RBCC Red Blood Cell Collection

KRT1 (KRTA) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Keratin, type II cytoskeletal 1 (67 kDa cytokeratin; Cytokeratin-1; CK-1; Hair alpha protein; Keratin-1; K1; Type-II keratin Kb1)

UniProt P04264
ID K2C1_HUMAN Reviewed; 644 AA.
AC P04264; B2RA01; Q14720; Q6GSJ0; Q9H298;
DT 20-MAR-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 26-MAY-2009, sequence version 6.
DT 22-JAN-2014, entry version 171.
DE RecName: Full=Keratin, type II cytoskeletal 1;
DE AltName: Full=67 kDa cytokeratin;
DE AltName: Full=Cytokeratin-1;
DE Short=CK-1;
DE AltName: Full=Hair alpha protein;
DE AltName: Full=Keratin-1;
DE Short=K1;
DE AltName: Full=Type-II keratin Kb1;
GN Name=KRT1; Synonyms=KRTA;
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 VARIANTS ASN-358 AND ARG-633.
RX PubMed=2580302; DOI=10.1073/pnas.82.7.1896;
RA Johnson L.D., Idler W.W., Zhou X.-M., Roop D.R., Steinert P.M.;
RT "Structure of a gene for the human epidermal 67-kDa keratin.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:1896-1900(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ASN-358 AND ARG-633.
RX PubMed=10903910; DOI=10.1006/bbrc.2000.3110;
RA Whittock N.V., Eady R.A.J., McGrath J.A.;
RT "Genomic organization and amplification of the human epidermal type II
RT keratin genes K1 and K5.";
RL Biochem. Biophys. Res. Commun. 274:149-152(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], INVOLVEMENT IN NEPPK, AND VARIANT
RP ARG-633.
RX PubMed=11286630; DOI=10.1046/j.1523-1747.2001.13041234.x;
RA Hatsell S.J., Eady R.A.J., Wennerstrand L., Dopping-Hepenstal P.J.,
RA Leigh I.M., Munro C., Kelsell D.P.;
RT "Novel splice site mutation in keratin 1 underlies mild epidermolytic
RT palmoplantar keratoderma in three kindreds.";
RL J. Invest. Dermatol. 116:606-609(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Tongue;
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 [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ARG-633.
RC TISSUE=Skin;
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 [7]
RP PROTEIN SEQUENCE OF 2-8.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [8]
RP PROTEIN SEQUENCE OF 13-30; 66-82; 186-240; 258-276; 278-298; 344-355;
RP 365-386; 396-403; 408-416; 418-432; 442-455 AND 461-588, METHYLATION
RP AT ARG-82 AND LYS-276, AND MASS SPECTROMETRY.
RC TISSUE=Ovarian carcinoma;
RA Bienvenut W.V., Lilla S., von Kriegsheim A., Lempens A., Kolch W.;
RL Submitted (DEC-2008) to UniProtKB.
RN [9]
RP PRELIMINARY NUCLEOTIDE SEQUENCE [MRNA] OF 152-644, AND VARIANTS
RP CYS-537 AND ARG-633.
RX PubMed=2581964;
RA Steinert P.M., Parry D.A.D., Idler W.W., Johnson L.D., Steven A.C.,
RA Roop D.R.;
RT "Amino acid sequences of mouse and human epidermal type II keratins of
RT Mr 67,000 provide a systematic basis for the structural and functional
RT diversity of the end domains of keratin intermediate filament
RT subunits.";
RL J. Biol. Chem. 260:7142-7149(1985).
RN [10]
RP PROTEIN SEQUENCE OF 377-386, AND MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [11]
RP CITRULLINATION.
RX PubMed=8780679; DOI=10.1006/bbrc.1996.1240;
RA Senshu T., Kan S., Ogawa H., Manabe M., Asaga H.;
RT "Preferential deimination of keratin K1 and filaggrin during the
RT terminal differentiation of human epidermis.";
RL Biochem. Biophys. Res. Commun. 225:712-719(1996).
RN [12]
RP INVOLVEMENT IN IHCM.
RX PubMed=11286616; DOI=10.1046/j.1523-1747.2001.01292.x;
RA Sprecher E., Ishida-Yamamoto A., Becker O.M., Marekov L.N.,
RA Miller C.J., Steinert P.M., Neldner K., Richard G.;
RT "Evidence for novel functions of the keratin tail emerging from a
RT mutation causing ichthyosis hystrix.";
RL J. Invest. Dermatol. 116:511-519(2001).
RN [13]
RP CITRULLINATION.
RX PubMed=11841545; DOI=10.1046/j.0022-202x.2001.01671.x;
RA Ishida-Yamamoto A., Senshu T., Eady R.A.J., Takahashi H., Shimizu H.,
RA Akiyama M., Iizuka H.;
RT "Sequential reorganization of cornified cell keratin filaments
RT involving filaggrin-mediated compaction and keratin 1 deimination.";
RL J. Invest. Dermatol. 118:282-287(2002).
RN [14]
RP INVOLVEMENT IN SPPK3.
RX PubMed=11982762; DOI=10.1046/j.1523-1747.2002.01750.x;
RA Whittock N.V., Smith F.J., Wan H., Mallipeddi R., Griffiths W.A.D.,
RA Dopping-Hepenstal P.J., Ashton G.H.S., Eady R.A.J., McLean W.H.I.,
RA McGrath J.A.;
RT "Frameshift mutation in the V2 domain of human keratin 1 results in
RT striate palmoplantar keratoderma.";
RL J. Invest. Dermatol. 118:838-844(2002).
RN [15]
RP FUNCTION, INTERACTION WITH GNB2L1 AND ITGB1, SUBCELLULAR LOCATION, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=17956333; DOI=10.1042/BST0351292;
RA Chuang N.N., Huang C.C.;
RT "Interaction of integrin beta1 with cytokeratin 1 in neuroblastoma
RT NMB7 cells.";
RL Biochem. Soc. Trans. 35:1292-1294(2007).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-66, AND MASS
RP 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 [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21; SER-66 AND SER-344,
RP AND 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 [19]
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 [20]
RP FUNCTION, AND INTERACTION WITH C1QBP.
RX PubMed=21544310; DOI=10.1160/TH10-09-0591;
RA Pixley R.A., Espinola R.G., Ghebrehiwet B., Joseph K., Kao A.,
RA Bdeir K., Cines D.B., Colman R.W.;
RT "Interaction of high-molecular-weight kininogen with endothelial cell
RT binding proteins suPAR, gC1qR and cytokeratin 1 determined by surface
RT plasmon resonance (BiaCore).";
RL Thromb. Haemost. 105:1053-1059(2011).
RN [21]
RP VARIANT EHK PRO-161.
RX PubMed=1381288; DOI=10.1016/0092-8674(92)90315-4;
RA Chipev C.C., Korge B.P., Markova N., Bale S.J., Digiovanna J.J.,
RA Compton J.G., Steinert P.M.;
RT "A leucine-->proline mutation in the H1 subdomain of keratin 1 causes
RT epidermolytic hyperkeratosis.";
RL Cell 70:821-828(1992).
RN [22]
RP VARIANT ALLELE 1B 560-GLY--TYR-566 DEL.
RX PubMed=1281859; DOI=10.1111/1523-1747.ep12614149;
RA Korge B.P., Compton J.G., Steinert P.M., Mischke D.;
RT "The two size alleles of human keratin 1 are due to a deletion in the
RT glycine-rich carboxyl-terminal V2 subdomain.";
RL J. Invest. Dermatol. 99:697-702(1992).
RN [23]
RP VARIANT EHK GLN-490.
RX PubMed=1380725; DOI=10.1126/science.257.5073.1128;
RA Rothnagel J.A., Dominey A.M., Dempsey L.D., Longley M.A.,
RA Greenhalgh D.A., Gagne T.A., Huber M., Frenk E., Hohl D., Roop D.R.;
RT "Mutations in the rod domains of keratins 1 and 10 in epidermolytic
RT hyperkeratosis.";
RL Science 257:1128-1130(1992).
RN [24]
RP VARIANT EHK CYS-482.
RX PubMed=7512983; DOI=10.1172/JCI117132;
RA Syder A.J., Yu Q.-C., Paller A.S., Giudice G., Pearson R., Fuchs E.;
RT "Genetic mutations in the K1 and K10 genes of patients with
RT epidermolytic hyperkeratosis. Correlation between location and disease
RT severity.";
RL J. Clin. Invest. 93:1533-1542(1994).
RN [25]
RP VARIANTS EHK GLY-155; SER-188 AND PRO-193.
RX PubMed=7507151; DOI=10.1111/1523-1747.ep12371725;
RA Yang J.-M., Chipev C.C., Digiovanna J.J., Bale S.J., Marekov L.N.,
RA Steinert P.M., Compton J.G.;
RT "Mutations in the H1 and 1A domains in the keratin 1 gene in
RT epidermolytic hyperkeratosis.";
RL J. Invest. Dermatol. 102:17-23(1994).
RN [26]
RP VARIANTS EHK PRO-186 AND SER-188.
RX PubMed=7507152; DOI=10.1111/1523-1747.ep12371726;
RA McLean W.H.I., Eady R.A.J., Dopping-Hepenstal P.J.C., McMillan J.R.,
RA Leigh I.M., Navsaria H.A., Higgins C., Harper J.I., Paige D.G.,
RA Morley S.M.;
RT "Mutations in the rod 1A domain of keratins 1 and 10 in bullous
RT congenital ichthyosiform erythroderma (BCIE).";
RL J. Invest. Dermatol. 102:24-30(1994).
RN [27]
RP VARIANT NEPPK ILE-74.
RX PubMed=7528239; DOI=10.1111/1523-1747.ep12412771;
RA Kimonis V., DiGiovanna J.J., Yang J.-M., Doyle S.Z., Bale S.J.,
RA Compton J.G.;
RT "A mutation in the V1 end domain of keratin 1 in non-epidermolytic
RT palmar-plantar keratoderma.";
RL J. Invest. Dermatol. 103:764-769(1994).
RN [28]
RP VARIANT EHK VAL-340.
RX PubMed=9856846; DOI=10.1046/j.1523-1747.1998.00389.x;
RA Kremer H., Lavrijsen A.P., McLean W.H.I., Lane E.B., Melchers D.,
RA Ruiter D.J., Mariman E.C., Steijlen P.M.;
RT "An atypical form of bullous congenital ichthyosiform erythroderma is
RT caused by a mutation in the L12 linker region of keratin 1.";
RL J. Invest. Dermatol. 111:1224-1226(1998).
RN [29]
RP VARIANTS AEI PHE-479 AND THR-479.
RX PubMed=10053007; DOI=10.1086/302278;
RA Sybert V.P., Francis J.S., Corden L.D., Smith L.T., Weaver M.,
RA Stephens K., McLean W.H.I.;
RT "Cyclic ichthyosis with epidermolytic hyperkeratosis: a phenotype
RT conferred by mutations in the 2B domain of keratin K1.";
RL Am. J. Hum. Genet. 64:732-738(1999).
RN [30]
RP VARIANT EHK THR-188.
RX PubMed=10232403; DOI=10.1111/j.1600-0625.1999.tb00359.x;
RA Arin M.J., Longley M.A., Kuster W., Huber M., Hohl D., Rothnagel J.A.,
RA Roop D.R.;
RT "An asparagine to threonine substitution in the 1A domain of keratin
RT 1: a novel mutation that causes epidermolytic hyperkeratosis.";
RL Exp. Dermatol. 8:124-127(1999).
RN [31]
RP VARIANT AEI PHE-479.
RX PubMed=10597140; DOI=10.1111/j.1600-0625.1999.tb00309.x;
RA Michael E.J., Schneiderman P., Grossman M.E., Christiano A.M.;
RT "Epidermolytic hyperkeratosis with polycyclic psoriasiform plaques
RT resulting from a mutation in the keratin 1 gene.";
RL Exp. Dermatol. 8:501-503(1999).
RN [32]
RP VARIANT EHK PRO-214.
RX PubMed=10844506; DOI=10.1046/j.1365-2230.2000.00625.x;
RA Cserhalmi-Friedman P.B., Squeo R., Gordon D., Garzon M.,
RA Schneiderman P., Grossman M.E., Christiano A.M.;
RT "Epidermolytic hyperkeratosis in a Hispanic family resulting from a
RT mutation in the keratin 1 gene.";
RL Clin. Exp. Dermatol. 25:241-243(2000).
RN [33]
RP VARIANT EHK THR-479.
RX PubMed=10688370; DOI=10.1034/j.1600-0625.2000.009001016.x;
RA Arin M.J., Longley M.A., Epstein E.H. Jr., Rothnagel J.A., Roop D.R.;
RT "Identification of a novel mutation in keratin 1 in a family with
RT epidermolytic hyperkeratosis.";
RL Exp. Dermatol. 9:16-19(2000).
RN [34]
RP VARIANT EHK ASP-155.
RX PubMed=11531804; DOI=10.1046/j.1365-2133.2001.04327.x;
RA Whittock N.V., Ashton G.H.S., Griffiths W.A.D., Eady R.A.J.,
RA McGrath J.A.;
RT "New mutations in keratin 1 that cause bullous congenital
RT ichthyosiform erythroderma and keratin 2e that cause ichthyosis
RT bullosa of Siemens.";
RL Br. J. Dermatol. 145:330-335(2001).
RN [35]
RP VARIANTS PALMOPLANTAR KERATODERMA VAL-176--LYS-197 DEL AND
RP ALA-459--466-GLN DEL.
RX PubMed=12406346; DOI=10.1046/j.1523-1747.2002.00186.x;
RA Terron-Kwiatkowski A., Paller A.S., Compton J., Atherton D.J.,
RA McLean W.H., Irvine A.D.;
RT "Two cases of primarily palmoplantar keratoderma associated with novel
RT mutations in keratin 1.";
RL J. Invest. Dermatol. 119:966-971(2002).
RN [36]
RP VARIANTS EHK LYS-188 AND PRO-486.
RX PubMed=12406348; DOI=10.1046/j.1523-1747.2002.00061.x;
RA Lee D.-Y., Ahn K.-S., Lee C.-H., Rho N.-K., Lee J.-H., Lee E.-S.,
RA Steinert P.M., Yang J.-M.;
RT "Two novel mutations in the keratin 1 gene in epidermolytic
RT hyperkeratosis.";
RL J. Invest. Dermatol. 119:976-977(2002).
