS LEAAIADAEQ RGELAIKDAN AKLSELEAAL
QRAKQDMARQ LREYQELMNV KLALDIEIAT YRKLLEGEES RLESGMQNMS IHTKTTSGYA
GGLSSAYGGL TSPGLSYSLG SSFGSGAGSS SFSRTSSSRA VVVKKIETRD GKLVSESSDV
LPK
//
ID K2C8_HUMAN Reviewed; 483 AA.
AC P05787; A8K4H3; B0AZN5; F8VXB4; Q14099; Q14716; Q14717; Q53GJ0;
read moreAC Q6DHW5; Q6GMY0; Q6P4C7; Q96J60;
DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 7.
DT 22-JAN-2014, entry version 172.
DE RecName: Full=Keratin, type II cytoskeletal 8;
DE AltName: Full=Cytokeratin-8;
DE Short=CK-8;
DE AltName: Full=Keratin-8;
DE Short=K8;
DE AltName: Full=Type-II keratin Kb8;
GN Name=KRT8; Synonyms=CYK8;
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 [GENOMIC DNA], AND VARIANT GLY-417.
RX PubMed=1691124; DOI=10.1016/0378-1119(90)90285-Y;
RA Krauss S., Franke W.W.;
RT "Organization and sequence of the human gene encoding cytokeratin 8.";
RL Gene 86:241-249(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1692965;
RA Yamamoto R., Kao L.C., McKnight C.E., Strauss J.F. III;
RT "Cloning and sequence of cDNA for human placental cytokeratin 8.
RT Regulation of the mRNA in trophoblastic cells by cAMP.";
RL Mol. Endocrinol. 4:370-374(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=1705144;
RA Waseem A., Alexander C.M., Steel J.B., Lane E.B.;
RT "Embryonic simple epithelial keratins 8 and 18: chromosomal location
RT emphasizes difference from other keratin pairs.";
RL New Biol. 2:464-478(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PHOSPHORYLATION AT SER-24
RP AND SER-432.
RX PubMed=9054461; DOI=10.1074/jbc.272.11.7556;
RA Ku N.-O., Omary M.B.;
RT "Phosphorylation of human keratin 8 in vivo at conserved head domain
RT serine 23 and at epidermal growth factor-stimulated tail domain serine
RT 431.";
RL J. Biol. Chem. 272:7556-7564(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP CYS-62.
RC TISSUE=Colon, Liver, Lung, and Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-231 (ISOFORM 1).
RX PubMed=2471065;
RA Kulesh D.A., Cecena G., Darmon Y.M., Vasseur M., Oshima R.G.;
RT "Posttranslational regulation of keratins: degradation of mouse and
RT human keratins 18 and 8.";
RL Mol. Cell. Biol. 9:1553-1565(1989).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 205-483 (ISOFORM 1), AND VARIANTS
RP GLY-417 AND ASP-429.
RX PubMed=2434381; DOI=10.1111/j.1432-0436.1986.tb00412.x;
RA Leube R.E., Bosch F.X., Romano V., Zimbelmann R., Hofler H.,
RA Franke W.W.;
RT "Cytokeratin expression in simple epithelia. III. Detection of mRNAs
RT encoding human cytokeratins nos. 8 and 18 in normal and tumor cells by
RT hybridization with cDNA sequences in vitro and in situ.";
RL Differentiation 33:69-85(1986).
RN [12]
RP PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Colon carcinoma;
RX PubMed=9150948; DOI=10.1002/elps.1150180344;
RA Ji H., Reid G.E., Moritz R.L., Eddes J.S., Burgess A.W., Simpson R.J.;
RT "A two-dimensional gel database of human colon carcinoma proteins.";
RL Electrophoresis 18:605-613(1997).
RN [13]
RP GLYCOSYLATION.
RX PubMed=1371281;
RA Chou C.F., Smith A.J., Omary M.B.;
RT "Characterization and dynamics of O-linked glycosylation of human
RT cytokeratin 8 and 18.";
RL J. Biol. Chem. 267:3901-3906(1992).
RN [14]
RP PHOSPHORYLATION AT SER-9 AND SER-24.
RX PubMed=1374067; DOI=10.1083/jcb.117.3.583;
RA Omary M.B., Baxter G.T., Chou C.F., Riopel C.L., Lin W.Y.,
RA Strulovici B.;
RT "PKC epsilon-related kinase associates with and phosphorylates
RT cytokeratin 8 and 18.";
RL J. Cell Biol. 117:583-593(1992).
RN [15]
RP INTERACTION WITH KRT20, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=10973561; DOI=10.1016/S0003-9969(00)00050-9;
RA Barrett A.W., Cort E.M., Patel P., Berkovitz B.K.B.;
RT "An immunohistological study of cytokeratin 20 in human and mammalian
RT oral epithelium.";
RL Arch. Oral Biol. 45:879-887(2000).
RN [16]
RP INTERACTION WITH PNN.
RX PubMed=10809736; DOI=10.1074/jbc.275.20.14910;
RA Shi J., Sugrue S.P.;
RT "Dissection of protein linkage between keratins and pinin, a protein
RT with dual location at desmosome-intermediate filament complex and in
RT the nucleus.";
RL J. Biol. Chem. 275:14910-14915(2000).
RN [17]
RP PHOSPHORYLATION AT SER-74.
RX PubMed=11781324; DOI=10.1074/jbc.M111436200;
RA He T., Stepulak A., Holmstrom T.H., Omary M.B., Eriksson J.E.;
RT "The intermediate filament protein keratin 8 is a novel cytoplasmic
RT substrate for c-Jun N-terminal kinase.";
RL J. Biol. Chem. 277:10767-10774(2002).
RN [18]
RP PHOSPHORYLATION AT SER-74, AND MUTAGENESIS OF LEU-72 AND SER-74.
RX PubMed=11788583; DOI=10.1074/jbc.M107623200;
RA Ku N.O., Azhar S., Omary M.B.;
RT "Keratin 8 phosphorylation by p38 kinase regulates cellular keratin
RT filament reorganization: modulation by a keratin 1-like disease
RT causing mutation.";
RL J. Biol. Chem. 277:10775-10782(2002).
RN [19]
RP INTERACTION WITH TCHP.
RX PubMed=15731013; DOI=10.1242/jcs.01667;
RA Nishizawa M., Izawa I., Inoko A., Hayashi Y., Nagata K., Yokoyama T.,
RA Usukura J., Inagaki M.;
RT "Identification of trichoplein, a novel keratin filament-binding
RT protein.";
RL J. Cell Sci. 118:1081-1090(2005).
RN [20]
RP FUNCTION, SUBUNIT, AND TISSUE SPECIFICITY.
RX PubMed=16000376; DOI=10.1091/mbc.E05-02-0112;
RA Stone M.R., O'Neill A., Catino D., Bloch R.J.;
RT "Specific interaction of the actin-binding domain of dystrophin with
RT intermediate filaments containing keratin 19.";
RL Mol. Biol. Cell 16:4280-4293(2005).
RN [21]
RP INTERACTION WITH HCV CORE PROTEIN.
RX PubMed=15846844; DOI=10.1002/pmic.200401093;
RA Kang S.-M., Shin M.-J., Kim J.-H., Oh J.-W.;
RT "Proteomic profiling of cellular proteins interacting with the
RT hepatitis C virus core protein.";
RL Proteomics 5:2227-2237(2005).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-253 AND SER-330, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [23]
RP INTERACTION WITH KRT20.
RX PubMed=16608857; DOI=10.1074/jbc.M512284200;
RA Zhou Q., Cadrin M., Herrmann H., Chen C.-H., Chalkley R.J.,
RA Burlingame A.L., Omary M.B.;
RT "Keratin 20 serine 13 phosphorylation is a stress and intestinal
RT goblet cell marker.";
RL J. Biol. Chem. 281:16453-16461(2006).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-253 AND SER-258, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21; SER-24; SER-27;
RP SER-34; SER-36; SER-37; SER-43; SER-253; SER-258; SER-400; SER-410;
RP SER-432; SER-475 AND SER-478, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [27]
RP INTERACTION WITH APEX1, MASS SPECTROMETRY, AND SUBCELLULAR LOCATION.
RX PubMed=19188445; DOI=10.1128/MCB.01337-08;
RA Vascotto C., Fantini D., Romanello M., Cesaratto L., Deganuto M.,
RA Leonardi A., Radicella J.P., Kelley M.R., D'Ambrosio C., Scaloni A.,
RA Quadrifoglio F., Tell G.;
RT "APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in
RT the rRNA quality control process.";
RL Mol. Cell. Biol. 29:1834-1854(2009).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-253, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [29]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-117; LYS-207; LYS-295;
RP LYS-325 AND LYS-347, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [30]
RP GLYCOSYLATION.
RX PubMed=20729549; DOI=10.1074/jbc.M109.098996;
RA Srikanth B., Vaidya M.M., Kalraiya R.D.;
RT "O-GlcNAcylation determines the solubility, filament organization, and
RT stability of keratins 8 and 18.";
RL J. Biol. Chem. 285:34062-34071(2010).
RN [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-475 AND SER-478, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [32]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [33]
RP MALONYLATION AT LYS-101.
RX PubMed=21908771; DOI=10.1074/mcp.M111.012658;
RA Peng C., Lu Z., Xie Z., Cheng Z., Chen Y., Tan M., Luo H., Zhang Y.,
RA He W., Yang K., Zwaans B.M., Tishkoff D., Ho L., Lombard D., He T.C.,
RA Dai J., Verdin E., Ye Y., Zhao Y.;
RT "The first identification of lysine malonylation substrates and its
RT regulatory enzyme.";
RL Mol. Cell. Proteomics 10:M111.012658.01-M111.012658.12(2011).
RN [34]
RP INTERACTION WITH GPER1.