CC -!- FUNCTION: May regulate the activity of kinases such as PKC and SRC
CC via binding to integrin beta-1 (ITB1) and the receptor of
CC activated protein kinase C (RACK1/GNB2L1). In complex with C1QBP
CC is a high affinity receptor for kininogen-1/HMWK.
CC -!- SUBUNIT: Heterotetramer of two type I and two type II keratins.
CC Keratin-1 is generally associated with keratin-10. Interacts with
CC ITGB1 in the presence of GNB2L1 and SRC, and with GNB2L1.
CC Interacts with C1QBP; the association represents a cell surface
CC kininogen receptor.
CC -!- SUBCELLULAR LOCATION: Cell membrane. Note=Located on plasma
CC membrane of neuroblastoma NMB7 cells.
CC -!- TISSUE SPECIFICITY: The source of this protein is neonatal
CC foreskin. The 67-kDa type II keratins are expressed in terminally
CC differentiating epidermis.
CC -!- PTM: Undergoes deimination of some arginine residues
CC (citrullination).
CC -!- POLYMORPHISM: There are two size variants of KRT1, termed allele
CC 1A and allele 1B with allelic frequencies of 0.61 and 0.39. Allele
CC 1B lacks 7 residues compared to allele 1A.
CC -!- DISEASE: Epidermolytic hyperkeratosis (EHK) [MIM:113800]: An
CC autosomal dominant skin disorder characterized by widespread
CC blistering and an ichthyotic erythroderma at birth that persist
CC into adulthood. Histologically there is a diffuse epidermolytic
CC degeneration in the lower spinous layer of the epidermis. Within a
CC few weeks from birth, erythroderma and blister formation diminish
CC and hyperkeratoses develop. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Ichthyosis hystrix, Curth-Macklin type (IHCM)
CC [MIM:146590]: A genodermatosis with severe verrucous
CC hyperkeratosis. Affected individuals manifest congenital verrucous
CC black scale on the scalp, neck, and limbs with truncal erythema,
CC palmoplantar keratoderma and keratoses on the lips, ears, nipples
CC and buttocks. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: Keratoderma, palmoplantar, non-epidermolytic (NEPPK)
CC [MIM:600962]: A dermatological disorder characterized by well-
CC demarcated hyperkeratosis is present over the palms and soles. A
CC red band is frequently present at the periphery of the keratosis.
CC It is usually non-transgredient, with a sharp demarcation of the
CC lesions at the wrists. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Ichthyosis annular epidermolytic (AEI) [MIM:607602]: A
CC skin disorder resembling bullous congenital ichthyosiform
CC erythroderma. Affected individuals present with bullous ichthyosis
CC in early childhood and hyperkeratotic lichenified plaques in the
CC flexural areas and extensor surfaces at later ages. The feature
CC that distinguishes AEI from BCIE is dramatic episodes of flares of
CC annular polycyclic plaques with scale, which coalesce to involve
CC most of the body surface and can persist for several weeks or even
CC months. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Keratoderma, palmoplantar, striate 3 (SPPK3)
CC [MIM:607654]: A dermatological disorder characterized by
CC thickening of the stratum corneum and epidermal layers on palms
CC and soles. There is no involvement of non-palmoplantar skin, and
CC both hair and nails are normal. Note=The disease is caused by
CC 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 -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/KRT1";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Keratin-1 entry;
CC URL="http://en.wikipedia.org/wiki/Keratin_1";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M98776; AAB47721.1; -; Genomic_DNA.
DR EMBL; AF237621; AAF60327.1; -; Genomic_DNA.
DR EMBL; AF304164; AAG41947.1; -; Genomic_DNA.
DR EMBL; AK313986; BAG36698.1; -; mRNA.
DR EMBL; AC055716; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC063697; AAH63697.1; -; mRNA.
DR EMBL; M10938; AAA36153.1; -; mRNA.
DR PIR; A22940; KRHU2.
DR RefSeq; NP_006112.3; NM_006121.3.
DR UniGene; Hs.80828; -.
DR ProteinModelPortal; P04264; -.
DR SMR; P04264; 180-319, 346-488.
DR IntAct; P04264; 19.
DR MINT; MINT-4990403; -.
DR STRING; 9606.ENSP00000252244; -.
DR PhosphoSite; P04264; -.
DR DMDM; 238054406; -.
DR REPRODUCTION-2DPAGE; P04264; -.
DR SWISS-2DPAGE; P04264; -.
DR PaxDb; P04264; -.
DR PRIDE; P04264; -.
DR ProMEX; P04264; -.
DR Ensembl; ENST00000252244; ENSP00000252244; ENSG00000167768.
DR GeneID; 3848; -.
DR KEGG; hsa:3848; -.
DR UCSC; uc001sau.1; human.
DR CTD; 3848; -.
DR GeneCards; GC12M053069; -.
DR H-InvDB; HIX0036813; -.
DR HGNC; HGNC:6412; KRT1.
DR HPA; CAB002153; -.
DR HPA; HPA017917; -.
DR MIM; 113800; phenotype.
DR MIM; 139350; gene.
DR MIM; 146590; phenotype.
DR MIM; 600962; phenotype.
DR MIM; 607602; phenotype.
DR MIM; 607654; phenotype.
DR neXtProt; NX_P04264; -.
DR Orphanet; 281139; Annular epidermolytic ichthyosis.
DR Orphanet; 312; Epidermolytic ichthyosis.
DR Orphanet; 2199; Epidermolytic palmoplantar keratoderma.
DR Orphanet; 79503; Ichthyosis hystrix of Curth-Macklin.
DR Orphanet; 50942; Keratosis palmoplantaris striata.
DR PharmGKB; PA30199; -.
DR eggNOG; NOG146769; -.
DR HOGENOM; HOG000230976; -.
DR HOVERGEN; HBG013015; -.
DR InParanoid; P04264; -.
DR KO; K07605; -.
DR OMA; THISETN; -.
DR OrthoDB; EOG7FV3Q8; -.
DR PhylomeDB; P04264; -.
DR GeneWiki; Keratin_1; -.
DR GenomeRNAi; 3848; -.
DR NextBio; 15141; -.
DR PRO; PR:P04264; -.
DR ArrayExpress; P04264; -.
DR Bgee; P04264; -.
DR CleanEx; HS_KRT1; -.
DR Genevestigator; P04264; -.
DR GO; GO:0005856; C:cytoskeleton; TAS:ProtInc.
DR GO; GO:0045095; C:keratin filament; IEA:Ensembl.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030246; F:carbohydrate binding; IPI:UniProtKB.
DR GO; GO:0004872; F:receptor activity; NAS:UniProtKB.
DR GO; GO:0005198; F:structural molecule activity; IEA:InterPro.
DR GO; GO:0001867; P:complement activation, lectin pathway; IPI:UniProtKB.
DR GO; GO:0042730; P:fibrinolysis; NAS:UniProtKB.
DR GO; GO:0045765; P:regulation of angiogenesis; NAS:UniProtKB.
DR GO; GO:0006979; P:response to oxidative stress; NAS:UniProtKB.
DR InterPro; IPR001664; IF.
DR InterPro; IPR018039; Intermediate_filament_CS.
DR InterPro; IPR003054; Keratin_II.
DR PANTHER; PTHR23239; PTHR23239; 1.
DR Pfam; PF00038; Filament; 1.
DR PRINTS; PR01276; TYPE2KERATIN.
DR PROSITE; PS00226; IF; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Citrullination; Coiled coil; Complete proteome;
KW Direct protein sequencing; Disease mutation; Ichthyosis;
KW Intermediate filament; Keratin; Membrane; Methylation;
KW Palmoplantar keratoderma; Phosphoprotein; Polymorphism;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 644 Keratin, type II cytoskeletal 1.
FT /FTId=PRO_0000063709.
FT REGION 2 179 Head.
FT REGION 180 489 Rod.
FT REGION 180 215 Coil 1A.
FT REGION 216 234 Linker 1.
FT REGION 235 326 Coil 1B.
FT REGION 327 350 Linker 12.
FT REGION 351 489 Coil 2.
FT REGION 490 644 Tail.
FT COMPBIAS 2 151 Gly/Phe/Ser-rich.
FT COMPBIAS 502 641 Gly/Ser-rich.
FT SITE 433 433 Stutter.
FT MOD_RES 21 21 Phosphoserine.
FT MOD_RES 66 66 Phosphoserine.
FT MOD_RES 82 82 Omega-N-methylarginine.
FT MOD_RES 276 276 N6,N6-dimethyllysine.
FT MOD_RES 344 344 Phosphoserine.
FT VARIANT 74 74 K -> I (in NEPPK; dbSNP:rs57977969).
FT /FTId=VAR_017819.
FT VARIANT 155 155 V -> D (in EHK).
FT /FTId=VAR_017820.
FT VARIANT 155 155 V -> G (in EHK; dbSNP:rs57959072).
FT /FTId=VAR_003853.
FT VARIANT 161 161 L -> P (in EHK; dbSNP:rs57695159).
FT /FTId=VAR_003854.
FT VARIANT 176 197 Missing (in palmoplantar keratoderma; and
FT mild ichthyosis largely limited to the
FT flexural areas).
FT /FTId=VAR_038627.
FT VARIANT 186 186 S -> P (in EHK; dbSNP:rs60022878).
FT /FTId=VAR_003855.
FT VARIANT 188 188 N -> K (in EHK; dbSNP:rs59429455).
FT /FTId=VAR_017821.
FT VARIANT 188 188 N -> S (in EHK; dbSNP:rs58928370).
FT /FTId=VAR_003856.
FT VARIANT 188 188 N -> T (in EHK; severe).
FT /FTId=VAR_017822.
FT VARIANT 193 193 S -> P (in EHK; dbSNP:rs60937700).
FT /FTId=VAR_003857.
FT VARIANT 214 214 L -> P (in EHK; dbSNP:rs61549035).
FT /FTId=VAR_017823.
FT VARIANT 312 312 I -> V.
FT /FTId=VAR_003858.
FT VARIANT 330 330 I -> T.
FT /FTId=VAR_003859.
FT VARIANT 340 340 D -> V (in EHK; dbSNP:rs58062863).
FT /FTId=VAR_017824.
FT VARIANT 358 358 Y -> N (in dbSNP:rs1050872).
FT /FTId=VAR_003860.
FT VARIANT 454 454 A -> S (in dbSNP:rs17678945).
FT /FTId=VAR_038628.
FT VARIANT 459 466 Missing (in palmoplantar keratoderma; and
FT mild ichthyosis largely limited to the
FT flexural areas).
FT /FTId=VAR_038629.
FT VARIANT 479 479 I -> F (in AEI; dbSNP:rs61218439).
FT /FTId=VAR_017825.
FT VARIANT 479 479 I -> T (in AEI and EHK;
FT dbSNP:rs57837128).
FT /FTId=VAR_017826.
FT VARIANT 482 482 Y -> C (in EHK; dbSNP:rs58420087).
FT /FTId=VAR_017827.
FT VARIANT 486 486 L -> P (in EHK; dbSNP:rs56914602).
FT /FTId=VAR_017828.
FT VARIANT 490 490 E -> Q (in EHK; dbSNP:rs60279707).
FT /FTId=VAR_003861.
FT VARIANT 537 537 G -> C.
FT /FTId=VAR_003862.
FT VARIANT 560 566 Missing (in allele 1B).
FT /FTId=VAR_003864.
FT VARIANT 633 633 K -> R (in dbSNP:rs14024).
FT /FTId=VAR_003863.
FT CONFLICT 201 201 L -> M (in Ref. 9; AAA36153).
FT CONFLICT 206 206 Q -> K (in Ref. 9; AAA36153).
FT CONFLICT 238 238 L -> S (in Ref. 9; AAA36153).
FT CONFLICT 344 345 SL -> QF (in Ref. 9; AAA36153).
FT CONFLICT 403 403 R -> H (in Ref. 4; BAG36698).
FT CONFLICT 404 404 V -> M (in Ref. 9; AAA36153).
FT CONFLICT 447 447 L -> M (in Ref. 9; AAA36153).
FT CONFLICT 463 463 R -> C (in Ref. 9; AAA36153).
FT CONFLICT 466 466 Q -> H (in Ref. 9; AAA36153).
FT CONFLICT 504 504 S -> T (in Ref. 9; AAA36153).
FT CONFLICT 511 512 TI -> SM (in Ref. 9; AAA36153).
FT CONFLICT 564 564 G -> S (in Ref. 9; AAA36153).
FT CONFLICT 613 613 I -> S (in Ref. 9; AAA36153).
FT CONFLICT 638 638 T -> S (in Ref. 9; AAA36153).
SQ SEQUENCE 644 AA; 66039 MW; CE5DDE97388F5017 CRC64;
MSRQFSSRSG YRSGGGFSSG SAGIINYQRR TTSSSTRRSG GGGGRFSSCG GGGGSFGAGG
GFGSRSLVNL GGSKSISISV ARGGGRGSGF GGGYGGGGFG GGGFGGGGFG GGGIGGGGFG
GFGSGGGGFG GGGFGGGGYG GGYGPVCPPG GIQEVTINQS LLQPLNVEID PEIQKVKSRE
REQIKSLNNQ FASFIDKVRF LEQQNQVLQT KWELLQQVDT STRTHNLEPY FESFINNLRR
RVDQLKSDQS RLDSELKNMQ DMVEDYRNKY EDEINKRTNA ENEFVTIKKD VDGAYMTKVD
LQAKLDNLQQ EIDFLTALYQ AELSQMQTQI SETNVILSMD NNRSLDLDSI IAEVKAQYED
IAQKSKAEAE SLYQSKYEEL QITAGRHGDS VRNSKIEISE LNRVIQRLRS EIDNVKKQIS
NLQQSISDAE QRGENALKDA KNKLNDLEDA LQQAKEDLAR LLRDYQELMN TKLALDLEIA
TYRTLLEGEE SRMSGECAPN VSVSVSTSHT TISGGGSRGG GGGGYGSGGS SYGSGGGSYG
SGGGGGGGRG SYGSGGSSYG SGGGSYGSGG GGGGHGSYGS GSSSGGYRGG SGGGGGGSSG
GRGSGGGSSG GSIGGRGSSS GGVKSSGGSS SVKFVSTTYS GVTR
//

MIM 113800
*RECORD*
*FIELD* NO
113800
*FIELD* TI
#113800 EPIDERMOLYTIC HYPERKERATOSIS; EHK
;;BULLOUS ERYTHRODERMA ICHTHYOSIFORMIS CONGENITA OF BROCQ;;
read moreBULLOUS CONGENITAL ICHTHYOSIFORM ERYTHRODERMA; BCIE;;
BULLOUS ICHTHYOSIFORM ERYTHRODERMA; BIE;;
EPIDERMOLYTIC ICHTHYOSIS
EPIDERMOLYTIC HYPERKERATOSIS, LATE-ONSET, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
epidermolytic hyperkeratosis (EHK) can be caused by heterozygous
mutation in the keratin-1 gene (KRT1; 139350) and by heterozygous or
homozygous mutation in the keratin-10 gene (KRT10; 148080).