RX PubMed=21149639; DOI=10.1124/mol.110.069500;
RA Sanden C., Broselid S., Cornmark L., Andersson K.,
RA Daszkiewicz-Nilsson J., Martensson U.E., Olde B., Leeb-Lundberg L.M.;
RT "G protein-coupled estrogen receptor 1/G protein-coupled receptor 30
RT localizes in the plasma membrane and traffics intracellularly on
RT cytokeratin intermediate filaments.";
RL Mol. Pharmacol. 79:400-410(2011).
RN [35]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-24; SER-34; SER-37;
RP SER-43; SER-253 AND SER-258, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [36]
RP GLYCOSYLATION.
RX PubMed=22967762; DOI=10.1016/j.bbagen.2012.08.024;
RA Drougat L., Olivier-Van Stichelen S., Mortuaire M., Foulquier F.,
RA Lacoste A.S., Michalski J.C., Lefebvre T., Vercoutter-Edouart A.S.;
RT "Characterization of O-GlcNAc cycling and proteomic identification of
RT differentially O-GlcNAcylated proteins during G1/S transition.";
RL Biochim. Biophys. Acta 1820:1839-1848(2012).
RN [37]
RP VARIANTS CIRRH VAL-53; CYS-54 AND CYS-62, AND VARIANT VAL-63.
RX PubMed=12724528; DOI=10.1073/pnas.0936165100;
RA Ku N.-O., Darling J.M., Krams S.M., Esquivel C.O., Keeffe E.B.,
RA Sibley R.K., Lee Y.M., Wright T.L., Omary M.B.;
RT "Keratin 8 and 18 mutations are risk factors for developing liver
RT disease of multiple etiologies.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:6063-6068(2003).
CC -!- FUNCTION: Together with KRT19, helps to link the contractile
CC apparatus to dystrophin at the costameres of striated muscle.
CC -!- SUBUNIT: Heterotetramer of two type I and two type II keratins.
CC KRT8 associates with KRT18. Associates with KRT20. Interacts with
CC HCV core protein and PNN. When associated with KRT19, interacts
CC with DMD. Interacts with TCHP. Interacts with APEX1. Interacts
CC with GPER1.
CC -!- INTERACTION:
CC P13569:CFTR; NbExp=7; IntAct=EBI-297852, EBI-349854;
CC P62993:GRB2; NbExp=3; IntAct=EBI-297852, EBI-401755;
CC Q9Y6K9:IKBKG; NbExp=2; IntAct=EBI-297852, EBI-81279;
CC P05783:KRT18; NbExp=8; IntAct=EBI-297852, EBI-297888;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus, nucleoplasm (By
CC similarity). Nucleus matrix (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P05787-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P05787-2; Sequence=VSP_046000;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Observed in muscle fibers accumulating in the
CC costameres of myoplasm at the sarcolemma membrane in structures
CC that contain dystrophin and spectrin. Expressed in gingival mucosa
CC and hard palate of the oral cavity.
CC -!- PTM: Phosphorylation on serine residues is enhanced during EGF
CC stimulation and mitosis. Ser-74 phosphorylation plays an important
CC role in keratin filament reorganization.
CC -!- PTM: O-glycosylated. O-GlcNAcylation at multiple sites increases
CC solubility, and decreases stability by inducing proteasomal
CC degradation.
CC -!- PTM: O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent
CC manner.
CC -!- DISEASE: Cirrhosis (CIRRH) [MIM:215600]: A liver disease
CC characterized by severe panlobular liver-cell swelling with
CC Mallory body formation, prominent pericellular fibrosis, and
CC marked deposits of copper. Clinical features include abdomen
CC swelling, jaundice and pulmonary hypertension. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: There are two types of cytoskeletal and
CC microfibrillar keratin: I (acidic; 40-55 kDa) and II (neutral to
CC basic; 56-70 kDa).
CC -!- SIMILARITY: Belongs to the intermediate filament family.
CC -!- WEB RESOURCE: Name=Human Intermediate Filament Mutation Database;
CC URL="http://www.interfil.org";
CC -----------------------------------------------------------------------
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DR EMBL; M34482; AAA35763.1; -; Genomic_DNA.
DR EMBL; M34225; AAA35748.1; -; mRNA.
DR EMBL; X74929; CAA52882.1; -; mRNA.
DR EMBL; X74981; CAA52916.1; -; Genomic_DNA.
DR EMBL; U76549; AAB18966.1; -; mRNA.
DR EMBL; AK290938; BAF83627.1; -; mRNA.
DR EMBL; AK310257; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AK315826; BAF98717.1; -; mRNA.
DR EMBL; AK222941; BAD96661.1; -; mRNA.
DR EMBL; AC107016; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471054; EAW96653.1; -; Genomic_DNA.
DR EMBL; BC000654; AAH00654.3; -; mRNA.
DR EMBL; BC063513; AAH63513.2; -; mRNA.
DR EMBL; BC073760; AAH73760.1; -; mRNA.
DR EMBL; BC075839; AAH75839.1; -; mRNA.
DR EMBL; M26512; AAA51542.1; -; mRNA.
DR EMBL; X12882; CAA31376.1; -; mRNA.
DR EMBL; X98614; CAA67203.1; -; mRNA.
DR PIR; A34720; A34720.
DR RefSeq; NP_001243222.1; NM_001256293.1.
DR RefSeq; NP_002264.1; NM_002273.3.
DR UniGene; Hs.533782; -.
DR UniGene; Hs.708445; -.
DR ProteinModelPortal; P05787; -.
DR SMR; P05787; 88-239, 303-397.
DR DIP; DIP-424N; -.
DR IntAct; P05787; 21.
DR MINT; MINT-256526; -.
DR DrugBank; DB00009; Alteplase.
DR DrugBank; DB00029; Anistreplase.
DR DrugBank; DB00015; Reteplase.
DR DrugBank; DB00031; Tenecteplase.
DR PhosphoSite; P05787; -.
DR UniCarbKB; P05787; -.
DR DMDM; 90110027; -.
DR SWISS-2DPAGE; P05787; -.
DR PaxDb; P05787; -.
DR PeptideAtlas; P05787; -.
DR PRIDE; P05787; -.
DR DNASU; 3856; -.
DR Ensembl; ENST00000293308; ENSP00000293308; ENSG00000170421.
DR Ensembl; ENST00000546897; ENSP00000447402; ENSG00000170421.
DR Ensembl; ENST00000552150; ENSP00000449404; ENSG00000170421.
DR Ensembl; ENST00000552551; ENSP00000447566; ENSG00000170421.
DR GeneID; 3856; -.
DR KEGG; hsa:3856; -.
DR UCSC; uc009zmk.1; human.
DR CTD; 3856; -.
DR GeneCards; GC12M053290; -.
DR H-InvDB; HIX0026255; -.
DR H-InvDB; HIX0034365; -.
DR H-InvDB; HIX0168895; -.
DR HGNC; HGNC:6446; KRT8.
DR HPA; CAB000131; -.
DR HPA; CAB001696; -.
DR HPA; HPA049866; -.
DR MIM; 148060; gene.
DR MIM; 215600; phenotype.
DR neXtProt; NX_P05787; -.
DR PharmGKB; PA30234; -.
DR eggNOG; NOG146769; -.
DR HOVERGEN; HBG013015; -.
DR InParanoid; P05787; -.
DR KO; K07605; -.
DR OMA; XRASLEA; -.
DR OrthoDB; EOG7FV3Q8; -.
DR PhylomeDB; P05787; -.
DR SignaLink; P05787; -.
DR GeneWiki; Keratin_8; -.
DR GenomeRNAi; 3856; -.
DR NextBio; 15173; -.
DR PMAP-CutDB; P05787; -.
DR PRO; PR:P05787; -.
DR ArrayExpress; P05787; -.
DR Bgee; P05787; -.
DR Genevestigator; P05787; -.
DR GO; GO:0043034; C:costamere; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0016010; C:dystrophin-associated glycoprotein complex; IEA:Ensembl.
DR GO; GO:0005882; C:intermediate filament; NAS:UniProtKB.
DR GO; GO:0045095; C:keratin filament; IEA:Ensembl.
DR GO; GO:0016363; C:nuclear matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl.
DR GO; GO:0030018; C:Z disc; IEA:Ensembl.
DR GO; GO:0005198; F:structural molecule activity; NAS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:Ensembl.
DR GO; GO:0060706; P:cell differentiation involved in embryonic placenta development; IEA:Ensembl.
DR GO; GO:0007010; P:cytoskeleton organization; NAS:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0051599; P:response to hydrostatic pressure; IEA:Ensembl.
DR GO; GO:0051707; P:response to other organism; IEA:Ensembl.
DR GO; GO:0045214; P:sarcomere organization; IEA:Ensembl.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IEA:Ensembl.
DR InterPro; IPR001664; IF.
DR InterPro; IPR018039; Intermediate_filament_CS.
DR InterPro; IPR003054; Keratin_II.
DR InterPro; IPR009053; Prefoldin.
DR PANTHER; PTHR23239; PTHR23239; 1.
DR Pfam; PF00038; Filament; 1.
DR PRINTS; PR01276; TYPE2KERATIN.
DR SUPFAM; SSF46579; SSF46579; 1.
DR PROSITE; PS00226; IF; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Coiled coil; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Disease mutation; Glycoprotein;
KW Host-virus interaction; Intermediate filament; Keratin; Nucleus;
KW Phosphoprotein; Polymorphism; Reference proteome.
FT CHAIN 1 483 Keratin, type II cytoskeletal 8.
FT /FTId=PRO_0000063740.
FT REGION 1 90 Head.
FT REGION 91 398 Rod.
FT REGION 91 126 Coil 1A.
FT REGION 127 143 Linker 1.
FT REGION 144 235 Coil 1B.
FT REGION 236 259 Linker 12.
FT REGION 260 398 Coil 2.
FT REGION 261 382 Necessary for interaction with PNN.
FT REGION 399 483 Tail.
FT COMPBIAS 9 49 Ser-rich.
FT SITE 342 342 Stutter.
FT MOD_RES 9 9 Phosphoserine; by PKC/PRKCE.
FT MOD_RES 13 13 Phosphoserine (By similarity).
FT MOD_RES 21 21 Phosphoserine.
FT MOD_RES 24 24 Phosphoserine; by PKC/PRKCE.
FT MOD_RES 27 27 Phosphoserine.
FT MOD_RES 34 34 Phosphoserine.
FT MOD_RES 36 36 Phosphoserine.
FT MOD_RES 37 37 Phosphoserine.
FT MOD_RES 43 43 Phosphoserine.
FT MOD_RES 74 74 Phosphoserine; by MAPK.
FT MOD_RES 101 101 N6-malonyllysine.
FT MOD_RES 117 117 N6-acetyllysine.
FT MOD_RES 207 207 N6-acetyllysine.
FT MOD_RES 253 253 Phosphoserine.
FT MOD_RES 258 258 Phosphoserine.
FT MOD_RES 295 295 N6-acetyllysine.
FT MOD_RES 325 325 N6-acetyllysine.
FT MOD_RES 330 330 Phosphoserine.
FT MOD_RES 347 347 N6-acetyllysine.
FT MOD_RES 400 400 Phosphoserine.
FT MOD_RES 410 410 Phosphoserine.
FT MOD_RES 417 417 Phosphoserine (By similarity).
FT MOD_RES 424 424 Phosphoserine (By similarity).
FT MOD_RES 432 432 Phosphoserine; by CaMK2 and MAPK.
FT MOD_RES 475 475 Phosphoserine.
FT MOD_RES 478 478 Phosphoserine.
FT VAR_SEQ 1 1 M -> MNGVSWSQDLQEGISAWFGPPASTPASTM (in
FT isoform 2).
FT /FTId=VSP_046000.
FT VARIANT 53 53 G -> V (in CIRRH; dbSNP:rs61710484).
FT /FTId=VAR_023058.
FT VARIANT 54 54 Y -> C (in CIRRH).
FT /FTId=VAR_023059.
FT VARIANT 62 62 G -> C (in CIRRH; dbSNP:rs11554495).
FT /FTId=VAR_023060.
FT VARIANT 63 63 I -> V (in dbSNP:rs59536457).
FT /FTId=VAR_023061.
FT VARIANT 401 401 R -> W (in dbSNP:rs2277330).
FT /FTId=VAR_049805.
FT VARIANT 417 417 S -> G (in dbSNP:rs1065591).
FT /FTId=VAR_069106.
FT VARIANT 429 429 G -> D (in dbSNP:rs1065648).
FT /FTId=VAR_069107.
FT MUTAGEN 72 72 L->P: Increases phosphorylation.
FT MUTAGEN 74 74 S->A: Generates normal-appearing
FT filaments, that remain stable after
FT okadaic acid treatment.
FT MUTAGEN 74 74 S->D: Generates normal-appearing
FT filaments, that are destabilized by
FT okadaic acid.
FT CONFLICT 56 56 G -> V (in Ref. 5; BAF83627).
FT CONFLICT 77 77 V -> S (in Ref. 2; AAA35748).
FT CONFLICT 201 201 D -> DVD (in Ref. 3; CAA52882).
FT CONFLICT 232 232 I -> L (in Ref. 11; CAA67203).
FT CONFLICT 257 257 D -> E (in Ref. 2; AAA35748).
FT CONFLICT 310 310 M -> I (in Ref. 11; CAA31376).
FT CONFLICT 324 324 L -> F (in Ref. 6; BAD96661).
FT CONFLICT 384 384 L -> M (in Ref. 11; CAA67203).
FT CONFLICT 387 387 E -> D (in Ref. 2; AAA35748).
FT CONFLICT 401 401 R -> P (in Ref. 2; AAA35748).
FT CONFLICT 430 433 LTSP -> SQA (in Ref. 1; AAA35763).
FT CONFLICT 431 431 T -> A (in Ref. 11; CAA67203).
FT CONFLICT 432 432 S -> D (in Ref. 2; AAA35748 and 11;
FT CAA67203/CAA31376).
SQ SEQUENCE 483 AA; 53704 MW; B0BC730B65929D37 CRC64;
MSIRVTQKSY KVSTSGPRAF SSRSYTSGPG SRISSSSFSR VGSSNFRGGL GGGYGGASGM
GGITAVTVNQ SLLSPLVLEV DPNIQAVRTQ EKEQIKTLNN KFASFIDKVR FLEQQNKMLE
TKWSLLQQQK TARSNMDNMF ESYINNLRRQ LETLGQEKLK LEAELGNMQG LVEDFKNKYE
DEINKRTEME NEFVLIKKDV DEAYMNKVEL ESRLEGLTDE INFLRQLYEE EIRELQSQIS
DTSVVLSMDN SRSLDMDSII AEVKAQYEDI ANRSRAEAES MYQIKYEELQ SLAGKHGDDL
RRTKTEISEM NRNISRLQAE IEGLKGQRAS LEAAIADAEQ RGELAIKDAN AKLSELEAAL
QRAKQDMARQ LREYQELMNV KLALDIEIAT YRKLLEGEES RLESGMQNMS IHTKTTSGYA
GGLSSAYGGL TSPGLSYSLG SSFGSGAGSS SFSRTSSSRA VVVKKIETRD GKLVSESSDV
LPK
//
MIM
148060
*RECORD*
*FIELD* NO
148060
*FIELD* TI
*148060 KERATIN 8; KRT8
;;K8;;
CYTOKERATIN 8
*FIELD* TX
CLONING
Keratin 8 is a type II keratin (Moll et al., 1982). Endo A is the mouse
read moreequivalent. Endo B, which is the equivalent of human keratin 18
(148070), a type I keratin, is coexpressed with Endo A; the 2 appear to
be the first intermediate filament (IF) proteins expressed during murine
development (Jackson et al., 1980). Yamamoto et al. (1990) studied a
full-length cDNA for cytokeratin 8 from placenta. They determined the
distribution of cytokeratin 8 mRNA in various fetal tissues and in
placentae of different gestational ages.
Krauss and Franke (1990) cloned cytokeratin 8 from a genomic library.
The 485-amino acid protein deduced from the exon sequences has a
calculated molecular mass of about 53.5 kD. CK8 shows strong homology
with the corresponding bovine, mouse, and Xenopus proteins. The human
and mouse CK8 share about 82% identity in the N-terminal head domain,
95% identity in the alpha helical rod domain, and 67.5% identity in the
C-terminal tail.
GENE FUNCTION
He et al. (2002) presented evidence that soluble depolymerized K8
subunits were phosphorylated on ser73 by c-Jun N-terminal kinase (JNK1;
601158) upon stimulation of the proapoptotic cytokine receptor Fas
(134637) in colon carcinoma cells. K8 was also phosphorylated following
exposure to ultraviolet light. Coimmunoprecipitation studies indicated
that JNK interacted directly with K8, and K8 was able to sequester a
substantial amount of the 54-kD isoform of JNK. The association of JNK
with K8 correlated with the decreased ability of JNK to phosphorylate
endogenous c-Jun (see 165160). He et al. (2002) hypothesized that K8
phosphorylation could regulate JNK signaling and/or keratin dynamics. Ku
et al. (2002) reported the phosphorylation of K8 ser73 by p38
mitogen-activated protein kinase (MAPK14; 600289). p38 MAPK associated
with K8/K18 complexes in transfected baby hamster kidney cells,
phosphorylated K8 on ser73, and bound specifically to K8 in vitro. Ku et
al. (2002) noted that the leu160-to-pro mutation in K1 (139350.0002)
leads to epidermolytic hyperkeratosis (113800). The comparable mutation
in K8 resulted in hyperphosphorylation of K8 due to neophosphorylation
of ser70 in addition to phosphorylation of ser73, and keratin filament
collapse in the presence of okadaic acid, a phosphatase inhibitor.
GENE STRUCTURE
Krauss and Franke (1990) determined that the CK8 gene contains 8 exons
instead of 9 as is found in all other type II cytokeratins due to lack
of intron 5, and the gene spans over 8.8 kb. The 5-prime flanking region
contains a TATA box, 1 SP1 (189906) motif, and an Alu-like sequence in
an orientation opposite that of the CK8 gene. Intron 1 is long (about
2.5 kb) and contains 3 SP1 sites, 1 AP1 (see 165160) site, and another
Alu element in the same orientation as CK8.
MAPPING
Keratins 8 and 18 of simple epithelia differ from the keratins of
stratified epithelia in tissue expression and regulation. Using PCR to
study DNAs from somatic cell hybrids, Waseem et al. (1990) located a
single active gene for keratin 8 on chromosome 12. This chromosome
contains several genes for type II keratins and also the gene for
keratin 18, the type I keratin that is coexpressed with keratin 8. This
location of both members of a keratin pair on a single chromosome is
unique among keratin genes; it is consistent with the hypothesis that
keratins 8 and 18 may be closer to an ancestral gene than the keratins
of more highly differentiated epithelia.
MOLECULAR GENETICS
About 10% of patients who undergo liver transplantation have cryptogenic
liver disease. In animal models, the absence of heteropolymeric keratins
8 and 18 or the presence of mutant keratins in hepatocytes causes or
promotes liver disease. Ku et al. (1997) demonstrated a germline
mutation in keratin 18 (148070.0001) in 1 of 28 patients with
cryptogenic cirrhosis (see 215600). Of 55 patients with cryptogenic
liver disease screened by Ku et al. (2001), 5 unrelated patients had
mutations in the keratin 8 gene that appeared to have predisposed them
to the disease. Three patients had a gly61-to-cys mutation at a highly
conserved glycine (148060.0001), and the other 2 had a tyr53-to-his
mutation (148060.0002). These mutations were not detected in patients
with other forms of liver disease or in randomly selected patients. In
transfected cells, the gly61-to-cys mutation limited keratin filament
reorganization when the cells were exposed to oxidative stress. In
contrast, the tyr53-to-his mutation destabilized keratin filaments when
transfected cells were exposed to heat or okadaic acid stress.