DESCRIPTION

Epidermolytic hyperkeratosis (EHK), also termed bullous congenital
ichthyosiform erythroderma (BCIE), is a keratinization disorder with an
incidence of approximately 1 in 200,000 in the USA. The clinical
phenotype of EHK is characterized by erythema and widespread formation
of epidermal blisters developing at birth. Later in life, bullous
erythema is replaced by progressive hyperkeratosis, involving thickening
of the cornified layer of the epidermis (summary by Muller et al.,
2006).

Goldsmith (1976) used the designation of epidermolytic hyperkeratosis
for the condition that is called bullous congenital ichthyosiform
erythroderma (BCIE) when generalized, and ichthyosis hystrix (see
146600) when localized. They are presumably distinct entities.

A form of epidermolytic hyperkeratosis that is limited to the palms and
soles, designated palmoplantar keratoderma (EPPK; 144200), is caused by
mutation in the keratin gene KRT9 (607606), and a mild form of EPPK can
also be caused by mutation in KRT1.

CLINICAL FEATURES

Clinically, BCIE presents at birth or soon afterwards with widespread
erythroderma, blistering, and scaling. Blistering tends to improve with
age. Warty thickening of the flexural skin usually appears by the third
or fourth year and persists into adult life. There is, in addition,
hyperkeratosis of the palms and soles. Life expectancy is usually normal
although the disease can be severely incapacitating. Death, often
associated with severe infection, may occur in infancy (review by Eady
et al., 1986).

Heimendinger and Schnyder (1962) described this disorder in a man and 2
of his 3 children, a son and a daughter.

Among 17 families with 2 or more affected persons, Gasser (1964) found
only sibs affected in 2 families, 2 successive generations affected in
12, and 3 generations affected in 3.

The variation in the height of the scale along normal skin markings in
this disorder produces a ridgelike appearance, particularly in the bends
of the elbows and knees, that has led to the designation 'porcupine
man;' see 146600. The rate of new cell formation is abnormally high;
keratinocytes traverse the epidermis from the basal layer to the stratum
corneum in as little as 4 days, a journey that takes 2 weeks in normal
skin. Several kindreds have been reported in which the first affected
member, presumably a mosaic for the new mutation, had linear or patchy
lesions and produced children with generalized bullous ichthyosiform
erythroderma (Epstein, 1992). Epstein (1992) suggested that the
'porcupine man' may have had BCIE.

- Autosomal Recessive Epidermolytic Hyperkeratosis

Muller et al. (2006) reported a consanguineous family in which 2 of 4
sibs had EHK. Both affected sibs showed collodion skin and generalized
erythroderma at birth, and in the months after birth, developed erosions
after mild mechanical trauma and progressive ichthyosis. At the time of
examination, the affected sibs exhibited generalized hyperkeratosis,
which was pronounced over the large joints and the volar surfaces of the
elbows and knees, with palmoplantar sparing. The 8-year-old boy showed
conspicuous cobblestone morphology of the hyperkeratosis in his neck
area, and his 6-year-old sister had erythema and hyperkeratosis as well
as spontaneous erosions on her back. Their first-cousin parents and 2
other sibs were clinically unaffected. Histopathologic examination of
skin biopsies from the affected children revealed hyperkeratosis,
acanthosis, and papillomatosis, with vacuolar degeneration of the
keratinocytes in the suprabasal epidermal layers and coarse
keratohyaline granules within the thickened granular layer. Electron
microscopy at low magnification showed cell morphology similar to that
of autosomal dominant EHK, with the hallmark clumps of loose and
irregularly shaped electrodense material, corresponding to aggregates of
keratin intermediate filaments, in the suprabasal epidermal layers. At
higher magnifications, however, the perinuclear shells often seen in
autosomal dominant EHK patients were absent, and the keratin clumps had
a nearly homogeneous, amorphous structure, in contrast to the keratin
clumps in autosomal dominant EHK which have a filamentous, thready
appearance. Electron microscopy of skin from the clinically unaffected
mother showed no ultrastructural abnormalities of the epidermal
keratinocytes.

Tsubota et al. (2008) reported a Turkish girl with mild BCIE, born of
first-cousin parents, who at birth had widespread, diffuse skin
blistering and erosive lesions. At 3 years of age, she was still
developing skin erosions at sites of trauma, primarily on the face and
trunk, and had brownish hyperkeratotic lesions over her chest, arms,
back, and knees, as well as scaly keratotic lesions on her scalp.
Palmoplantar surfaces were not affected, and nails, hair, and teeth were
normal, as was psychomotor development. Her parents and 3 sibs were
clinically unaffected, and there was no family history of skin diseases.
Electron microscopy showed disruption of the keratin filament network
only in the uppermost keratinocytes of the spinous and granular layers,
where irregularly shaped keratin clumps and cytolysis were seen;
perinuclear shells of clumped keratin filaments were absent.

Terheyden et al. (2009) described a girl with severe EHK from a
consanguineous family of Sudanese descent, who at birth had widespread
erythema and superficial erosions of the face, trunk, and proximal
extremities. In the first few days of life, she became increasingly
lethargic and developed hypernatremia, requiring intensive neonatal
care. Histopathology of a skin biopsy taken shortly after birth was
typical for EHK, showing vacuolar degeneration of suprabasal
keratinocytes and coarse keratohyalin granules in the thickened granular
layer. Electron microscopy showed cytolysis and loose, irregularly
shaped electrodense clumps within the keratinocytes of the suprabasal
layers of the epidermis; the authors noted that the clumps had a nearly
homogeneous, amorphous structure, in contrast to the filamentous,
thready appearance of clumps seen in autosomal dominant EHK. Terheyden
et al. (2009) concluded that a characteristic ultrastructural picture of
sparse keratin filaments and keratin clumps with a nearly homogeneous,
amorphous structure should prompt detailed analysis of the pedigree for
consanguinity and recessive inheritance.

Covaciu et al. (2010) reported an infant, born of first-cousin North
African parents, who had lethal epidermolytic ichthyosis. At birth the
patient had superficial, erythematous, nonbleeding erosions, delimited
by easily detachable epithelial sheets, that covered 70% of the body
surface, with no intact blisters seen. Hair and nails were not affected.
Sepsis and hypernatremic dehydration were early complications, and the
patient died at 3 days of age due to disseminated intravascular
coagulation.

INHERITANCE

Epidermolytic hyperkeratosis is usually transmitted following an
autosomal dominant inheritance pattern (see Heimendinger and Schnyder,
1962; Gasser, 1964), whereas EHK arises from sporadic mutations in up to
50% of cases. Covaciu et al. (2010) stated that the existence of a rare
form of autosomal recessive EHK has a major impact in genetic
counseling. Until now, in sporadic cases, the exclusion of features of
EHK in the parents significantly lowered recurrence risk; however, the
existence of an autosomal recessive form may increase the recurrence
risk from less than 1% to as high as 25% in specific cases, especially
in the presence of consanguineous parents.

PATHOGENESIS

Tonofibrils are fibrillar structural proteins in keratinocytes. They are
the morphologic equivalent of the biochemically well-characterized
prekeratin and precursors of the alpha-keratin of horn cells.
Anton-Lamprecht (1978) stated that 4 genetic disorders of keratinization
are known to have a structural defect of tonofibrils. (1) In the
harlequin fetus (242500), an abnormal x-ray diffraction pattern of the
horn material points to a cross-beta-protein structure instead of the
normal alpha-protein structure of keratin. (2) Bullous ichthyosiform
erythroderma is characterized by an early formation of clumps and
perinuclear shells due to an abnormal arrangement of tonofibrils. (3) In
the Curth-Macklin form of ichthyosis hystrix (146590), concentric
unbroken shells of abnormal tonofilaments form around the nucleus. (4)
In ichthyosis hystrix gravior (146600), only rudimentary tonofilaments
are found with compensatory production of mucous granules.

DIAGNOSIS

- Prenatal Diagnosis

Golbus et al. (1980) achieved prenatal diagnosis by fetal skin biopsy
through the amnioscope. See also Anton-Lamprecht (1981).

Eady et al. (1986) achieved prenatal diagnosis of BCIE at 20 weeks'
gestation by electron microscopic identification of the characteristic
aggregates of tonofilaments within skin-derived amniocytes and in fetal
skin. The mother was affected, an earlier born child was severely
affected and died at 6 days of age with generalized candidiasis, and the
fetus that was diagnosed as affected was aborted at 21 weeks.

MAPPING

The changes in the suprabasal keratinocytes in BCIE resemble those in
the basal keratinocytes in epidermolysis bullosa simplex (EBS; see
131760) in which keratin mutations have been identified (e.g.,
148066.0001). In both diseases, the intermediate filament (IF)
aggregates contain the keratins normally present in the particular
cells: keratins 5 and 14 in the basal cells of Dowling-Meara EBS and
keratins 1 and 10 in the suprabasal cells of BCIE. This fact prompted
Epstein (1992) and his colleagues to use linkage analysis to test
whether keratin gene mutations might also underlie BCIE. Bonifas et al.
(1992) indeed found that the BCIE phenotype was linked to markers in the
12q region containing genes encoding type II keratins. Expression of a
modified truncated human keratin-10 gene (KRT10; 148080) in transgenic
mice gives rise to skin with the morphologic and biochemical
characteristics of epidermolytic hyperkeratosis. As in KRT5 and KRT14
mutations that give rise to epidermolysis bullosa, mutant KRT10
interferes with proper filament network formation and leads to cell
degeneration, but in this case the phenotype is manifested in the
suprabasal layers of the epidermis. As epidermal cells differentiate,
KRT1 and KRT10 protein levels increase, and KRT14 and KRT5 protein
levels decrease. Therefore, as differentiation proceeds, an increasing
gradient of mutant/wildtype keratin is established, yielding epidermal
layers with progressively greater levels of filament disorganization and
cell degeneration. Compton et al. (1992) demonstrated complete linkage
of epidermolytic hyperkeratosis with the KRT1 gene on 12q11-q13.

MOLECULAR GENETICS

In a mother and son with epidermolytic hyperkeratosis, Rothnagel et al.
(1992) identified heterozygosity for a missense mutation in the KRT1
gene (E310Q; 139350.0001). In another mother/son pair and an unrelated
17-year-old male with EHK, the authors identified heterozygosity for 2
missense mutations in the KRT10 gene, L15S (148080.0002) and R10H
(148080.0001), respectively.

In the family with EHK in which Compton et al. (1992) demonstrated
linkage to the type II keratin gene cluster on 12q, Chipev et al. (1992)
identified a missense mutation in the KRT1 gene (L160P; 139350.0002).
Chipev et al. (1992) also found the R10H mutation in KRT10 in 2 EHK
families.

In 2 of 6 unrelated probands with EHK, Cheng et al. (1992) identified
heterozygosity for a missense mutation in the KRT10 gene (R156H;
148080.0003) that segregated with disease in family members and was not
found in 206 control chromosomes.

In a patient with severe EHK, Syder et al. (1994) identified a missense
mutation in the KRT1 gene (Y481C; 139350.0003).

Letai et al. (1993) reported that clinical severity of EHK and
epidermolysis bullosa simplex (EBS) is related to the location of point
mutations within the keratin polypeptides and the degree to which these
mutations perturb keratin IF structure. Point mutations in the most
severe forms have been clustered in the highly conserved ends of the
KRT5 or KRT14 rod domains in EBS (e.g., 148066.0002) and in the
corresponding regions of the KRT10 and KRT1 rod domains in EHK (e.g.,
148080.0003). Mutations in milder cases have been found in
less-conserved regions, either within or outside the rod domain. Of 11
known EBS or EHK mutations, 6 affected a single, highly evolutionarily
conserved arginine residue which, when mutated, markedly disturbs
keratin filament structure and network formation. The site also appeared
to be a hotspot for mutation by CpG methylation and deamination. Letai
et al. (1993) suggested that arg156 of KRT10 and arg125 of KRT14 must
play a special role in maintaining keratin network integrity.

Palmoplantar keratoderma (PPK; see 144200) is a more prominent feature
of patients with BCIE with mutations in KRT1 than in those with
mutations in KRT10 (DiGiovanna and Bale, 1994), possibly because
keratin-1 is the main expression partner of keratin-9 (607606) in
palmoplantar epidermis.