Following up on the observation that KRT8 and KRT18 mutations are found
in patients with cryptogenic cirrhosis, Ku et al. (2003) investigated
the role of keratin mutations in noncryptogenic cirrhosis and the
incidence of keratin mutations in the general population. The results
suggested that K8 and K18 are likely susceptibility genes for developing
both cryptogenic and noncryptogenic forms of liver disease. They studied
314 liver explants of patients who primarily had noncryptogenic
cirrhosis and compared the results with 349 blood bank volunteers. Seven
unique K8/K18 mutations were found in 11 independent patients with
biliary atresia, hepatitis B/C, alcoholism, primary biliary cirrhosis,
and fulminant hepatitis. Seven of the 11 patients had mutations
previously described in patients with cryptogenic cirrhosis: gly61 to
cys (148060.0001), tyr53 to his (148060.0002), and his127 to leu
(148070.0001). Of the 349 blood bank control samples, only 1 contained
the tyr53-to-his mutation and 1 the gly61-to-cys mutation. Livers with
keratin mutations had cytoplasmic filamentous deposits that were less
frequent in livers without the mutations (P = 0.03).
ANIMAL MODEL
Casanova et al. (1999) generated mice expressing the human KRT8 gene,
leading to a moderate increase in the content of keratin in simple
epithelia. These mice displayed progressive exocrine pancreas
alterations, including dysplasia and loss of acinar architecture,
redifferentiation of acinar to ductal cells, inflammation, fibrosis, and
substitution of exocrine by adipose tissue, as well as increased cell
proliferation and apoptosis. The phenotype was very similar to that
reported for transgenic mice expressing a dominant-negative mutant
TGF-beta type II receptor (TGFBR2; 190182). Casanova et al. (1999)
showed that these Tgfbr2 mutant mice also had elevated KRT8/KRT18
levels. The results indicated that simple epithelial keratins play a
relevant role in the regulation of exocrine pancreas homeostasis and
supported the idea that disruption of mechanisms that normally regulate
keratin expression in vivo could be related to inflammatory and
neoplastic pancreatic disorders.
Jaquemar et al. (2003) determined that the lethality seen in genetically
sensitive K8-null mouse embryos is due to disruption of the trophoblast
giant cell layer that normally forms a barrier between the maternal and
embryonic compartments. Massive hemorrhages of maternal blood were found
between the decidua capsularis and the parietal yolk sac. Maternal tumor
necrosis factor (TNF; 191160) and TNF receptor (see 191190) contributed
to the lethality.
*FIELD* AV
.0001
CIRRHOSIS, CRYPTOGENIC
CIRRHOSIS, NONCRYPTOGENIC, SUSCEPTIBILITY TO, INCLUDED
KRT8, GLY61CYS
In 3 of 55 patients with cryptogenic cirrhosis (see 215600), Ku et al.
(2001) found a gly61-to-cys (G61C) missense mutation in the keratin 8
gene.
Ku et al. (2003) found the G61C mutation in a few patients with
noncryptogenic cirrhosis, and concluded that this mutation causes
susceptibility to noncryptogenic cirrhosis.
.0002
CIRRHOSIS, CRYPTOGENIC
KRT8, TYR53HIS
In 2 of 55 patients with cryptogenic cirrhosis (see 215600), Ku et al.
(2001) found a tyr53-to-his (T53H) missense mutation in the KRT8 gene.
*FIELD* RF
1. Casanova, M. L.; Bravo, A.; Ramirez, A.; Morreale de Escobar, G.;
Were, F.; Merlino, G.; Vidal, M.; Jorcano, J. L.: Exocrine pancreatic
disorders in transsgenic (sic) mice expressing human keratin 8. J.
Clin. Invest. 103: 1587-1595, 1999.
2. He, T.; Stepulak, A.; Holmstrom, T. H.; Omary, M. B.; Eriksson,
J. E.: The intermediate filament protein kinase 8 is a novel cytoplasmic
substrate for c-Jun N-terminal kinase. J. Biol. Chem. 277: 10767-10774,
2002.
3. Jackson, B. W.; Grund, C.; Schmid, E.; Burke, K.; Franke, W.; Illmensee,
K.: Formation of cytoskeletal elements during mouse embryogenesis:
intermediate filaments of the cytokeratin type and desmosomes in preimplantation
embryos. Differentiation 17: 161-179, 1980.
4. Jaquemar, D.; Kupriyanov, S.; Wankell, M.; Avis, J.; Benirschke,
K.; Baribault, H.; Oshima, R. G.: Keratin 8 protection of placental
barrier function. J. Cell Biol. 161: 749-756, 2003.
5. Krauss, S.; Franke, W. W.: Organization and sequence of the human
gene encoding cytokeratin 8. Gene 86: 241-249, 1990.
6. Ku, N.-O.; Azhar, S.; Omary, M. B.: Keratin 8 phosphorylation
by p38 kinase regulates cellular keratin filament reorganization:
modulation by a keratin 1-like disease-causing mutation. J. Biol.
Chem. 277: 10775-10782, 2002.
7. Ku, N.-O.; Darling, J. M.; Krams, S. M.; Esquivel, C. O.; Keeffe,
E. B.; Sibley, R. K.; Lee, Y. M.; Wright, T. L.; Omary, M. B.: Keratin
8 and 18 mutations are risk factors for developing liver disease of
multiple etiologies. Proc. Nat. Acad. Sci. 100: 6063-6068, 2003.
8. Ku, N.-O.; Gish, R.; Wright, T. L.; Omary, M. B.: Keratin 8 mutations
in patients with cryptogenic liver disease. New Eng. J. Med. 344:
1580-1587, 2001.
9. Ku, N.-O.; Wright, T. L.; Terrault, N. A.; Gish, R.; Omary, M.
B.: Mutation of human keratin 18 in association with cryptogenic
cirrhosis. J. Clin. Invest. 99: 19-23, 1997.
10. Moll, R.; Franke, W. W.; Schiller, D. L.; Geiger, B.; Krepler,
R.: The catalog of human cytokeratins: patterns of expression in
normal epithelia, tumors and cultured cells. Cell 31: 11-24, 1982.
11. Waseem, A.; Alexander, C. M.; Steel, J. B.; Lane, E. B.: Embryonic
simple epithelial keratins 8 and 18: chromosomal location emphasizes
difference from other keratin pairs. New Biologist 2: 464-478, 1990.
12. Yamamoto, R.; Kao, L.-C.; McKnight, C. E.; Strauss, J. F., III
: Cloning and sequence of cDNA for human placental cytokeratin 8:
regulation of the mRNA in trophoblastic cells by cAMP. Molec. Endocr. 4:
370-374, 1990.
*FIELD* CN
Patricia A. Hartz - updated: 7/23/2003
Victor A. McKusick - updated: 6/19/2003
Victor A. McKusick - updated: 6/25/2001
Victor A. McKusick - updated: 7/14/1999
*FIELD* CD
Victor A. McKusick: 5/16/1989
*FIELD* ED
cwells: 08/06/2003
terry: 7/23/2003
alopez: 6/27/2003
alopez: 6/26/2003
terry: 6/19/2003
mcapotos: 7/6/2001
mcapotos: 6/28/2001
terry: 6/25/2001
jlewis: 7/27/1999
terry: 7/14/1999
mark: 10/16/1996
davew: 7/13/1994
warfield: 4/21/1994
carol: 4/1/1992
supermim: 3/16/1992
carol: 9/30/1991
carol: 8/20/1991
*RECORD*
*FIELD* NO
148060
*FIELD* TI
*148060 KERATIN 8; KRT8
;;K8;;
CYTOKERATIN 8
*FIELD* TX
CLONING
Keratin 8 is a type II keratin (Moll et al., 1982). Endo A is the mouse
read moreequivalent. Endo B, which is the equivalent of human keratin 18
(148070), a type I keratin, is coexpressed with Endo A; the 2 appear to
be the first intermediate filament (IF) proteins expressed during murine
development (Jackson et al., 1980). Yamamoto et al. (1990) studied a
full-length cDNA for cytokeratin 8 from placenta. They determined the
distribution of cytokeratin 8 mRNA in various fetal tissues and in
placentae of different gestational ages.
Krauss and Franke (1990) cloned cytokeratin 8 from a genomic library.
The 485-amino acid protein deduced from the exon sequences has a
calculated molecular mass of about 53.5 kD. CK8 shows strong homology
with the corresponding bovine, mouse, and Xenopus proteins. The human
and mouse CK8 share about 82% identity in the N-terminal head domain,
95% identity in the alpha helical rod domain, and 67.5% identity in the
C-terminal tail.
GENE FUNCTION
He et al. (2002) presented evidence that soluble depolymerized K8
subunits were phosphorylated on ser73 by c-Jun N-terminal kinase (JNK1;
601158) upon stimulation of the proapoptotic cytokine receptor Fas
(134637) in colon carcinoma cells. K8 was also phosphorylated following
exposure to ultraviolet light. Coimmunoprecipitation studies indicated
that JNK interacted directly with K8, and K8 was able to sequester a
substantial amount of the 54-kD isoform of JNK. The association of JNK
with K8 correlated with the decreased ability of JNK to phosphorylate
endogenous c-Jun (see 165160). He et al. (2002) hypothesized that K8
phosphorylation could regulate JNK signaling and/or keratin dynamics. Ku
et al. (2002) reported the phosphorylation of K8 ser73 by p38
mitogen-activated protein kinase (MAPK14; 600289). p38 MAPK associated
with K8/K18 complexes in transfected baby hamster kidney cells,
phosphorylated K8 on ser73, and bound specifically to K8 in vitro. Ku et
al. (2002) noted that the leu160-to-pro mutation in K1 (139350.0002)
leads to epidermolytic hyperkeratosis (113800). The comparable mutation
in K8 resulted in hyperphosphorylation of K8 due to neophosphorylation
of ser70 in addition to phosphorylation of ser73, and keratin filament
collapse in the presence of okadaic acid, a phosphatase inhibitor.