Sprecher et al. (2003) reported a 17-year-old male of Chinese ancestry
who had an unusual variant EHK phenotype. His skin appeared normal at
birth and during infancy. At 2 years of age, the skin of palms and soles
became thickened and he developed well-demarcated, yellowish
hyperkeratotic plaques over the ankles, elbows, and knees. Islands of
superficial peeling reminiscent of the 'mauserung' phenomenon in
ichthyosis bullosa of Siemens (146800) were observed on the skin of the
trunk and the extensor surface of the legs. The disease progressively
worsened during childhood. Histologic examination of a skin biopsy
revealed marked orthokeratotic hyperkeratosis, papillomatosis, and
acanthosis. Occasional foci of vacuolated cells and binucleated cells
were observed in the upper spinous and granular layers. Electron
microscopy demonstrated fractured and shortened keratin intermediate
filaments (KIFs) that remained connected to the desmosomes, occasional
KIF clumping, and abnormalities of the extracellular lamellar bilayers.
Sprecher et al. (2003) determined that this individual was heterozygous
for a single-nucleotide insertion (1752insG; 139350.0015) in the KRT1
gene.

- Mosaicism

Epidermal nevi (162900) appear at or shortly after birth as localized
epidermal thickening with hyperpigmentation that frequently follow the
lines of Blaschko, suggesting that they result from postzygotic somatic
mutation in the skin. A rare subgroup of epidermal nevus is clinically
indistinguishable from other epidermal nevi, but displays
histopathologic features typical of epidermolytic hyperkeratosis, with
normal basal cells and suprabasal cells that show clumping of the
keratin filaments that make up the structural framework of the epidermal
keratinocyte (Anton-Lamprecht, 1983). Patients with this type of
epidermal nevi sometimes have offspring with generalized EHK (Paller et
al., 1994).

Nazzaro et al. (1990) reported 2 unrelated families in both of which a
child with generalized EHK had a parent with linear epidermolytic
hyperkeratosis, otherwise known as epidermolytic epidermal nevus.
Gonadal mosaicism was postulated by Nazzaro et al. (1990).

Eng et al. (1991) observed an 8-year-old Puerto Rican boy with
epidermolytic hyperkeratosis of Brocq showing diffuse involvement of the
changes typical of this disorder as well as a systematized linear
pattern of 'hyperpigmented, hyperkeratotic and hypopigmented swirls'
covering large parts of his body. Happle and Konig (1999) suggested that
this represents a phenomenon of twin spotting with some patches of
excessive involvement and others with absent involvement. They
speculated that during embryogenesis, somatic recombination gave rise to
2 different daughter cells. One of them had become homozygous for a
mutation (in either keratin-1 or keratin-10), resulting in bands of
expressively involved hyperkeratotic skin, whereas the other cell had
become homozygous for the wildtype allele, resulting in bands of
expressively involved hyperkeratotic skin, whereas the other cell had
become homozygous for the wildtype allele, resulting in bands of
hypopigmented healthy skin. The encountering of some epidermolytic foci
within the hypopigmented skin would mirror the fact that mosaic
populations of cells often intermingle to some degree.

In a family with EHK in which Cheng et al. (1992) had identified an
R156H mutation in the KRT10 gene (148080.0003), Paller et al. (1994)
found that blood genomic DNA from the grandmother, who had markedly
milder EHK and extensive epidermal nevi, showed underrepresentation of
the mutation. Analysis of lesional skin revealed the presence of the
R156H mutation, whereas no mutation was detected in normal skin. Paller
et al. (1994) also analyzed the KRT1 and KRT10 genes in 2 parents with
epidermal nevi (linear form of EHK) and 4 of their offspring with EHK
from the families originally reported by Nazzaro et al. (1990) and
identified heterozygosity for 2 missense mutations in the KRT10 gene,
R156C (148080.0010) and M150T (148080.0013), respectively, in all cell
types examined from the offspring. Analysis of keratinocytes from the
parents' epidermolytic epidermal nevi revealed heterozygosity for the
mutations, respectively, which were not found in unaffected skin and
were absent or underrepresented in blood and skin fibroblasts from the
parents. Paller et al. (1994) concluded that epidermal nevus of the
epidermolytic hyperkeratotic type is a mosaic genetic disorder of
suprabasal keratin.

Happle (1997) noted that an early postzygotic mutation can cause
autosomal dominant skin disorders to become manifest in a mosaic form,
involving the body in a linear, patchy, or otherwise circumscribed
arrangement, in which the segmental lesions usually show the same degree
of severity as that found in the corresponding nonmosaic trait.
Occasionally, however, the intensity of involvement observed in the
circumscribed area is far more pronounced; Happle (1997) suggested that
this phenomenon can be explained by delineating a rule of dichotomous
segmental manifestations reflecting different states of zygosity.
Heterozygosity for the mutation results in severity corresponding to
that in the nonsegmental phenotype; loss of heterozygosity for the same
allele causes markedly more severe involvement. Happle (1997) pointed to
examples of these 2 forms classified by severity, type 1 and type 2
respectively, in epidermolytic hyperkeratosis of Brocq. Except in the
area of the epidermal nevus of epidermolytic type, the skin of these
mosaic individuals is completely normal. The mosaicism may, however,
involve the gonad and such individuals may give birth to children with
diffuse epidermolytic hyperkeratosis of Brocq (Nazzaro et al., 1990),
which Happle (1997) designated type 1 segmental involvement. Type 2
segmental involvement, he suggested, is represented by patients such as
the 21-year-old man reported by Hadlich and Linse (1989) to have typical
clinical and histopathologic features of epidermolytic hyperkeratosis of
Brocq with an additional feature of a linear verrucous nevus on his left
forearm that extended to the dorsal aspect of the hand. Happle (1997)
suggested that the linear lesion was an example of type 2 involvement,
representing a change from heterozygosity to either homozygosity or
hemizygosity for the Brocq mutation.

Nomura et al. (2001) studied a 19-year-old boy with severe ichthyosiform
erythroderma and prominent palmoplantar hyperkeratosis with digital
contractures. His mother exhibited only mild ichthyosiform skin,
granular verrucous lesions, and less severe streaky palmoplantar
hyperkeratosis. Mutation analysis in the proband showed a KRT1 mutation
(139350.0008). In the mother, the same mutation was recognized, but only
faintly in the leukocyte DNA, suggesting that she was most likely mosaic
for this mutation. These results suggested that mild forms of BCIE may
actually represent extensive epidermal nevi/keratin gene mosaicism.

- Recessive Epidermolytic Hyperkeratosis

In 2 affected sibs with EHK, born of first-cousin parents, Muller et al.
(2006) identified homozygosity for a nonsense mutation in the KRT10 gene
(148080.0019). The clinically unaffected parents and 2 unaffected sibs
as well as 3 other unaffected relatives were heterozygous for the
mutation, which was not found in 50 controls.

In a 3-year-old Turkish girl with mild BCIE, born of first-cousin
parents, Tsubota et al. (2008) identified homozygosity for a nonsense
mutation in the KRT10 gene (148080.0020); her unaffected parents were
heterozygous carriers and the mutation was not found in 50 controls.

In a girl with severe EHK from a consanguineous family of Sudanese
descent, Terheyden et al. (2009) identified homozygosity for a 1-bp
insertion in the KRT10 gene (148080.0021). Unaffected family members
were heterozygous carriers of the mutation.

In an infant with epidermolytic ichthyosis who was born of
consanguineous North African parents and died at 3 days of age, Covaciu
et al. (2010) identified homozygosity for a splice site mutation in the
KRT10 gene (148080.0022).

*FIELD* SA
Barker and Sachs (1953); Bonifas et al. (1992)
*FIELD* RF
1. Anton-Lamprecht, I.: Prenatal diagnosis of genetic disorders of
the skin by means of electron microscopy. Hum. Genet. 59: 392-405,
1981.

2. Anton-Lamprecht, I.: Electron microscopy in the early diagnosis
of genetic disorders of the skin. Dermatologica 157: 65-85, 1978.

3. Anton-Lamprecht, I.: Genetically induced abnormalities of epidermal
differentiation and ultrastructure in ichthyoses and epidermolyses:
pathogenesis, heterogeneity, fetal manifestation, and prenatal diagnosis. J.
Invest. Derm. 81 (suppl.): 149S-156S, 1983.

4. Barker, L. P.; Sachs, W.: Bullous congenital ichthyosiform erythrodermia. Arch.
Derm. 67: 443-455, 1953.

5. Bonifas, J. M.; Bare, J. W.; Chen, M. A.; Lee, M. K.; Slater, C.
A.; Goldsmith, L. A.; Epstein, E. H., Jr.: Linkage of the epidermolytic
hyperkeratosis phenotype and the region of the type II keratin gene
cluster on chromosome 12. J. Invest. Derm. 99: 524-527, 1992.

6. Bonifas, J. M.; Bare, W.; Chen, M. A.; Niemi, K. M.; Epstein, E.
H., Jr.: Epidermolytic hyperkeratosis: linkage to keratin gene regions
on chromosomes 12q and 17q in two families. J. Invest. Derm. 98:
573 only, 1992.

7. Cheng, J.; Syder, A. J.; Yu, Q.-C.; Letai, A.; Paller, A. S.; Fuchs,
E.: The genetic basis of epidermolytic hyperkeratosis: a disorder
of differentiation-specific epidermal keratin genes. Cell 70: 811-819,
1992.

8. Chipev, C. C.; Korge, B. P.; Markova, N.; Bale, S. J.; DiGiovanna,
J. J.; Compton, J. G.; Steinert, P. M.: A leucine-to-proline mutation
in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis. Cell 70:
821-828, 1992.

9. Compton, J. G.; DiGiovanna, J. J.; Santucci, S. K.; Kearns, K.
S.; Amos, C. I.; Abangan, D. L.; Korge, B. P.; McBride, O. W.; Steinert,
P. M.; Bale, S. J.: Linkage of epidermolytic hyperkeratosis to the
type II keratin gene cluster on chromosome 12q. Nature Genet. 1:
301-305, 1992.

10. Covaciu, C.; Castori, M.; De Luca, N.; Ghirri, P.; Nannipieri,
A.; Ragone, G.; Zambruno, G.; Castiglia, D.: Lethal autosomal recessive
epidermolytic ichthyosis due to a novel donor splice-site mutation
in KRT10. Brit. J. Derm. 162: 1384-1387, 2010.

11. DiGiovanna, J. J.; Bale, S. J.: Clinical heterogeneity in epidermolytic
hyperkeratosis. Arch. Derm. 130: 1026-1035, 1994.

12. Eady, R. A. J.; Gunner, D. B.; Carbone, L. D. L.; Dagna Bricarelli,
F.; Gosden, C. M.; Rodeck, C. H.: Prenatal diagnosis of bullous ichthyosiform
erythroderma: detection of tonofilament clumps in fetal epidermal
and amniotic fluid cells. J. Med. Genet. 23: 46-51, 1986.

13. Eng, A. M.; Brody, P.; Rhee, H. L.; Bronson, D. M.: Congenital
ichthyosiform erythroderma and epidermal nevus. Int. J. Derm. 30:
284-287, 1991.

14. Epstein, E. H., Jr.: Personal Communication. San Francisco,
Calif. 5/29/1992.

15. Gasser, V.: Zur Klinik, Histologie und Genetik der 'Erythrodermie
congenitale ichthyosiforme bulleuse (Brocq.)'. Arch. Klaus Stift.
Vererbungsforsch. 38: 23-59, 1964.

16. Golbus, M. S.; Sagebiel, R. W.; Filly, R. A.; Gindhart, T. D.;
Hall, J. G.: Prenatal diagnosis of congenital bullous ichthyosiform
erythroderma (epidermolytic hyperkeratosis) by fetal skin biopsy. New
Eng. J. Med. 302: 93-95, 1980.

17. Goldsmith, L. A.: The ichthyoses. Prog. Med. Genet. 1: 185-210,
1976.

18. Hadlich, J.; Linse, R.: Keratosen mit granularer Degeneration
und ihre Beziehungen zueinander. II. Heterophanie von epidermolytic
Hyperkeratosis (Erythrodermia congenitalis ichthyosiformis bullosa),
Naevus verrucosus hystricoides und Keratosis palmoplantaris cum degeneratione
granulosa Vorner. Derm. Monats. 175: 418-424, 1989.

19. Happle, R.: A rule concerning the segmental manifestation of
autosomal dominant skin disorders: review of clinical examples providing
evidence for dichotomous types of severity. Arch. Derm. 133: 1505-1509,
1997.

20. Happle, R.; Konig, A.: Dominant traits may give rise to paired
patches of either excessive or absent involvement. (Letter) Am. J.
Med. Genet. 84: 176-177, 1999.

21. Heimendinger, J.; Schnyder, U. W.: Bullose 'Erythrodermie ichthyosiforme
congenitale' in zwei Generationen. Helv. Paediat. Acta 17: 47-55,
1962.

22. Letai, A.; Coulombe, P. A.; McCormick, M. B.; Yu, Q.-C.; Hutton,
E.; Fuchs, E.: Disease severity correlates with position of keratin
point mutations in patients with epidermolysis bullosa simplex. Proc.
Nat. Acad. Sci. 90: 3197-3201, 1993.

23. Muller, F. B.; Huber, M.; Kinaciyan, T.; Hausser, I.; Schaffrath,
C.; Krieg, T.; Hohl, D.; Korge, B. P.; Arin, M. J.: A human keratin
10 knockout causes recessive epidermolytic hyperkeratosis. Hum. Molec.
Genet. 15: 1133-1141, 2006.

24. Nazzaro, V.; Ermacora, E.; Santucci, B.; Caputo, R.: Epidermolytic
hyperkeratosis: generalized form in children from parents with systematized
linear form. Brit. J. Derm. 122: 417-422, 1990.

25. Nomura, K.; Umeki, K.; Hatayama, I.; Kuronuma, T.: Phenotypic
heterogeneity in bullous congenital ichthyosiform erythroderma: possible
somatic mosaicism for keratin gene mutation in the mildly affected
mother of the proband. Arch. Derm. 137: 1192-1195, 2001.

26. Paller, A. S.; Syder, A. J.; Chan, Y.-M.; Yu, Q.-C.; Hutton, E.;
Tadini, G.; Fuchs, E.: Genetic and clinical mosaicism in a type of
epidermal nevus. New Eng. J. Med. 331: 1408-1415, 1994.

27. Rothnagel, J. A.; Dominey, A. M.; Dempsey, L. D.; Longley, M.
A.; Greenhalgh, D. A.; Gagne, T. A.; Huber, M.; Frenk, E.; Hohl, D.;
Roop, D. R.: Mutations in the rod domains of keratins 1 and 10 in
epidermolytic hyperkeratosis. Science 257: 1128-1130, 1992.

28. Sprecher, E.; Yosipovitch, G.; Bergman, R.; Ciubutaro, D.; Indelman,
M.; Pfendner, E.; Goh, L. C.; Miller, C. J.; Uitto, J.; Richard, G.
: Epidermolytic hyperkeratosis and epidermolysis bullosa simplex caused
by frameshift mutations altering the V2 tail domains of keratin 1
and keratin 5. J. Invest. Derm. 120: 623-626, 2003.

29. Syder, A. J.; Yu, Q.-C.; Paller, A. S.; Giudice, G.; Pearson,
R.; Fuchs, E.: Genetic mutations in the K1 and K10 genes of patients
with epidermolytic hyperkeratosis: correlation between location and
disease severity. J. Clin. Invest. 93: 1533-1542, 1994.

30. Terheyden, P.; Grimberg, G.; Hausser, I.; Rose, C.; Korge, B.
P.; Krieg, T.; Arin, M. J.: Recessive epidermolytic hyperkeratosis
caused by a previously unreported termination codon mutation in the
keratin 10 gene. (Letter) J. Invest. Derm. 129: 2721-2723, 2009.

31. Tsubota, A.; Akiyama, M.; Kanitakis, J.; Sakai, K.; Nomura, T.;
Claudy, A.; Shimizu, H.: Mild recessive bullous congenital ichthyosiform
erythroderma due to a previously unidentified homozygous keratin 10
nonsense mutation. J. Invest. Derm. 128: 1648-1652, 2008.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKIN, NAILS, HAIR:
[Skin];
Generalized erythroderma;
Skin blistering;
Scaly skin;
Hyperkeratosis of palms and soles;
Warty thickening of flexural skin;
HISTOLOGY:;
Acanthotic epidermis;
Hyperkeratosis of stratum corneum;
Keratin clumping in suprabasal epidermal layers;
Vacuolation of stratum granulosum;
ELECTRON MICROSCOPY:;
Tonofilament aggregation in suprabasal keratinocytes

MOLECULAR BASIS:
Caused by mutation in the keratin 1 gene (KRT1, 139350.0001);
Caused by mutation in the keratin 10 gene (KRT10, 148080.0001)

*FIELD* CN
Marla J. F. O'Neill - revised: 04/26/2013

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

*FIELD* ED
joanna: 04/26/2013
alopez: 3/7/2003

*FIELD* CN
Marla J. F. O'Neill - updated: 4/15/2011
Marla J. F. O'Neill - updated: 8/5/2009
Marla J. F. O'Neill - updated: 7/13/2009
Gary A. Bellus - updated: 4/10/2003
Gary A. Bellus - updated: 3/18/2003
Victor A. McKusick - updated: 8/5/1999
Victor A. McKusick - updated: 5/10/1999

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 01/24/2013
joanna: 12/19/2012
wwang: 4/27/2011
terry: 4/15/2011
carol: 8/5/2009
terry: 7/13/2009
carol: 7/13/2009
alopez: 4/10/2003
alopez: 3/18/2003
alopez: 3/10/2003
alopez: 3/7/2003
mcapotos: 7/25/2000
terry: 2/8/2000
jlewis: 8/25/1999
terry: 8/5/1999
terry: 5/20/1999
mgross: 5/13/1999
mgross: 5/12/1999
terry: 5/10/1999
alopez: 5/14/1998
mimadm: 4/14/1994
carol: 4/12/1994
warfield: 4/7/1994
carol: 12/14/1993
carol: 5/21/1993
carol: 12/23/1992

MIM 139350
*RECORD*
*FIELD* NO
139350
*FIELD* TI
*139350 KERATIN 1; KRT1
;;CYTOKERATIN 1
*FIELD* TX

CLONING

Popescu et al. (1989) isolated 2 type II keratin genes, one coding for
read morekeratin-1, and another closely linked gene, 10 to 15 kb upstream, of
unknown gene product.

GENE FUNCTION

Keratin-1 is a specific marker for terminal differentiation in mammalian
epidermis. Data of Lessin et al. (1988) demonstrated that although genes
K1 and K10 (148080) are coexpressed in terminally differentiated
epidermis, they are not linked in the genome, implying the existence of
trans-acting factors involved in the regulation of their expression.

Schimkat et al. (1990) demonstrated 4 isokeratin patterns by means of
one-dimensional SDS electrophoresis of low-sulfur proteins in human
hair. The phenotypes had the following frequencies: K1 = 70%, K1m = 18%,
K3 = 9%, and K3m = 3%. Pedigree analysis and evaluation of observed and
expected frequencies of the phenotypes led Schimkat et al. (1990) to
conclude that the phenotypes are controlled by genes at 2 independent
autosomal loci designated K and m. They suggested that the K3 and m
alleles are dominant, whereas the K1 and non-m alleles are recessive.

MAPPING

In the mouse, alpha-keratin is encoded by a gene on chromosome 15 in a
segment closely linked to that encoding the Hox3 genes (Nadeau, 1987).
Homology of synteny would indicate that alpha-keratin is coded by a gene
on chromosome 12, specifically in the segment 12q11-q21, in man. Indeed,
by use of specific cDNA clones in conjunction with somatic cell hybrid
analysis and in situ hybridization, Lessin et al. (1988) showed that the
gene they referred to as K1, a type II keratin of 67 kD, maps to
12q11-q13. In somatic cell hybrid analysis, the K1 gene segregated
concordantly with the HOX3 gene cluster.

By in situ hybridization, Popescu et al. (1989) localized the KRT1 gene
to 12q11-q13.

Yoon et al. (1994) demonstrated that 8 previously known type II keratin
genes are located in a cluster at 12q13 as determined by the study of a
YAC contig. The cytogenetic location of the type II keratin cluster was
established by fluorescence in situ hybridization. The 8 type II keratin
genes assigned to that region were KRT1, KRT2, KRT4, KRT5, KRT6A, KRT6B,
KRT7, and KRT8. Yoon et al. (1994) suspected that other keratin genes
were located in the cluster. They identified one type I keratin gene,
KRT18, situated next to its type II partner, KRT8, in this cluster.

MOLECULAR GENETICS

In a large family with epidermolytic hyperkeratosis (EHK; 113800),
Pulkkinen et al. (1993) found close linkage with markers flanking the
keratin gene cluster on 12q; maximum lod = 3.61 at theta = 0.0. This
finding implicated KRT1, the type II keratin expressed in the
suprabasilar keratinocytes, as a candidate gene for EHK in this family.

In a mother and son with epidermolytic hyperkeratosis, Rothnagel et al.
(1992) identified heterozygosity for a missense mutation in the KRT1
gene (E310Q; 139350.0001). Mutations in the KRT10 gene (148080) also
cause EHK, a finding consistent with the fact that this keratin pair
forms heterodimers and comprises the keratin intermediate filaments in
the suprabasal epidermal cells.

Compton (1994) reviewed 31 known keratin mutations in epidermolytic
hyperkeratosis, epidermolysis bullosa simplex (see 131760), and
epidermolytic palmoplantar keratoderma (EPPK; 144200) identified to that
date: 7 in keratin-1, 5 in keratin-5 (148040), 8 in keratin-10 (148080),
4 in keratin-9 (607606), and 7 in keratin-14 (148066).

In a 4-generation family segregating autosomal dominant nonepidermolytic
palmoplantar keratoderma (NEPPK; 600962) that mapped to chromosome
12q11-q13, Kimonis et al. (1994) identified a missense mutation in the
V1 end domain of keratin-1 (K73I; 139350.0004).

In 3 Scottish families with a mild form of EPPK, Hatsell et al. (2001)
identified a splice site mutation in the KRT1 gene (139350.0014).

*FIELD* AV
.0001
EPIDERMOLYTIC HYPERKERATOSIS
KRT1, GLU310GLN

In a family in which mother and son had epidermolytic hyperkeratosis
(113800), Rothnagel et al. (1992) demonstrated heterozygosity for a
G-to-C transversion predicted to result in substitution of glutamine for
glutamic acid at position 310 of the keratin-1 protein. The mutation was
in the highly conserved carboxyl terminal of the rod domain of the
protein. Structural analysis of the mutation predicted that heterodimer
formation would be unaffected, although filament assembly and elongation
would be severely compromised. The data implied that an intact keratin
intermediate filament network is required for the maintenance of both
cellular and tissue integrity. The affected persons in this family
exhibited rare blistering neonatally and during treatment with
retinoids. Otherwise, they suffered primarily from disseminated
hyperkeratotic lesions over joints, hands, and feet.

.0002
EPIDERMOLYTIC HYPERKERATOSIS
KRT1, LEU160PRO

In a large family with epidermolytic hyperkeratosis (113800) in which
Compton et al. (1992) demonstrated linkage to the type II keratin gene
cluster on 12q, Chipev et al. (1992) demonstrated a CTT-to-CCT
transition in codon 160 resulting in the substitution of proline for
leucine. This nonconservative substitution in the H1 subdomain was
predicted to introduce a significant change in protein structure.

.0003
EPIDERMOLYTIC HYPERKERATOSIS
KRT1, TYR481CYS

In a patient with severe epidermolytic hyperkeratosis (113800), Syder et
al. (1994) demonstrated a tyr481-to-cys mutation in the KRT1 gene.

.0004
PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC
KRT1, LYS73ILE

In a large family in which multiple members suffered from
nonepidermolytic palmoplantar keratoderma (600962), Kimonis et al.
(1994) demonstrated linkage of the disorder with the type II keratin
cluster on chromosome 12. The mutation was a change of codon 73 from AAA
to ATA. Sequence analysis identified a single base change in the
amino-terminal V1 variable subdomain of keratin-1, resulting in a
lys-to-ile substitution. This nonconservative mutation completely
cosegregated with the disease and was not observed in 50 unrelated
unaffected persons. They found that the V1 subdomain contains a
22-residue window that is conserved among most type II keratins. The
altered lysine is an invariant residue in this conserved sequence.
Previously described keratin mutations affect the central regions of the
protein important for filament assembly and stability, and cause
diseases characterized by cellular degeneration or disruption, e.g.,
epidermolytic palmoplantar keratoderma. The disease mutation described
by Kimonis et al. (1994) was the first found in a keratin chain variable
end region. The fact that epidermolysis was not associated supports the
concept that the amino-terminal domain of keratins is involved in
supramolecular interactions of keratin filaments rather than stability.

.0005
ICHTHYOSIS, CYCLIC, WITH EPIDERMOLYTIC HYPERKERATOSIS
KRT1, ILE479THR

In an individual with cyclic ichthyosis with epidermolytic
hyperkeratosis (607602), Sybert et al. (1999) demonstrated a
heterozygous 1436T-C mutation in the KRT1 gene, predicting a change of
isoleucine to threonine (I479T) in the highly conserved
helix-termination motif.

.0006
ICHTHYOSIS, CYCLIC, WITH EPIDERMOLYTIC HYPERKERATOSIS
KRT1, ILE479PHE

See 139350.0005. In a second family with autosomal dominant cyclic
ichthyosis with epidermolytic hyperkeratosis (607602), Sybert et al.
(1999) found a 1435A-T mutation, predicting an
isoleucine-to-phenylalanine substitution in codon 479 (I479F).

.0007
EPIDERMOLYTIC HYPERKERATOSIS
KRT1, VAL155ASP

In a woman with epidermolytic hyperkeratosis (113800), Whittock et al.
(2001) identified a 464T-A transversion in the KRT1 gene that resulted
in a val155-to-asp (V155D) substitution within the H1 region of the
keratin-1 rod domain. This valine residue is highly conserved among all
type II keratins, suggesting that minor changes at this residue may
affect keratin conformation.

.0008
EPIDERMOLYTIC HYPERKERATOSIS
KRT1, ASN187LYS

In a patient with primarily palmoplantar epidermolytic hyperkeratosis
(113800) grade 2, Lee et al. (2002) reported a C-to-A transversion at
nucleotide 564 in exon 1 of the KRT1 gene that resulted in an
asn187-to-lys (N187K) mutation, at the eighth residue of the 1A rod
domain segment.

In a 19-year-old male with severe ichthyosiform erythroderma and
prominent palmoplantar hyperkeratosis with digital contractures, Nomura
et al. (2001) identified the N187K mutation in the KRT1 gene. The
mutation was recognized only faintly in the leukocyte DNA of his mother,
who had a milder phenotype, suggesting that she was mosaic for the
mutation.

.0009
EPIDERMOLYTIC HYPERKERATOSIS
KRT1, LEU475PRO

In a patient with primarily palmoplantar epidermolytic hyperkeratosis
(113800) grade 2, Lee et al. (2002) reported a 1457T-C transition in
exon 7 of the KRT1 gene that caused a leu475-to-pro (L475P) amino acid
change, at the tenth residue from the end of 2B rod domain segment.

.0010
PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC
KRT1, IVS1, T-A, +2

In a 34-year-old man and his daughter, who both had mild diffuse PPK at
birth (600962) and developed mild flexural-limited scaling,
Terron-Kwiatkowski et al. (2002) identified a 5-prime donor splice site
mutation in exon 1 (591+2T-A) of the KRT1 gene that predicted a 22-amino
acid in-frame deletion in the keratin-1 1A domain. The mutation was not
found in 50 controls from the local population.