GENE STRUCTURE
Krauss and Franke (1990) determined that the CK8 gene contains 8 exons
instead of 9 as is found in all other type II cytokeratins due to lack
of intron 5, and the gene spans over 8.8 kb. The 5-prime flanking region
contains a TATA box, 1 SP1 (189906) motif, and an Alu-like sequence in
an orientation opposite that of the CK8 gene. Intron 1 is long (about
2.5 kb) and contains 3 SP1 sites, 1 AP1 (see 165160) site, and another
Alu element in the same orientation as CK8.
MAPPING
Keratins 8 and 18 of simple epithelia differ from the keratins of
stratified epithelia in tissue expression and regulation. Using PCR to
study DNAs from somatic cell hybrids, Waseem et al. (1990) located a
single active gene for keratin 8 on chromosome 12. This chromosome
contains several genes for type II keratins and also the gene for
keratin 18, the type I keratin that is coexpressed with keratin 8. This
location of both members of a keratin pair on a single chromosome is
unique among keratin genes; it is consistent with the hypothesis that
keratins 8 and 18 may be closer to an ancestral gene than the keratins
of more highly differentiated epithelia.
MOLECULAR GENETICS
About 10% of patients who undergo liver transplantation have cryptogenic
liver disease. In animal models, the absence of heteropolymeric keratins
8 and 18 or the presence of mutant keratins in hepatocytes causes or
promotes liver disease. Ku et al. (1997) demonstrated a germline
mutation in keratin 18 (148070.0001) in 1 of 28 patients with
cryptogenic cirrhosis (see 215600). Of 55 patients with cryptogenic
liver disease screened by Ku et al. (2001), 5 unrelated patients had
mutations in the keratin 8 gene that appeared to have predisposed them
to the disease. Three patients had a gly61-to-cys mutation at a highly
conserved glycine (148060.0001), and the other 2 had a tyr53-to-his
mutation (148060.0002). These mutations were not detected in patients
with other forms of liver disease or in randomly selected patients. In
transfected cells, the gly61-to-cys mutation limited keratin filament
reorganization when the cells were exposed to oxidative stress. In
contrast, the tyr53-to-his mutation destabilized keratin filaments when
transfected cells were exposed to heat or okadaic acid stress.
Following up on the observation that KRT8 and KRT18 mutations are found
in patients with cryptogenic cirrhosis, Ku et al. (2003) investigated
the role of keratin mutations in noncryptogenic cirrhosis and the
incidence of keratin mutations in the general population. The results
suggested that K8 and K18 are likely susceptibility genes for developing
both cryptogenic and noncryptogenic forms of liver disease. They studied
314 liver explants of patients who primarily had noncryptogenic
cirrhosis and compared the results with 349 blood bank volunteers. Seven
unique K8/K18 mutations were found in 11 independent patients with
biliary atresia, hepatitis B/C, alcoholism, primary biliary cirrhosis,
and fulminant hepatitis. Seven of the 11 patients had mutations
previously described in patients with cryptogenic cirrhosis: gly61 to
cys (148060.0001), tyr53 to his (148060.0002), and his127 to leu
(148070.0001). Of the 349 blood bank control samples, only 1 contained
the tyr53-to-his mutation and 1 the gly61-to-cys mutation. Livers with
keratin mutations had cytoplasmic filamentous deposits that were less
frequent in livers without the mutations (P = 0.03).
ANIMAL MODEL
Casanova et al. (1999) generated mice expressing the human KRT8 gene,
leading to a moderate increase in the content of keratin in simple
epithelia. These mice displayed progressive exocrine pancreas
alterations, including dysplasia and loss of acinar architecture,
redifferentiation of acinar to ductal cells, inflammation, fibrosis, and
substitution of exocrine by adipose tissue, as well as increased cell
proliferation and apoptosis. The phenotype was very similar to that
reported for transgenic mice expressing a dominant-negative mutant
TGF-beta type II receptor (TGFBR2; 190182). Casanova et al. (1999)
showed that these Tgfbr2 mutant mice also had elevated KRT8/KRT18
levels. The results indicated that simple epithelial keratins play a
relevant role in the regulation of exocrine pancreas homeostasis and
supported the idea that disruption of mechanisms that normally regulate
keratin expression in vivo could be related to inflammatory and
neoplastic pancreatic disorders.
Jaquemar et al. (2003) determined that the lethality seen in genetically
sensitive K8-null mouse embryos is due to disruption of the trophoblast
giant cell layer that normally forms a barrier between the maternal and
embryonic compartments. Massive hemorrhages of maternal blood were found
between the decidua capsularis and the parietal yolk sac. Maternal tumor
necrosis factor (TNF; 191160) and TNF receptor (see 191190) contributed
to the lethality.
*FIELD* AV
.0001
CIRRHOSIS, CRYPTOGENIC
CIRRHOSIS, NONCRYPTOGENIC, SUSCEPTIBILITY TO, INCLUDED
KRT8, GLY61CYS
In 3 of 55 patients with cryptogenic cirrhosis (see 215600), Ku et al.
(2001) found a gly61-to-cys (G61C) missense mutation in the keratin 8
gene.
Ku et al. (2003) found the G61C mutation in a few patients with
noncryptogenic cirrhosis, and concluded that this mutation causes
susceptibility to noncryptogenic cirrhosis.
.0002
CIRRHOSIS, CRYPTOGENIC
KRT8, TYR53HIS
In 2 of 55 patients with cryptogenic cirrhosis (see 215600), Ku et al.
(2001) found a tyr53-to-his (T53H) missense mutation in the KRT8 gene.
*FIELD* RF
1. Casanova, M. L.; Bravo, A.; Ramirez, A.; Morreale de Escobar, G.;
Were, F.; Merlino, G.; Vidal, M.; Jorcano, J. L.: Exocrine pancreatic
disorders in transsgenic (sic) mice expressing human keratin 8. J.
Clin. Invest. 103: 1587-1595, 1999.
2. He, T.; Stepulak, A.; Holmstrom, T. H.; Omary, M. B.; Eriksson,
J. E.: The intermediate filament protein kinase 8 is a novel cytoplasmic
substrate for c-Jun N-terminal kinase. J. Biol. Chem. 277: 10767-10774,
2002.
3. Jackson, B. W.; Grund, C.; Schmid, E.; Burke, K.; Franke, W.; Illmensee,
K.: Formation of cytoskeletal elements during mouse embryogenesis:
intermediate filaments of the cytokeratin type and desmosomes in preimplantation
embryos. Differentiation 17: 161-179, 1980.
4. Jaquemar, D.; Kupriyanov, S.; Wankell, M.; Avis, J.; Benirschke,
K.; Baribault, H.; Oshima, R. G.: Keratin 8 protection of placental
barrier function. J. Cell Biol. 161: 749-756, 2003.
5. Krauss, S.; Franke, W. W.: Organization and sequence of the human
gene encoding cytokeratin 8. Gene 86: 241-249, 1990.
6. Ku, N.-O.; Azhar, S.; Omary, M. B.: Keratin 8 phosphorylation
by p38 kinase regulates cellular keratin filament reorganization:
modulation by a keratin 1-like disease-causing mutation. J. Biol.
Chem. 277: 10775-10782, 2002.
7. Ku, N.-O.; Darling, J. M.; Krams, S. M.; Esquivel, C. O.; Keeffe,
E. B.; Sibley, R. K.; Lee, Y. M.; Wright, T. L.; Omary, M. B.: Keratin
8 and 18 mutations are risk factors for developing liver disease of
multiple etiologies. Proc. Nat. Acad. Sci. 100: 6063-6068, 2003.
8. Ku, N.-O.; Gish, R.; Wright, T. L.; Omary, M. B.: Keratin 8 mutations
in patients with cryptogenic liver disease. New Eng. J. Med. 344:
1580-1587, 2001.
9. Ku, N.-O.; Wright, T. L.; Terrault, N. A.; Gish, R.; Omary, M.
B.: Mutation of human keratin 18 in association with cryptogenic
cirrhosis. J. Clin. Invest. 99: 19-23, 1997.
10. Moll, R.; Franke, W. W.; Schiller, D. L.; Geiger, B.; Krepler,
R.: The catalog of human cytokeratins: patterns of expression in
normal epithelia, tumors and cultured cells. Cell 31: 11-24, 1982.
11. Waseem, A.; Alexander, C. M.; Steel, J. B.; Lane, E. B.: Embryonic
simple epithelial keratins 8 and 18: chromosomal location emphasizes
difference from other keratin pairs. New Biologist 2: 464-478, 1990.
12. Yamamoto, R.; Kao, L.-C.; McKnight, C. E.; Strauss, J. F., III
: Cloning and sequence of cDNA for human placental cytokeratin 8:
regulation of the mRNA in trophoblastic cells by cAMP. Molec. Endocr. 4:
370-374, 1990.
*FIELD* CN
Patricia A. Hartz - updated: 7/23/2003
Victor A. McKusick - updated: 6/19/2003
Victor A. McKusick - updated: 6/25/2001
Victor A. McKusick - updated: 7/14/1999
*FIELD* CD
Victor A. McKusick: 5/16/1989
*FIELD* ED
cwells: 08/06/2003
terry: 7/23/2003
alopez: 6/27/2003
alopez: 6/26/2003
terry: 6/19/2003
mcapotos: 7/6/2001
mcapotos: 6/28/2001
terry: 6/25/2001
jlewis: 7/27/1999
terry: 7/14/1999
mark: 10/16/1996
davew: 7/13/1994
warfield: 4/21/1994
carol: 4/1/1992
supermim: 3/16/1992
carol: 9/30/1991
carol: 8/20/1991
MIM
215600
*RECORD*
*FIELD* NO
215600
*FIELD* TI
#215600 CIRRHOSIS, FAMILIAL
CIRRHOSIS, FAMILIAL, WITH PULMONARY HYPERTENSION, INCLUDED;;
read moreINDIAN CHILDHOOD CIRRHOSIS, INCLUDED; ICC, INCLUDED;;
SEN SYNDROME, INCLUDED;;
COPPER-OVERLOAD CIRRHOSIS, INCLUDED;;
ENDEMIC TYROLEAN INFANTILE CIRRHOSIS, INCLUDED; ETIC, INCLUDED;;
COPPER TOXICOSIS, IDIOPATHIC, INCLUDED; ICT, INCLUDED;;
CIRRHOSIS, CRYPTOGENIC, INCLUDED;;
CIRRHOSIS, NONCRYPTOGENIC, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of a clear genetic
heterogeneity and demonstration of specific genetic causes in a number
of instances. These include mutations of keratin 8 (KRT8; 148060) and
keratin 18 (KRT18; 148070), which cause cryptogenic cirrhosis as well as
susceptibility to noncryptogenic cirrhosis.
Aside from Wilson disease (277900), type IV glycogen storage disease
(232500), and galactosemia (230400), which are well-known causes of
familial cirrhosis, families with multiple affected sibs and normal
parents have been observed (Iber and Maddrey, 1965). The group is
probably heterogeneous and in some instances nongenetic factors may be
responsible for the familial aggregation. Iber and Maddrey (1965)
reviewed 13 reported families and 8 of their own, each with 2 or more
affected members. They pointed out that with 1 exception the multiple
cases were in the same generation. Within a given family, age of onset,
clinical course, and biopsy findings were very similar, but there were
wide differences between families. Baber (1956) described cases of
congenital cirrhosis with generalized amino aciduria. Some of these
patients may be examples of Wilson disease. Others may have tyrosinemia
(Zetterstrom, 1963; Gentz et al., 1965). See tyrosinemia (276700). In
India, so-called Indian childhood cirrhosis (Sen syndrome) affects
multiple sibs (Chaudhuri and Chaudhuri, 1965). The disorder usually has
its onset between ages 6 and 18 months and is said to be several times
more frequent in males than in females; familial cases are frequent
(Srivastava, 1956). Lefkowitch et al. (1982) described 4 white American
sibs who died between ages 4.5 and 6 years of cirrhosis. Progressive
lethargy, abdominal swelling, jaundice, and fever developed 4 to 7
months before death. The liver histopathology closely resembled that of
the childhood cirrhosis of Asiatic Indians and included severe
panlobular liver-cell swelling with Mallory body formation, prominent
pericellular fibrosis, 'micro-micronodular' cirrhosis, and marked
deposits of copper and copper-binding protein. Hepatic copper levels
were as much as 40 times normal. The parents were apparently not
related. The father was adopted. The mother, of Scottish and Irish
extraction, had a single sib, a brother who died at the age of 10 years
of cirrhosis. Copper-overload is a feature of the Indian childhood
cirrhosis also. Before the report by Lefkowitch et al. (1982), the
clinical syndrome had been described only in children in India,
Pakistan, Sri Lanka, and Burma (Mowat, 1979) and rarely in immigrants to
Britain from India (Tanner et al., 1978). The family history is said to
be positive in about 30% of cases. Although one might suspect (in view
of the population distribution) autosomal recessive inheritance with an
occult selectively advantageous polymorphism in heterozygotes, no formal
proof is available.
Kalra et al. (1982) studied the families of 220 cases of Indian
childhood cirrhosis and 70 families of age-matched controls. The
hypotheses of autosomal recessive, partial sex-linkage, and doubly
recessive inheritance were found untenable. Multifactorial inheritance
was found more plausible. In a review of the subject, Kumar (1984)
concluded that multifactorial inheritance is likely. Gahl et al. (1988)
pointed out that the use of brass cooking utensils in Indian families
with ICC suggests an environmental source of copper toxicity; however,
the 25% frequency of familial disease points to a genetic basis as well.
Gahl et al. (1988) studied a 2-year-old boy with features of ICC whose
parents were third cousins of European descent. He was normal at birth
but had poor growth in infancy. At 18 months he developed nephrogenic
diabetes insipidus. At 21 months liver enzymes were elevated and biopsy
showed mild fibrosis and electron-dense granules, which electron probe
analysis showed to contain sulfur and copper. By 29 months progressive
liver failure and advanced micronodular cirrhosis with occasional
Mallory bodies were found. The remaining hepatocytes stained strongly
with rhodamine (for copper) and with orcein (for copper-binding
proteins). The patient died at 32 months of an esophageal variceal
bleed. The patient's disease was manifest in cultured fibroblasts. This
may represent a lysosomal storage disorder. Yet another cause of
congenital cirrhosis is alpha-1-antitrypsin deficiency (613490).
Familial aggregation of chronic active hepatitis due to hepatitis B
virus is discussed elsewhere (118900). The coincidence of liver disease
and 'primary' pulmonary hypertension was indicated by 2 brothers in a
family originally reported by Maddrey and Iber (1964), according to
follow-up information from Summer and Herlong (1982); 3 brothers, 2 of
them identical twins, were by then affected.
Muller et al. (1996) described 138 cases of endemic Tyrolean infantile
cirrhosis (ETIC) which was clinically and pathologically
indistinguishable from Indian childhood cirrhosis (ICC) and idiopathic
copper toxicosis (ICT) (Scheinberg and Sternlieb, 1996). It also
resembled the early-onset form of Wilson disease. Although ETIC, ICC,
and ICT require copper-enriched diets to become manifest (Tanner et al.,
1983), it was thought that these disorders might represent allelic
variants of Wilson disease. ETIC, like Wilson disease, shows autosomal
recessive inheritance. In contrast to the 30 isolated cases described
worldwide, the high frequency of ETIC in the Tyrol (Muller et al., 1996)
suggested a founder effect. Wijmenga et al. (1998) published a pedigree
with 11 affected children in 6 sibships, all of consanguineous parents
and all with both parents tracing back to a common ancestral couple 10
generations ago. The lethality of the disease meant that no living
children were available, but 8 pairs of parents were identified with at
least 1 ETIC child. Wijmenga et al. (1998) studied the possible role of
the ATP7B gene, mutant in Wilson disease, in ETIC by investigating
association and haplotype sharing in obligate gene carriers. Haplotypes
in ETIC carriers did not demonstrate sharing and the association studies
did not detect linkage disequilibrium between ETIC and the individual
markers at 13q14.3 where the ATP7B gene maps.
Muller et al. (1999) encountered 8 cases of infantile liver cirrhosis in
5 families in Emsland, a circumscribed and predominantly rural area of
Northern Germany; ICT was definitely proven in 2 cases. Clinical
presentation and liver pathology in 6 additional cases were consistent
with the diagnosis of ICT. Pedigrees of affected families revealed
complex relationships with occasional consanguinity of parents,
suggesting autosomal recessive inheritance. The households were served
by private wells with water of low pH flowing through copper pipes,
suggesting the possibility of increased alimentary copper exposure.
These findings supported an earlier conclusion that ICT develops when an
infant with a genetic predisposition is exposed to a copper-enriched
diet.
Pulmonary hypertension can develop as a complication of portal
hypertension (Krowka, 1993). Hadengue et al. (1991) suggested that the
pulmonary endothelial damage in this hepatopulmonary syndrome may be
caused by nonmetabolized substances in the portal blood that reach the
pulmonary vasculature through portal systemic shunting.
Patel and Parekh (1997) reported that parents and social workers
observed an absence of rigor mortis for a minimum of 12 hours to a
maximum of 30 hours postmortem in 37 children who died of ICC between
the ages of 10 months and 2 years; the authors observed absence of rigor
mortis for 22 to 36 hours after death in 5 hospitalized patients.
Children who died from other causes developed body stiffness within 4 to
6 hours. Patel and Parekh (1997) noted that the absence of rigor mortis
had not been mentioned in previous studies of ICC and postulated that
excess glycogen in the muscles of these patients would facilitate
postmortem ATP resynthesis and so delay the development of rigor.
*FIELD* SA
Altman et al. (1979); Kocak and Ozsoylu (1979); Miller (1967)
*FIELD* RF
1. Altman, A. R.; Gottfried, E. B.; Paronetto, F.; Lieber, C. S.:
Idiopathic familial cirrhosis and stenosis in adults. Gastroenterology 77:
1211-1216, 1979.
2. Baber, M. D.: Case of congenital cirrhosis of the liver with renal
tubular defects akin to those in the Fanconi syndrome. Arch. Dis.
Child. 31: 335-339, 1956.
3. Chaudhuri, A.; Chaudhuri, K. C.: The karyotype in infantile cirrhosis
of the liver (Sen's syndrome). Indian J. Pediat. 32: 209-218, 1965.
4. Gahl, W.; Adamson, M.; Goodman, Z.; Reiner, B.; Olson, J.; Oliver,
C.; Plotnick, L.: Hepatic copper storage resembling Indian childhood
cirrhosis (ICC) in a non-Indian boy--a genetic disease. (Abstract) Am.
J. Hum. Genet. 43: A7 only, 1988.
5. Gentz, J.; Jagenburg, R.; Zetterstrom, R.: Tyrosinemia: an inborn
error of tyrosine metabolism with cirrhosis of the liver and multiple
renal tubular defects. J. Pediat. 66: 670-696, 1965.
6. Hadengue, A.; Benhayoun, M. K.; Lebrec, D.; Benhamou, J. P.: Pulmonary
hypertension complicating portal hypertension: prevalence and relation
to splanchnic hemodynamics. Gastroenterology 100: 520-528, 1991.
7. Iber, F. L.; Maddrey, W. C.: Familial hepatic diseases with cirrhosis
or without portal hypertension. Prog. Liver Dis. 2: 290-302, 1965.
8. Kalra, V.; Roy, S.; Ghai, O. P.; Jain, J. P.: Indian childhood
cirrhosis--a heritable disease. Hum. Hered. 32: 170-175, 1982.