.0011
PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC
KRT1, 24-BP DEL, NT1376

In an 8-year-old girl with diffuse palmoplantar keratoderma at birth
(600962) who developed fine scaling over the lateral and anterior neck,
lower back, external ears, and axillae, Terron-Kwiatkowski et al. (2002)
identified an in-frame deletion in exon 7 of the KRT1 gene (1376del24)
that predicted a foreshortened 2B coiled-coil domain of keratin-1. The
mutation was not found in 50 controls from the local population.

.0012
KERATOSIS PALMOPLANTARIS STRIATA III
KRT1, 1-BP DEL, 1628G

Whittock et al. (2002) reported a kindred affected with SPPK (607654)
that was caused by a frameshift mutation, 1628delG, within the V2 domain
of keratin-1, which led to the partial loss of the glycine loop motif in
the V2 domain and the gain of a novel 70-amino acid peptide. The authors
noted that this mutation is very similar to one described by Sprecher et
al. (2001) in a family with ichthyosis hystrix, a frameshift mutation
within the third glycine loop (139350.0013), the only significant
difference in molecular terms between the severe mutilating form of
ichthyosis hystrix and milder SPPK being the number of glycine loops
present. Whittock et al. (2002) stated that the changes in the keratin
intermediate filaments produced by the 2 mutations were very different.

.0013
ICHTHYOSIS HISTRIX, CURTH-MACKLIN TYPE
KRT1, 5191GG-A

In a family with ichthyosis hystrix, Curth-Macklin type (IHCM; 146590),
Sprecher et al. (2001) reported a 5191GG-A mutation in exon 9 of the
KRT1 gene leading to a frameshift and premature termination codon 229 bp
downstream. The mutation occurred in a sequence encoding the V2 domain
of K1 and was predicted to result in frameshift and translation of an
aberrant and truncated protein tail of 77 residues, 32 residues shorter
than the wildtype protein. Structural analyses disclosed a failure in
keratin intermediate filament bundling, retraction of the cytoskeleton
from the nucleus, and failed translocation of loricrin (152445) to the
desmosomal plaques.

Ishida-Yamamoto et al. (2003) studied the distribution pattern of mutant
K1 protein as well as the desmosomal ultrastructure in skin samples of a
patient with IHCM by immunohistochemistry and immunoelectron microscopy.
They referred to this mutation as 1609-1610delGGinsA. Ishida-Yamamoto et
al. (2003) showed that the predicted mutant K1 allele leading to IHCM is
indeed expressed in vivo and not subjected to nonsense-mediated mRNA
decay. Ishida-Yamamoto et al. (2003) suggested that this K1 mutant
interferes with bundling of keratin intermediate filaments, possibly in
a dominant-negative fashion, thus perturbing the keratin intermediate
filament cytoskeleton. They found normal desmosome formation in IHCM,
suggesting that the cytopathologic effects leading to hyperkeratosis and
PPK in this disorder differ from those in SPPK, and may be related to
abnormalities in supramolecular keratin intermediate filament
organization and cytoplasmic trafficking of insoluble proteins, such as
loricrin, as suggested by Sprecher et al. (2001). Ishida-Yamamoto et al.
(2003) suggested that is also possible that mutant K1 affects shapes of
the cells and integrity of other cellular structures, such as organelles
and the nucleus, leading to gross alteration in the overall structures
of the epidermis.

.0014
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC
KRT1, IVS6, G-A, +1

In 3 Scottish kindreds with a mild form of epidermolytic palmoplantar
keratoderma (144200), Hatsell et al. (2001) identified a 4134G-A
transition in the splice donor site of exon 6 of the KRT1 gene. The
nucleotide substitution led to the utilization of a novel in-frame
splice site 54 bases downstream of the mutation with the subsequent
insertion of 18 amino acids into the 2B rod domain. This mutation
appears to have had a milder effect than previously described mutations
in the helix initiation and termination sequence on the function of the
rod domain, with regard to filament assembly and stability. Affected
individuals displayed only mild focal epidermolysis in the spinous layer
of palmoplantar epidermis. The mutation was not found in 50 unrelated
controls.

.0015
EPIDERMOLYTIC HYPERKERATOSIS, LATE-ONSET
KRT1, 1-BP INS, 1752G

Sprecher et al. (2003) reported a 17-year-old male of Chinese ancestry
who had an unusual variant epidermolytic hyperkeratosis (113800)
phenotype with late onset. They determined that this individual was
heterozygous for a single-nucleotide insertion (1752insG) in KRT1. As a
result of the 1752insG mutation, the variable K1 end domain was
predicted to be replaced by an aberrant sequence of 69 amino acids very
rich in arginine and tryptophan residues that is 8 amino acids longer
than the wildtype protein. The mutation eliminated 2 of the 10 glycine
loops that are thought to be crucial for interactions of the K1 tail
with proteins of the cornified cell envelope. Sprecher et al. (2003)
concluded that these changes are likely to alter significantly the
structural and chemical characteristics of the K1 tail.

*FIELD* SA
Fraser et al. (1976); Lee et al. (1978)
*FIELD* RF
1. Chipev, C. C.; Korge, B. P.; Markova, N.; Bale, S. J.; DiGiovanna,
J. J.; Compton, J. G.; Steinert, P. M.: A leucine-to-proline mutation
in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis. Cell 70:
821-828, 1992.

2. Compton, J. G.: Epidermal disease: faulty keratin filaments take
their toll. Nature Genet. 6: 6-7, 1994.

3. Compton, J. G.; DiGiovanna, J. J.; Santucci, S. K.; Kearns, K.
S.; Amos, C. I.; Abangan, D. L.; Korge, B. P.; McBride, O. W.; Steinert,
P. M.; Bale, S. J.: Linkage of epidermolytic hyperkeratosis to the
type II keratin gene cluster on chromosome 12q. Nature Genet. 1:
301-305, 1992.

4. Fraser, R. D. B.; MacRae, T. P.; Suzuki, E.: Structure of the
alpha-keratin microfibril. J. Molec. Biol. 108: 435-452, 1976.

5. Hatsell, S. J.; Eady, R. A.; Wennerstrand, L.; Dopping-Hepenstal,
P.; Leigh, I. M.; Munro, C.; Kelsell, D. P.: Novel splice site mutation
in keratin 1 underlies mild epidermolytic palmoplantar keratoderma
in three kindreds. J. Invest. Derm. 116: 606-609, 2001.

6. Ishida-Yamamoto, A.; Richard, G.; Takahashi, H.; Iizuka, H.: In
vivo studies of mutant keratin 1 in ichthyosis hystrix Curth-Macklin. J.
Invest. Derm. 120: 498-500, 2003.

7. Kimonis, V.; DiGiovanna, J. J.; Yang, J.-M.; Doyle, S. Z.; Bale,
S. J.; Compton, J. G.: A mutation in the V1 end domain of keratin
1 in non-epidermolytic palmar-plantar keratoderma. J. Invest. Derm. 103:
764-769, 1994.

8. Lee, D.-Y.; Ahn, K.-S.; Lee, C.-H.; Rho, N.-K.; Lee, J.-H.; Lee,
E.-S.; Steinert, P. M.; Yang, J.-M.: Two novel mutations in the keratin
1 gene in epidermolytic hyperkeratosis. J. Invest. Derm. 119: 976-977,
2002.

9. Lee, L. D.; Ludwig, K.; Baden, H. P.: Matrix proteins of human
hair as a tool for identification of individuals. Forensic Sci. 11:
115-121, 1978.

10. Lessin, S. R.; Huebner, K.; Isobe, M.; Croce, C. M.; Steinert,
P. M.: Chromosomal mapping of human keratin genes: evidence of non-linkage. J.
Invest. Derm. 91: 572-578, 1988.

11. Nadeau, J. H.: Personal Communication. Bar Harbor, Me. 7/29/1987.

12. Nomura, K.; Umeki, K.; Hatayama, I.; Kuronuma, T.: Phenotypic
heterogeneity in bullous congenital ichthyosiform erythroderma: possible
somatic mosaicism for keratin gene mutation in the mildly affected
mother of the proband. Arch. Derm. 137: 1192-1195, 2001.

13. Popescu, N. C.; Bowden, P. E.; DiPaolo, J. A.: Two type II keratin
genes are localized on human chromosome 12. Hum. Genet. 82: 109-112,
1989.

14. Pulkkinen, L.; Christiano, A. M.; Knowlton, R. G.; Uitto, J.:
Epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma):
genetic linkage to chromosome 12q in the region of the type II keratin
gene cluster. J. Clin. Invest. 91: 357-361, 1993.

15. Rothnagel, J. A.; Dominey, A. M.; Dempsey, L. D.; Longley, M.
A.; Greenhalgh, D. A.; Gagne, T. A.; Huber, M.; Frenk, E.; Hohl, D.;
Roop, D. R.: Mutations in the rod domains of keratins 1 and 10 in
epidermolytic hyperkeratosis. Science 257: 1128-1130, 1992.

16. Schimkat, M.; Baur, M. P.; Henke, J.: Inheritance of some electrophoretic
phenotypes of human hair. Hum. Genet. 85: 311-314, 1990.

17. Sprecher, E.; Ishida-Yamamoto, A.; Becker, O. M.; Marekov, L.;
Miller, C. J.; Steinert, P. M.; Neldner, K.; Richard, G.: Evidence
for novel functions of the keratin tail emerging from a mutation causing
ichthyosis hystrix. J. Invest. Derm. 116: 511-519, 2001.

18. Sprecher, E.; Yosipovitch, G.; Bergman, R.; Ciubutaro, D.; Indelman,
M.; Pfendner, E.; Goh, L. C.; Miller, C. J.; Uitto, J.; Richard, G.
: Epidermolytic hyperkeratosis and epidermolysis bullosa simplex caused
by frameshift mutations altering the V2 tail domains of keratin 1
and keratin 5. J. Invest. Derm. 120: 623-626, 2003.

19. Sybert, V. P.; Francis, J. S.; Corden, L. D.; Smith, L. T.; Weaver,
M.; Stephens, K.; McLean, W. H. I.: Cyclic ichthyosis with epidermolytic
hyperkeratosis: a phenotype conferred by mutations in the 2B domain
of keratin K1. Am. J. Hum. Genet. 64: 732-738, 1999.

20. Syder, A. J.; Yu, Q.-C.; Paller, A. S.; Giudice, G.; Pearson,
R.; Fuchs, E.: Genetic mutations in the K1 and K10 genes of patients
with epidermolytic hyperkeratosis: correlation between location and
disease severity. J. Clin. Invest. 93: 1533-1542, 1994.

21. Terron-Kwiatkowski, A.; Paller, A. S.; Compton, J.; Atherton,
D. J.; McLean, W. H. I.; Irvine, A. D.: Two cases of primarily palmoplantar
keratoderma associated with novel mutations in keratin 1. J. Invest.
Derm. 119: 966-971, 2002.

22. Whittock, N. V.; Ashton, G. H. S.; Griffiths, W. A. D.; Eady,
R. A. J.; McGrath, J. A.: New mutations in keratin 1 that cause bullous
congenital ichthyosiform erythroderma and keratin 2e that cause ichthyosis
bullosa of Siemens. Brit. J. Derm. 145: 330-335, 2001.

23. Whittock, N. V.; Smith, F. J.; Wan, H.; Mallipeddi, R.; Griffiths,
W. A.; Dopping-Hepenstal, P.; Ashton, G. H.; Eady, R. A.; McLean,
W. H. I.; McGrath, J. A.: Frameshift mutation in the V2 domain of
human keratin 1 results in striate palmoplantar keratoderma. J. Invest.
Derm. 118: 838-844, 2002.

24. Yoon, S.-J.; LeBlanc-Straceski, J.; Ward, D.; Krauter, K.; Kucherlapati,
R.: Organization of the human keratin type II gene cluster at 12q13. Genomics 24:
502-508, 1994.

*FIELD* CN
Marla J. F. O'Neill - updated: 7/10/2009
Gary A. Bellus - updated: 4/10/2003
Gary A. Bellus - updated: 3/25/2003
Gary A. Bellus - updated: 3/11/2003
Gary A. Bellus - updated: 3/10/2003
Gary A. Bellus - updated: 3/7/2003
Victor A. McKusick - updated: 3/22/1999
Alan F. Scott - updated: 1/12/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 12/21/2012
carol: 7/10/2009
joanna: 7/6/2009
alopez: 4/10/2003
alopez: 3/28/2003
alopez: 3/25/2003
alopez: 3/12/2003
alopez: 3/11/2003
alopez: 3/10/2003
alopez: 3/7/2003
alopez: 3/6/2003
carol: 4/5/1999
terry: 3/22/1999
joanna: 9/10/1997
terry: 4/17/1996
mark: 1/12/1996
carol: 3/19/1995
terry: 10/26/1994
warfield: 4/8/1994
carol: 2/18/1993
carol: 10/9/1992
carol: 9/8/1992

MIM 146590
*RECORD*
*FIELD* NO
146590
*FIELD* TI
#146590 ICHTHYOSIS HYSTRIX, CURTH-MACKLIN TYPE; IHCM
*FIELD* TX
A number sign (#) is used with this entry because Curth-Macklin type
read moreichthyosis hystrix can be caused by mutation in the KRT1 gene (139350).

DESCRIPTION

Anton-Lamprecht (1978) stated that 4 genetic disorders of keratinization
were known to have a structural defect of tonofibrils. (1) In the
harlequin fetus (242500), an abnormal x-ray diffraction pattern of the
horn material points to a cross-beta-protein structure instead of the
normal alpha-protein structure of keratin. (2) Bullous ichthyosiform
erythroderma (EHK; 113800) is characterized by an early formation of
clumps and perinuclear shells due to an abnormal arrangement of
tonofibrils. (3) In the Curth-Macklin form of ichthyosis hystrix,
concentric unbroken shells of abnormal tonofilaments form around the
nucleus. (4) In ichthyosis hystrix gravior (146600), only rudimentary
tonofilaments are found with compensatory production of mucous granules.

CLINICAL FEATURES

This form of ichthyosis was first reported by Curth and Macklin (1954)
and was restudied by Ollendorff-Curth et al. (1972) and Anton-Lamprecht
et al. (1973). An abnormality of tonofibrils is demonstrated by electron
microscopy, namely, formation of concentric unbroken shells of
tonofilaments surrounding the nucleus. Tonofibrils are fibrillar
structural proteins in keratinocytes which, although already present in
dividing basal cells, are formed in increasing amounts by the
differentiating cells. They are the morphologic equivalent of the
biochemically well-characterized prekeratin and precursors of the
alpha-keratin of horn cells. Blister formation does not occur.

Pinkus and Nagao (1970) observed a case in an African American.

Bonifas et al. (1993) indicated that, during the previous 4 decades, 2
families with IHCM had been described: the family of Curth and Macklin
(1954) and the family of Niemi et al. (1990). In the latter family,
patients had thick, furrowed-appearing hyperkeratosis over joints.

MAPPING

By linkage studies, Bonifas et al. (1993) excluded linkage between IHCM
and the cluster of keratin genes on 12q and 17q. They concluded that
abnormalities of genes encoding proteins other than keratins may disrupt
the keratin intermediate filament network and be associated with
binucleated keratinocytes. For example, the finding of disruption of the
intermediate filament network following transfection of DNA encoding a
mutant desmoplakin (125647) (Stappenbeck and Green, 1992) is compatible
with that conclusion.

Sprecher et al. (2001) evaluated a 3-generation African American family
with IHCM with 5 affected members. Linkage results excluded potential
candidate regions on 1q, 17q, and 18q. Potential linkage to the type II
keratin cluster at 12q was found (lod score of 1.5 at locus D12S1622),
and affected members shared a common disease-associated haplotype across
18 cM in 12q.

MOLECULAR GENETICS

In affected members of a 3-generation family with IHCM showing linkage
to chromosome 12q, Sprecher et al. (2001) identified a 5191GG-A mutation
in the KRT1 gene (139350.0013) leading to a frameshift and premature
termination codon 229 bp downstream. Structural analyses disclosed a
failure in keratin intermediate filament bundling, retraction of the
cytoskeleton from the nucleus, and failed translocation of loricrin
(152445) to the desmosomal plaques. Bonifas et al. (1993) had excluded
IHCM from both keratin gene loci; however, the phenotypic features of
the family assessed in that study, including localized hyperkeratotic
plaques over the joints and sparing of palms and soles, were milder and
distinct from those found in the family reported by Sprecher et al.
(2001). Therefore, genetic heterogeneity cannot be excluded in IHCM.

KRT1 frameshift mutations at almost the same position have been found in
IHCM (139350.0013) and in striate palmoplantar keratoderma III (SPPK3;
607654) (139350.0012). Ishida-Yamamoto et al. (2003) found normal
desmosome formation in IHCM, suggesting that the cytopathologic effects
leading to hyperkeratosis and PPK in this disorder differ from those in
SPPK, and may be related to abnormalities in supramolecular keratin
intermediate filament organization and cytoplasmic trafficking of
insoluble proteins, such as loricrin, as suggested by Sprecher et al.
(2001). Ishida-Yamamoto et al. (2003) suggested that is also possible
that mutant KRT1 affects shapes of the cells and integrity of other
cellular structures, such as organelles and the nucleus, leading to
gross alteration in the overall structures of the epidermis.

*FIELD* RF
1. Anton-Lamprecht, I.: Electron microscopy in the early diagnosis
of genetic disorders of the skin. Dermatologica 157: 65-85, 1978.

2. Anton-Lamprecht, I.; Curth, H. O.; Schnyder, U. W.: Zur Ultrastrukture
hereditaerer Verhornungsstoerungen. II. Ichthyosis hystrix Typ Curth-Macklin. Arch.
Derm. Forsch. 346: 77-91, 1973.

3. Bonifas, J. M.; Bare, J. W.; Chen, M. A.; Ranki, A.; Neimi, K.-M.;
Epstein, E. H., Jr.: Evidence against keratin gene mutations in a
family with ichthyosis hystrix Curth-Macklin. J. Invest. Derm. 101:
890-891, 1993.

4. Curth, H. O.; Macklin, M. T.: The genetic basis of various types
of ichthyosis in a family group. Am. J. Hum. Genet. 6: 371-381,
1954.

5. Ishida-Yamamoto, A.; Richard, G.; Takahashi, H.; Iizuka, H.: In
vivo studies of mutant keratin 1 in ichthyosis hystrix Curth-Macklin. J.
Invest. Derm. 120: 498-500, 2003.

6. Niemi, K.-M.; Virtanen, I.; Kanerva, L.; Muttilainen, M.: Altered
keratin expression in ichthyosis hystrix Curth-Macklin. Arch. Derm.
Res. 282: 227-233, 1990.

7. Ollendorff-Curth, H.; Allen, F. H., Jr.; Schnyder, U. W.; Anton-Lamprecht,
I.: Follow-up of a family group suffering from ichthyosis hystrix
type Curth-Macklin. Humangenetik 17: 37-48, 1972.

8. Pinkus, H.; Nagao, S.: A case of biphasic ichthyosiform dermatosis:
light and electron microscopic study. Arch. Klin. Exp. Derm. 237:
727-748, 1970.

9. Sprecher, E.; Ishida-Yamamoto, A.; Becker, O. M.; Marekov, L.;
Miller, C. J.; Steinert, P. M.; Neldner, K.; Richard, G.: Evidence
for novel functions of the keratin tail emerging from a mutation causing
ichthyosis hystrix. J. Invest. Derm. 116: 511-519, 2001.

10. Stappenbeck, T. S.; Green, K. J.: The desmoplakin carboxyl terminus
coaligns with and specifically disrupts intermediate filament networks
when expressed in cultured cells. J. Cell Biol. 116: 1197-1209,
1992.

*FIELD* CS

Skin:
Ichthyosis hystrix

Lab:
Abnormal tonofibrils with formation of concentric unbroken shells
of tonofilaments surrounding the nucleus on EM

Inheritance:
Autosomal dominant

*FIELD* CN
Gary A. Bellus - updated: 3/11/2003
Gary A. Bellus - updated: 3/10/2003

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
wwang: 04/27/2011
carol: 7/13/2009
alopez: 3/11/2003
alopez: 3/10/2003
mimadm: 11/5/1994
carol: 5/24/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988

MIM 600962
*RECORD*
*FIELD* NO
600962
*FIELD* TI
#600962 PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC; NEPPK
;;NONEPIDERMOLYTIC PALMOPLANTAR KERATODERMA;;
read moreKERATODERMA, NONEPIDERMOLYTIC PALMOPLANTAR;;
TYLOSIS
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
diffuse nonepidermolytic palmoplantar keratoderma (NEPPK) is caused by
heterozygous mutation in the KRT1 gene (139350) on chromosome 12q.

A focal form of NEPPK (FNEPPk; 613000) is caused by mutation in the
KRT16 gene (148067) on chromosome 17q. The diffuse Bothnian-type of
NEPPK (PPKB; 600231) is caused by mutation in the AQP5 gene (600442) on
chromosome 12q13. The diffuse Nagashima-type of NEPPK (PPKN; 615598) is
caused by mutation in the SERPINB7 gene (603357) on chromosome 18q21.

For discussion of phenotypic and genetic heterogeneity of palmoplantar
keratoderma, see epidermolytic PPK (144200).

NOMENCLATURE

Vorner (1901) provided an early description of localized epidermolytic
hyperkeratosis of the palms and soles, whereas Thost (1880) and Unna
(1883) reported what appeared to be a nonepidermolytic diffuse form of
palmoplantar keratoderma; the designations 'Vorner' and 'Unna-Thost'
thus became eponymous for the epidermolytic and nonepidermolytic forms
of the disorder, respectively. However, Kuster and Becker (1992) and
Kuster et al. (2002) reinvestigated the Thost kindred and found features
of epidermolytic hyperkeratosis in a study of a descendant; Lind et al.
(1994) stated that the designation 'Unna-Thost' is misleading and should
be avoided.

CLINICAL FEATURES

Rogaev et al. (1993) studied a large 5-generation Uzbek pedigree
segregating autosomal dominant nonepidermolytic palmoplantar
keratoderma. Affected individuals had thick, white, smooth skin that
desquamated in large flakes on the palmar surfaces of the hands and the
soles of the feet. Skin creases displayed deep fissures, nails were
often stubby with numerous hangnails, and the skin over the joint
surfaces of the hands and feet was thickened, red, and edematous with
poor elasticity. The skin on the backs of the hands, tops of the feet,
and in the interdigital spaces was reddened and wrinkled, with very fine
desquamation. Blistering, either spontaneously or in response to mild
mechanical or thermal stress, was not a feature of the disease in this
pedigree, and skin in other parts of the body was unaffected. Skin
biopsies from affected individuals lacked cytolysis and abnormal
keratohyalin granules and were thus consistent with nonepidermolytic
hyperkeratosis.

Kimonis et al. (1994) examined 6 affected and 1 unaffected member across
3 generations of a family segregating autosomal dominant
nonepidermolytic palmoplantar keratoderma. In adults the disease
manifested as moderate to severe thickening of the skin on palms and
soles, with extension of hyperkeratosis along the Achilles tendon of the
foot and occasionally the extensor tendon of the great toe. However,
involvement stopped abruptly at the wrist flexure and at the border of
the dorsal aspect of the hands and feet, with an erythematous halo
separating hyperkeratotic from normal-appearing skin. There were
discrete hyperkeratotic pads over several knuckles of the hands, and
some adult patients experienced mild limitation of extension of the
digits; nails showed a slight beaking (concave) deformity. Three of the
4 adult patients examined had dermatophyte infection of the toenails and
feet, and 2 had involvement of the palms. Hyperkeratosis of the
umbilicus and nipple areolae were present, as well as very mild
thickening and dryness of the knees and elbows. The 2 affected children
who were examined had presented at birth with mild thickening of the
palms and soles; both had generalized dryness with fine, powdery scale,
and hyperkeratosis of the areolae and umbilicus. Biopsy of affected
palms and elbow showed hyperkeratosis of the stratum corneum with no
evidence of epidermolysis; on electron microscopy, cells of the granular
and spinous layers did not show the aggregated tonofilaments or large
keratohyalin granules characteristic of epidermolytic hyperkeratosis.
Kimonis et al. (1994) stated that the NEPPK in this family was
consistent with that described previously by Thost (1880) and Unna
(1883).

Lind et al. (1994) described an autosomal dominant form of NEPPK with a
high prevalence in northern Sweden (see Bothnian-type PPK, 600231).

Kelsell et al. (1999) studied 3 families from the south of England with
nonepidermolytic PPK that was present at birth: affected individuals had
diffuse smooth waxy thickening of the entire palmoplantar surface
including the non-weight-bearing digits, and secondary fungal infection
was a common clinical problem leading to desquamation of the palms and
soles. Two of the families had previously been reported by Kelsell et
al. (1995), and skin biopsies from 2 affected individuals from each
family confirmed the nonepidermolytic pattern of PPK.

Terron-Kwiatkowski et al. (2002) reported 2 families with PPK. In the
first family, a single affected girl who was born to unaffected parents
had symmetric diffuse PPK at birth, but no history of skin fragility or
blistering even in the neonatal period. At 8 years of age, she was noted
to have diffuse PPK with some superficial scale as well as fine scaling
over the lateral and anterior neck, lower back, external ears, and
axillae. In the second family, an affected father and daughter each had
mild diffuse PPK at birth with no history of neonatal fragility or
blistering. The 34-year-old father had persistent mild diffuse PPK and
mild flexural-limited scaling; the daughter had similarly mild disease
with involvement limited to the palms and soles, popliteal fossae, and
axillae.

MAPPING

Kimonis et al. (1994) performed linkage analysis in a 4-generation
family segregating autosomal dominant nonepidermolytic PPK and excluded
the chromosomal region of the type I keratins; they obtained a maximum
multipoint lod score of 3.61 (theta = 0.0) in the type II keratin region
on chromosome 12q11-q13 with markers D12S96, D12S103, and D12S90.

In 2 unrelated families from the south of England segregating autosomal
dominant diffuse NEPPK, Kelsell et al. (1995) found linkage to
chromosome 12q, with a 2-point lod score of 3.83 at D12S368 (theta =
0.0). A crossover event in an affected individual from 1 of the families
placed the susceptibility locus centromeric to marker D12S96.

In 3 unrelated families from the south of England with diffuse NEPPK,
including 2 families previously reported by Kelsell et al. (1995),
Kelsell et al. (1999) performed fine mapping and further analysis of the
previously identified crossover event, which placed the disease locus
centromeric to D12S803, proximal to the type II keratin gene cluster.

- Heterogeneity

Rogaev et al. (1993) analyzed anonymous microsatellite and VNTR markers
in a large 5-generation Uzbek family with NEPPK and obtained lod scores
greater than 3.00 for markers clustered in the 17q12-q22 interval over a
range of assumptions concerning penetrance, disease allele frequency,
and marker allele frequencies. Haplotype analysis localized the NEPPK
defect to an 8-cM region between THRA1 and D17S806 containing a cluster
of keratin genes as well as the retinoic acid receptor alpha gene (RARA;
180240); an informative insertion/deletion polymorphism within the
coding sequence of the C-terminal domain of the KRT10 gene (148080) was
shown to segregate with the disease (lod score, 8.36 at theta = 0.00).