9. Kocak, N.; Ozsoylu, S.: Familial cirrhosis. Am. J. Dis. Child. 133:
1160-1162, 1979.
10. Krowka, M. J.: Clinical management of hepatopulmonary syndrome. Semin.
Liver Dis. 13: 414-422, 1993.
11. Kumar, D.: Genetics of Indian childhood cirrhosis. Trop. Geogr.
Med. 36: 313-316, 1984.
12. Lefkowitch, J. H.; Honig, C. L.; King, M. E.; Hagstrom, J. W.
C.: Hepatic copper overload and features of Indian childhood cirrhosis
in an American sibship. New Eng. J. Med. 307: 271-277, 1982.
13. Maddrey, W. C.; Iber, F. L.: Familial cirrhosis: a clinical and
pathological study. Ann. Intern. Med. 61: 667-679, 1964.
14. Miller, M. C.: Familial cirrhosis with hepatoma. Am. J. Dig.
Dis. 12: 633-638, 1967.
15. Mowat, A. P.: Liver Disorders in Childhood. London: Butterworths
(pub.) 1979. Pp. 288-291.
16. Muller, T.; Feichtinger, H.; Berger, H.; Muller, W.: Endemic
Tyrolean infantile cirrhosis: an ecogenetic disorder. Lancet 347:
877-880, 1996.
17. Muller, T.; Schafer, H.; Rodeck, B.; Haupt, G.; Koch, H.; Bosse,
H.; Welling, P.; Lange, H.; Krech, R.; Feist, D.; Muhlendahl, K. E.;
Bramswig, J.; Feichtinger, H.; Muller, W.: Familial clustering of
infantile cirrhosis in Northern Germany: a clue to the etiology of
idiopathic copper toxicosis. J. Pediat. 135: 189-196, 1999.
18. Patel, B. D.; Parekh, S. R.: Absence of rigor mortis in Indian
childhood cirrhosis. Lancet 349: 100-101, 1997.
19. Scheinberg, I. H.; Sternlieb, I.: Wilson disease and idiopathic
copper toxicosis. Am. J. Clin. Nutr. 63: 842S-845S, 1996.
20. Srivastava, J. R.: The genetic factor in infantile cirrhosis
of the liver. Indian J. Med. Sci. 10: 191-197, 1956.
21. Summer, W. R.; Herlong, H. F.: Personal Communication. Baltimore,
Md. 1982.
22. Tanner, M. S.; Kantarijan, A. H.; Bhave, S. A.; Pandit, A. N.
: Early introduction of copper-contaminated animal milk feeds as a
possible cause of Indian childhood cirrhosis. Lancet 322: 992-995,
1983. Note: Originally Volume II.
23. Tanner, M. S.; Portmann, B.; Mowat, A. P.; Williams, R.: Indian
childhood cirrhosis presenting in Britain with orcein-positive deposits
in liver and kidney. Brit. Med. J. 2: 928-929, 1978.
24. Wijmenga, C.; Muller, T.; Murli, I. S.; Brunt, T.; Feichtinger,
H.; Schonitzer, D.; Houwen, R. H. J.; Muller, W.; Sandkuijl, L. A.;
Pearson, P. L.: Endemic Tyrolean infantile cirrhosis is not an allelic
variant of Wilson's disease. Europ. J. Hum. Genet. 6: 624-628, 1998.
25. Zetterstrom, R.: Tyrosinosis. Ann. N.Y. Acad. Sci. 111: 220-226,
1963.
*FIELD* CS
GI:
Congenital cirrhosis;
Childhood cirrhosis;
Esophageal varices
Abdomen:
Swelling
Skin:
Jaundice
Vascular:
'Primary' pulmonary hypertension
Neuro:
Lethargy
Misc:
Fever
Lab:
Liver histopathology shows severe panlobular liver-cell swelling with
Mallory body formation, prominent pericellular fibrosis, 'micro-micronodular'
cirrhosis, and marked deposits of copper and copper-binding protein;
Hepatic copper increased
Inheritance:
Autosomal recessive cases, probably heterogeneous
*FIELD* CN
Marla J. F. O'Neill - updated: 9/29/2005
Victor A. McKusick - updated: 6/19/2003
Victor A. McKusick - updated: 9/29/1999
Victor A. McKusick - updated: 3/17/1999
Victor A. McKusick - updated: 1/11/1999
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 08/13/2010
terry: 2/24/2009
wwang: 10/7/2005
terry: 9/29/2005
terry: 4/18/2005
alopez: 6/27/2003
terry: 6/19/2003
mgross: 10/13/1999
terry: 9/29/1999
terry: 6/9/1999
carol: 3/31/1999
terry: 3/17/1999
carol: 1/19/1999
terry: 1/11/1999
terry: 7/24/1998
terry: 4/21/1994
warfield: 4/15/1994
mimadm: 4/14/1994
carol: 4/1/1992
supermim: 3/16/1992
supermim: 3/20/1990
*RECORD*
*FIELD* NO
215600
*FIELD* TI
#215600 CIRRHOSIS, FAMILIAL
CIRRHOSIS, FAMILIAL, WITH PULMONARY HYPERTENSION, INCLUDED;;
read moreINDIAN CHILDHOOD CIRRHOSIS, INCLUDED; ICC, INCLUDED;;
SEN SYNDROME, INCLUDED;;
COPPER-OVERLOAD CIRRHOSIS, INCLUDED;;
ENDEMIC TYROLEAN INFANTILE CIRRHOSIS, INCLUDED; ETIC, INCLUDED;;
COPPER TOXICOSIS, IDIOPATHIC, INCLUDED; ICT, INCLUDED;;
CIRRHOSIS, CRYPTOGENIC, INCLUDED;;
CIRRHOSIS, NONCRYPTOGENIC, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of a clear genetic
heterogeneity and demonstration of specific genetic causes in a number
of instances. These include mutations of keratin 8 (KRT8; 148060) and
keratin 18 (KRT18; 148070), which cause cryptogenic cirrhosis as well as
susceptibility to noncryptogenic cirrhosis.
Aside from Wilson disease (277900), type IV glycogen storage disease
(232500), and galactosemia (230400), which are well-known causes of
familial cirrhosis, families with multiple affected sibs and normal
parents have been observed (Iber and Maddrey, 1965). The group is
probably heterogeneous and in some instances nongenetic factors may be
responsible for the familial aggregation. Iber and Maddrey (1965)
reviewed 13 reported families and 8 of their own, each with 2 or more
affected members. They pointed out that with 1 exception the multiple
cases were in the same generation. Within a given family, age of onset,
clinical course, and biopsy findings were very similar, but there were
wide differences between families. Baber (1956) described cases of
congenital cirrhosis with generalized amino aciduria. Some of these
patients may be examples of Wilson disease. Others may have tyrosinemia
(Zetterstrom, 1963; Gentz et al., 1965). See tyrosinemia (276700). In
India, so-called Indian childhood cirrhosis (Sen syndrome) affects
multiple sibs (Chaudhuri and Chaudhuri, 1965). The disorder usually has
its onset between ages 6 and 18 months and is said to be several times
more frequent in males than in females; familial cases are frequent
(Srivastava, 1956). Lefkowitch et al. (1982) described 4 white American
sibs who died between ages 4.5 and 6 years of cirrhosis. Progressive
lethargy, abdominal swelling, jaundice, and fever developed 4 to 7
months before death. The liver histopathology closely resembled that of
the childhood cirrhosis of Asiatic Indians and included severe
panlobular liver-cell swelling with Mallory body formation, prominent
pericellular fibrosis, 'micro-micronodular' cirrhosis, and marked
deposits of copper and copper-binding protein. Hepatic copper levels
were as much as 40 times normal. The parents were apparently not
related. The father was adopted. The mother, of Scottish and Irish
extraction, had a single sib, a brother who died at the age of 10 years
of cirrhosis. Copper-overload is a feature of the Indian childhood
cirrhosis also. Before the report by Lefkowitch et al. (1982), the
clinical syndrome had been described only in children in India,
Pakistan, Sri Lanka, and Burma (Mowat, 1979) and rarely in immigrants to
Britain from India (Tanner et al., 1978). The family history is said to
be positive in about 30% of cases. Although one might suspect (in view
of the population distribution) autosomal recessive inheritance with an
occult selectively advantageous polymorphism in heterozygotes, no formal
proof is available.
Kalra et al. (1982) studied the families of 220 cases of Indian
childhood cirrhosis and 70 families of age-matched controls. The
hypotheses of autosomal recessive, partial sex-linkage, and doubly
recessive inheritance were found untenable. Multifactorial inheritance
was found more plausible. In a review of the subject, Kumar (1984)
concluded that multifactorial inheritance is likely. Gahl et al. (1988)
pointed out that the use of brass cooking utensils in Indian families
with ICC suggests an environmental source of copper toxicity; however,
the 25% frequency of familial disease points to a genetic basis as well.
Gahl et al. (1988) studied a 2-year-old boy with features of ICC whose
parents were third cousins of European descent. He was normal at birth
but had poor growth in infancy. At 18 months he developed nephrogenic
diabetes insipidus. At 21 months liver enzymes were elevated and biopsy
showed mild fibrosis and electron-dense granules, which electron probe
analysis showed to contain sulfur and copper. By 29 months progressive
liver failure and advanced micronodular cirrhosis with occasional
Mallory bodies were found. The remaining hepatocytes stained strongly
with rhodamine (for copper) and with orcein (for copper-binding
proteins). The patient died at 32 months of an esophageal variceal
bleed. The patient's disease was manifest in cultured fibroblasts. This
may represent a lysosomal storage disorder. Yet another cause of
congenital cirrhosis is alpha-1-antitrypsin deficiency (613490).
Familial aggregation of chronic active hepatitis due to hepatitis B
virus is discussed elsewhere (118900). The coincidence of liver disease
and 'primary' pulmonary hypertension was indicated by 2 brothers in a
family originally reported by Maddrey and Iber (1964), according to
follow-up information from Summer and Herlong (1982); 3 brothers, 2 of
them identical twins, were by then affected.