MOLECULAR GENETICS

In a 4-generation family with nonepidermolytic PPK mapping to chromosome
12q11-q13, Kimonis et al. (1994) identified a missense mutation in the
KRT1 gene (K73I; 139350.0004) that segregated completely with the
disease and was not found in 50 unrelated controls.

In 2 families with mild PPK, Terron-Kwiatkowski et al. (2002) identified
a splice site mutation (139350.0010) and a deletion (139350.0011) in the
KRT1 gene, respectively.

- Heterogeneity

In 3 affected and 3 unaffected members of a large 5-generation Uzbek
pedigree with NEPPK mapping to chromosome 17q12-q22, Rogaev et al.
(1993) analyzed exon 1 of the KRT10 gene (in which mutations had been
found in patients with generalized epidermolytic hyperkeratosis; see
113800) but found no mutations.

GENOTYPE/PHENOTYPE CORRELATIONS

Both epidermolytic and nonepidermolytic forms of palmoplantar
keratoderma have been observed with various mutations in the KRT1 gene
(139350). Kimonis et al. (1994) suggested that the specific region of
the keratin protein affected by mutation might be a major determining
factor in the different clinical and histologic consequences. Mutations
of the KRT1 and KRT9 genes that are associated with the epidermolytic
form of PPK affect the central regions of the protein that are important
for filament assembly and stability, and for that reason lead to
cellular degeneration or disruption. On the other hand, the mutation of
the KRT1 gene that Kimonis et al. (1994) found in association with PPK
was located in the amino-terminal variable end region, which may be
involved in supramolecular interactions of keratin filaments rather than
stability.

*FIELD* RF
1. Kelsell, D. P.; Stevens, H. P.; Purkis, P. E.; Talas, U.; Rustin,
M. H. A.; Leigh, I. M.: Fine genetic mapping of diffuse non-epidermolytic
palmoplantar keratoderma to chromosome 12q11-q13: exclusion of the
mapped type II keratins. Exp. Derm. 8: 388-391, 1999.

2. Kelsell, D. P.; Stevens, H. P.; Ratnavel, R.; Bryant, S. P.; Bishop,
D. T.; Leigh, I. M.; Spurr, N. K.: Genetic linkage studies in non-epidermolytic
palmoplantar keratoderma: evidence for heterogeneity. Hum. Molec.
Genet. 4: 1021-1025, 1995.

3. Kimonis, V.; DiGiovanna, J. J.; Yang, J.-M.; Doyle, S. Z.; Bale,
S. J.; Compton, J. G.: A mutation in the V1 end domain of keratin
1 in non-epidermolytic palmar-plantar keratoderma. J. Invest. Derm. 103:
764-769, 1994.

4. Kuster, W.; Becker, A.: Indication for the identity of palmoplantar
keratoderma type Unna-Thost with type Vorner: Thost's family revisited
110 years later. Acta Derm. Venerol. 72: 120-122, 1992.

5. Kuster, W.; Reis, A.; Hennies, H. C.: Epidermolytic palmoplantar
keratoderma of Vorner: re-evaluation of Vorner's original family and
identification of a novel keratin 9 mutation. Arch. Derm. Res. 294:
268-272, 2002.

6. Lind, L.; Lundstrom, A.; Hofer, P.-A.; Holmgren, G.: The gene
for diffuse palmoplantar keratoderma of the type found in northern
Sweden is localized to chromosome 12q11-q13. Hum. Molec. Genet. 3:
1789-1793, 1994.

7. Rogaev, E. I.; Rogaeva, E. A.; Ginter, E. K.; Korovaitseva, G.
I.; Farrer, L. A.; Shlensky, A. B.; Pritkov, A. N.; Mordovtsev, V.
N.; St. George-Hyslop, P. H.: Identification of the genetic locus
for keratosis palmaris et plantaris on chromosome 17 near the RARA
and keratin type I genes. Nature Genet. 5: 158-162, 1993.

8. Terron-Kwiatkowski, A.; Paller, A. S.; Compton, J.; Atherton, D.
J.; McLean, W. H. I.; Irvine, A. D.: Two cases of primarily palmoplantar
keratoderma associated with novel mutations in keratin 1. J. Invest.
Derm. 119: 966-971, 2002.

9. Thost, A.: Ueber erbliche Ichthyosis palmaris et plantaris cornea.
Dissertation: Heidelberg (pub.) 1880.

10. Unna, P. G.: Ueber das Keratoma palmare et plantare hereditarium. Arch.
Derm. Syph. 15: 231-270, 1883.

11. Vorner, H.: Zur Kenntniss des Keratoma hereditarium palmare et
plantare. Arch. Derm. Syph. 56: 3-31, 1901.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKIN, NAILS, HAIR:
[Skin];
Smooth, waxy, thick skin over palms and soles, desquamating in large
flakes;
Well-defined erythematous border;
Deep fissures of skin creases;
Skin over joint surfaces of hands and feet is thick, red, and edematous;
Hyperkeratosis of skin at nipples and umbilicus;
HISTOLOGY:;
Hyperkeratosis of stratum corneum;
No cytolysis;
No abnormal keratohyalin granules;
ELECTRON MICROSCOPY:;
No aggregated tonofilaments;
No large keratohyalin granules

MOLECULAR BASIS:
Caused by mutation in the keratin 1 gene (KRT1, 139350.0004)

*FIELD* CN
Marla J. F. O'Neill - revised: 04/26/2013

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

*FIELD* ED
joanna: 04/26/2013
alopez: 3/10/2003

*FIELD* CN
Marla J. F. O'Neill - updated: 1/9/2014
Marla J. F. O'Neill - updated: 9/27/2013
Marla J. F. O'Neill - reorganized: 7/10/2009
Marla J. F. O'Neill - updated: 7/10/2009
Gary A. Bellus - updated: 4/18/2002

*FIELD* CD
Victor A. McKusick: 1/4/1996

*FIELD* ED
carol: 01/10/2014
mcolton: 1/9/2014
carol: 1/7/2014
carol: 9/27/2013
wwang: 9/3/2009
carol: 7/27/2009
terry: 7/13/2009
carol: 7/10/2009
carol: 7/9/2009
joanna: 5/7/2009
terry: 11/10/2005
alopez: 3/28/2003
alopez: 3/12/2003
alopez: 3/10/2003
alopez: 4/18/2002
alopez: 3/13/2001
carol: 5/27/1999
mgross: 5/24/1999
terry: 7/28/1997
jamie: 10/23/1996
jamie: 10/16/1996
mark: 9/23/1996
mark: 1/5/1996
mark: 1/4/1996

MIM 607602
*RECORD*
*FIELD* NO
607602
*FIELD* TI
#607602 ICHTHYOSIS, CYCLIC, WITH EPIDERMOLYTIC HYPERKERATOSIS
;;CIEHK;;
EPIDERMOLYTIC ICHTHYOSIS, ANNULAR; AEI
read more*FIELD* TX
A number sign (#) is used with this entry because the phenotype can be
caused by mutation in the keratin 1 gene (KRT1; 139350) or the keratin
10 gene (KRT10; 148080).

CLINICAL FEATURES

Sybert et al. (1999) described 4 individuals from 2 families with a
unique clinical disorder with histologic findings of epidermolytic
hyperkeratosis, a hallmark feature of bullous congenital ichthyosiform
erythroderma (113800) on light and electron microscopy. Affected
individuals manifested erythema and superficial erosions at birth, which
improved during the first few months of life; later, palmoplantar
hyperkeratosis with patchy erythema and scale developed elsewhere on the
body. Three affected individuals exhibited dramatic episodic flares of
annular, polycyclic erythematous plaques with scale, which coalesced to
involve most of the body surface. The flares lasted weeks to months. In
the interim periods the skin was normal except for palmoplantar
hyperkeratosis. Abnormal keratin-filament aggregates were observed in
suprabasal keratinocytes from both probands.

Joh et al. (1997) reported a family with a similar phenotype,
characterized by blistering in childhood accompanying and followed by
polycyclic erythematous hyperkeratosis but without palmoplantar
involvement. The proband suffered from bullous ichthyosis and had bouts
of disease activity associated with the development of numerous annular
and polycyclic erythematous, hyperkeratotic plaques on the trunk and the
proximal extremities.

MOLECULAR GENETICS

In the proband of one family affected with cyclic ichthyosis with
epidermolytic hyperkeratosis, Sybert et al. (1999) found a 1436T-C
transition mutation in the keratin 1 gene that predicted an amino acid
change from isoleucine to threonine at codon 479 (I479T; 139350.0005).
This alteration in the highly conserved portion of helix 2B, known as
the helix termination motif, created a new BsmAI restriction site. In
the second family, Sybert et al. (1999) detected a 1435A-T translation
that predicted a substitution of isoleucine-479 by phenylalanine (I479F;
139350.0006). This mutation was carried by the proband, his mother, and
his maternal aunt. Both mutations were found in heterozygosity.

A mutation in the 2B helical segment of the KRT10 protein, arg83 to glu
(R83E; 148080.0014), caused the phenotype in the family of Joh et al.
(1997). KRT10 encodes the partner keratin of KRT1; both are present in
suprabasal cells.

*FIELD* RF
1. Joh, G.-Y.; Traupe, H.; Metze, D.; Nashan, D.; Huber, M.; Hohl,
D.; Longley, M. A.; Rothnagel, J. A.; Roop, D. R.: A novel dinucleotide
mutation in keratin 10 in the annular epidermolytic ichthyosis variant
of bullous congenital ichthyosiform erythroderma. J. Invest. Derm. 108:
357-361, 1997.

2. Sybert, V. P.; Francis, J. S.; Corden, L. D.; Smith, L. T.; Weaver,
M.; Stephens, K.; McLean, W. H. I.: Cyclic ichthyosis with epidermolytic
hyperkeratosis: a phenotype conferred by mutations in the 2B domain
of keratin K1. Am. J. Hum. Genet. 64: 732-738, 1999.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKIN, NAILS, HAIR:
[Skin];
Neonatal blisters and erosions;
Hyperkeratosis of the palms and soles;
Erythema, blisters, pustules (cyclical, explosive episodes);
Ichthyosis of scalp and flexural areas;
Migratory plaques of thickened, sharply demarcated erythema and hyperkeratosis;
HISTOLOGY:;
Intraepidermal vesicles;
Epidermal spongiosis;
Eosinophils and neutrophils in the epidermis;
Superficial and deep perivascular infiltrates in the dermis;
ELECTRON MICROSCOPY:;
Cytolysis;
Circumscribed clumps of keratin filaments (some associated with desmosomes);
Dense whorls of keratin filaments in the lower and middle spinous
layers;
[Nails];
Normal;
[Hair];
Normal

MOLECULAR BASIS:
Caused by mutation in the keratin 1 gene (KRT1, 139350.0005);
Caused by mutation in the keratin 10 gene (KRT10, 148080.0014)

*FIELD* CN
Ada Hamosh - reviewed: 3/28/2003

*FIELD* CD
Gary A. Bellus: 3/6/2003

*FIELD* ED
wwang: 04/27/2011
joanna: 2/2/2009
joanna: 2/15/2008
joanna: 2/14/2008
joanna: 4/3/2003
joanna: 4/2/2003
joanna: 3/28/2003
joanna: 3/19/2003
alopez: 3/6/2003

*FIELD* CD
Anne M. Stumpf: 3/6/2003

*FIELD* ED
alopez: 08/28/2003
alopez: 3/6/2003

MIM 607654
*RECORD*
*FIELD* NO
607654
*FIELD* TI
#607654 KERATOSIS PALMOPLANTARIS STRIATA III; PPKS3
;;STRIATE PALMOPLANTAR KERATODERMA III; SPPK3;;
read moreKERATODERMA, PALMOPLANTAR, STRIATE FORM III; KPPS3
*FIELD* TX
A number sign (#) is used with this entry because mutation in the
keratin-1 gene (KRT1; 139350) has been shown to cause this form of
keratosis palmoplantaris striata.

For discussion of genetic heterogeneity of the striate form of
palmoplantar keratoderma, see PPKS1 (148700).

CLINICAL FEATURES

Whittock et al. (2002) studied a 4-generation family of British descent
with striate palmoplantar keratoderma. Autosomal dominant inheritance
was demonstrated. Affected individuals presented during early childhood
with PPKS on the palms and more diffuse changes on the soles. There was
no involvement of nonpalmoplantar skin, and both hair and nails were
normal. Ultrastructural studies showed that intermediate filaments of
suprabasal keratinocytes were finer than those of the basal layer. In
addition, desmosome numbers were normal, but their inner plaques and
midline structures were attenuated.

MAPPING

In a 4-generation family with PPKS, Whittock et al. (2002) observed
linkage to chromosome 12q using marker D12S368, with a maximum 2-point
lod score of 3.496 at a recombination fraction of 0.

MOLECULAR GENETICS

By direct sequencing, Whittock et al. (2002) found a frameshift mutation
in exon 9 (1628delG; 139350.0012) of the KRT1 gene that led to the
partial loss of the glycine loop motif in the V2 domain and the gain of
a novel 70-amino acid peptide. Using expression studies, Whittock et al.
(2002) showed that the V2 domain is essential for normal function of
keratin intermediate filaments. Whittock et al. (2002) noted that
although the molecular defect in this family was similar to a KRT1
mutation causing ichthyosis hystrix (139350.0013), the changes in the
keratin intermediate filaments were very different.

*FIELD* RF
1. Whittock, N. V.; Smith, F. J.; Wan, H.; Mallipeddi, R.; Griffiths,
W. A.; Dopping-Hepenstal, P.; Ashton, G. H.; Eady, R. A.; McLean,
W. H. I.; McGrath, J. A.: Frameshift mutation in the V2 domain of
human keratin 1 results in striate palmoplantar keratoderma. J. Invest.
Derm. 118: 838-844, 2002.

*FIELD* CN
Marla J. F. O'Neill - updated: 7/10/2009

*FIELD* CD
Gary A. Bellus: 3/25/2003

*FIELD* ED
carol: 07/10/2009
alopez: 3/25/2003