Muller et al. (1996) described 138 cases of endemic Tyrolean infantile
cirrhosis (ETIC) which was clinically and pathologically
indistinguishable from Indian childhood cirrhosis (ICC) and idiopathic
copper toxicosis (ICT) (Scheinberg and Sternlieb, 1996). It also
resembled the early-onset form of Wilson disease. Although ETIC, ICC,
and ICT require copper-enriched diets to become manifest (Tanner et al.,
1983), it was thought that these disorders might represent allelic
variants of Wilson disease. ETIC, like Wilson disease, shows autosomal
recessive inheritance. In contrast to the 30 isolated cases described
worldwide, the high frequency of ETIC in the Tyrol (Muller et al., 1996)
suggested a founder effect. Wijmenga et al. (1998) published a pedigree
with 11 affected children in 6 sibships, all of consanguineous parents
and all with both parents tracing back to a common ancestral couple 10
generations ago. The lethality of the disease meant that no living
children were available, but 8 pairs of parents were identified with at
least 1 ETIC child. Wijmenga et al. (1998) studied the possible role of
the ATP7B gene, mutant in Wilson disease, in ETIC by investigating
association and haplotype sharing in obligate gene carriers. Haplotypes
in ETIC carriers did not demonstrate sharing and the association studies
did not detect linkage disequilibrium between ETIC and the individual
markers at 13q14.3 where the ATP7B gene maps.
Muller et al. (1999) encountered 8 cases of infantile liver cirrhosis in
5 families in Emsland, a circumscribed and predominantly rural area of
Northern Germany; ICT was definitely proven in 2 cases. Clinical
presentation and liver pathology in 6 additional cases were consistent
with the diagnosis of ICT. Pedigrees of affected families revealed
complex relationships with occasional consanguinity of parents,
suggesting autosomal recessive inheritance. The households were served
by private wells with water of low pH flowing through copper pipes,
suggesting the possibility of increased alimentary copper exposure.
These findings supported an earlier conclusion that ICT develops when an
infant with a genetic predisposition is exposed to a copper-enriched
diet.
Pulmonary hypertension can develop as a complication of portal
hypertension (Krowka, 1993). Hadengue et al. (1991) suggested that the
pulmonary endothelial damage in this hepatopulmonary syndrome may be
caused by nonmetabolized substances in the portal blood that reach the
pulmonary vasculature through portal systemic shunting.
Patel and Parekh (1997) reported that parents and social workers
observed an absence of rigor mortis for a minimum of 12 hours to a
maximum of 30 hours postmortem in 37 children who died of ICC between
the ages of 10 months and 2 years; the authors observed absence of rigor
mortis for 22 to 36 hours after death in 5 hospitalized patients.
Children who died from other causes developed body stiffness within 4 to
6 hours. Patel and Parekh (1997) noted that the absence of rigor mortis
had not been mentioned in previous studies of ICC and postulated that
excess glycogen in the muscles of these patients would facilitate
postmortem ATP resynthesis and so delay the development of rigor.
*FIELD* SA
Altman et al. (1979); Kocak and Ozsoylu (1979); Miller (1967)
*FIELD* RF
1. Altman, A. R.; Gottfried, E. B.; Paronetto, F.; Lieber, C. S.:
Idiopathic familial cirrhosis and stenosis in adults. Gastroenterology 77:
1211-1216, 1979.
2. Baber, M. D.: Case of congenital cirrhosis of the liver with renal
tubular defects akin to those in the Fanconi syndrome. Arch. Dis.
Child. 31: 335-339, 1956.
3. Chaudhuri, A.; Chaudhuri, K. C.: The karyotype in infantile cirrhosis
of the liver (Sen's syndrome). Indian J. Pediat. 32: 209-218, 1965.
4. Gahl, W.; Adamson, M.; Goodman, Z.; Reiner, B.; Olson, J.; Oliver,
C.; Plotnick, L.: Hepatic copper storage resembling Indian childhood
cirrhosis (ICC) in a non-Indian boy--a genetic disease. (Abstract) Am.
J. Hum. Genet. 43: A7 only, 1988.
5. Gentz, J.; Jagenburg, R.; Zetterstrom, R.: Tyrosinemia: an inborn
error of tyrosine metabolism with cirrhosis of the liver and multiple
renal tubular defects. J. Pediat. 66: 670-696, 1965.
6. Hadengue, A.; Benhayoun, M. K.; Lebrec, D.; Benhamou, J. P.: Pulmonary
hypertension complicating portal hypertension: prevalence and relation
to splanchnic hemodynamics. Gastroenterology 100: 520-528, 1991.
7. Iber, F. L.; Maddrey, W. C.: Familial hepatic diseases with cirrhosis
or without portal hypertension. Prog. Liver Dis. 2: 290-302, 1965.
8. Kalra, V.; Roy, S.; Ghai, O. P.; Jain, J. P.: Indian childhood
cirrhosis--a heritable disease. Hum. Hered. 32: 170-175, 1982.
9. Kocak, N.; Ozsoylu, S.: Familial cirrhosis. Am. J. Dis. Child. 133:
1160-1162, 1979.
10. Krowka, M. J.: Clinical management of hepatopulmonary syndrome. Semin.
Liver Dis. 13: 414-422, 1993.
11. Kumar, D.: Genetics of Indian childhood cirrhosis. Trop. Geogr.
Med. 36: 313-316, 1984.
12. Lefkowitch, J. H.; Honig, C. L.; King, M. E.; Hagstrom, J. W.
C.: Hepatic copper overload and features of Indian childhood cirrhosis
in an American sibship. New Eng. J. Med. 307: 271-277, 1982.
13. Maddrey, W. C.; Iber, F. L.: Familial cirrhosis: a clinical and
pathological study. Ann. Intern. Med. 61: 667-679, 1964.
14. Miller, M. C.: Familial cirrhosis with hepatoma. Am. J. Dig.
Dis. 12: 633-638, 1967.
15. Mowat, A. P.: Liver Disorders in Childhood. London: Butterworths
(pub.) 1979. Pp. 288-291.
16. Muller, T.; Feichtinger, H.; Berger, H.; Muller, W.: Endemic
Tyrolean infantile cirrhosis: an ecogenetic disorder. Lancet 347:
877-880, 1996.
17. Muller, T.; Schafer, H.; Rodeck, B.; Haupt, G.; Koch, H.; Bosse,
H.; Welling, P.; Lange, H.; Krech, R.; Feist, D.; Muhlendahl, K. E.;
Bramswig, J.; Feichtinger, H.; Muller, W.: Familial clustering of
infantile cirrhosis in Northern Germany: a clue to the etiology of
idiopathic copper toxicosis. J. Pediat. 135: 189-196, 1999.
18. Patel, B. D.; Parekh, S. R.: Absence of rigor mortis in Indian
childhood cirrhosis. Lancet 349: 100-101, 1997.
19. Scheinberg, I. H.; Sternlieb, I.: Wilson disease and idiopathic
copper toxicosis. Am. J. Clin. Nutr. 63: 842S-845S, 1996.
20. Srivastava, J. R.: The genetic factor in infantile cirrhosis
of the liver. Indian J. Med. Sci. 10: 191-197, 1956.
21. Summer, W. R.; Herlong, H. F.: Personal Communication. Baltimore,
Md. 1982.
22. Tanner, M. S.; Kantarijan, A. H.; Bhave, S. A.; Pandit, A. N.
: Early introduction of copper-contaminated animal milk feeds as a
possible cause of Indian childhood cirrhosis. Lancet 322: 992-995,
1983. Note: Originally Volume II.
23. Tanner, M. S.; Portmann, B.; Mowat, A. P.; Williams, R.: Indian
childhood cirrhosis presenting in Britain with orcein-positive deposits
in liver and kidney. Brit. Med. J. 2: 928-929, 1978.
24. Wijmenga, C.; Muller, T.; Murli, I. S.; Brunt, T.; Feichtinger,
H.; Schonitzer, D.; Houwen, R. H. J.; Muller, W.; Sandkuijl, L. A.;
Pearson, P. L.: Endemic Tyrolean infantile cirrhosis is not an allelic
variant of Wilson's disease. Europ. J. Hum. Genet. 6: 624-628, 1998.
25. Zetterstrom, R.: Tyrosinosis. Ann. N.Y. Acad. Sci. 111: 220-226,
1963.
*FIELD* CS
GI:
Congenital cirrhosis;
Childhood cirrhosis;
Esophageal varices
Abdomen:
Swelling
Skin:
Jaundice
Vascular:
'Primary' pulmonary hypertension
Neuro:
Lethargy
Misc:
Fever
Lab:
Liver histopathology shows severe panlobular liver-cell swelling with
Mallory body formation, prominent pericellular fibrosis, 'micro-micronodular'
cirrhosis, and marked deposits of copper and copper-binding protein;
Hepatic copper increased
Inheritance:
Autosomal recessive cases, probably heterogeneous
*FIELD* CN
Marla J. F. O'Neill - updated: 9/29/2005
Victor A. McKusick - updated: 6/19/2003
Victor A. McKusick - updated: 9/29/1999
Victor A. McKusick - updated: 3/17/1999
Victor A. McKusick - updated: 1/11/1999
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 08/13/2010
terry: 2/24/2009
wwang: 10/7/2005
terry: 9/29/2005
terry: 4/18/2005
alopez: 6/27/2003
terry: 6/19/2003
mgross: 10/13/1999
terry: 9/29/1999
terry: 6/9/1999
carol: 3/31/1999
terry: 3/17/1999
carol: 1/19/1999
terry: 1/11/1999
terry: 7/24/1998
terry: 4/21/1994
warfield: 4/15/1994
mimadm: 4/14/1994
carol: 4/1/1992
supermim: 3/16/1992
supermim: 3/20/1990