RBCC Red Blood Cell Collection

KRT9 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Keratin, type I cytoskeletal 9 (Cytokeratin-9; CK-9; Keratin-9; K9)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P35527
ID K1C9_HUMAN Reviewed; 623 AA.
AC P35527; O00109; Q0IJ47; Q14665;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-JUN-2009, sequence version 3.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Keratin, type I cytoskeletal 9;
DE AltName: Full=Cytokeratin-9;
DE Short=CK-9;
DE AltName: Full=Keratin-9;
DE Short=K9;
GN Name=KRT9;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, FUNCTION, AND
RP TISSUE SPECIFICITY.
RC TISSUE=Foot sole tissue;
RX PubMed=7507869; DOI=10.1111/j.1432-0436.1993.tb00033.x;
RA Langbein L., Heid H.W., Moll I., Franke W.W.;
RT "Molecular characterization of the body site-specific human epidermal
RT cytokeratin 9: cDNA cloning, amino acid sequence, and tissue
RT specificity of gene expression.";
RL Differentiation 55:57-72(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS EPPK LYS-161; GLN-163
RP AND TRP-163.
RX PubMed=7512862; DOI=10.1038/ng0294-174;
RA Reis A., Hennies H.-C., Langbein L., Digweed M., Mischke D.,
RA Dreschler M., Schroek E., Royer-Pokora B., Franke W.W., Sperling K.,
RA Kuester W.;
RT "Keratin 9 gene mutations in epidermolytic palmoplantar keratoderma
RT (EPPK).";
RL Nat. Genet. 6:174-179(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [4]
RP PROTEIN SEQUENCE OF 14-29, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RA Bienvenut W.V.;
RL Submitted (AUG-2005) to UniProtKB.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 147-372, AND VARIANT EPPK GLN-163.
RX PubMed=8647270; DOI=10.1016/0014-5793(96)00393-6;
RA Kobayashi S., Tanaka T., Matsuyoshi N., Imamura S.;
RT "Keratin 9 point mutation in the pedigree of epidermolytic hereditary
RT palmoplantar keratoderma perturbs keratin intermediate filament
RT network formation.";
RL FEBS Lett. 386:149-155(1996).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 157-623.
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 450-466.
RX PubMed=2140676; DOI=10.1016/0006-291X(90)91140-N;
RA Rosen E.M., Meromsky L., Romero R., Setter E., Goldberg I.;
RT "Human placenta contains an epithelial scatter protein.";
RL Biochem. Biophys. Res. Commun. 168:1082-1088(1990).
RN [8]
RP FUNCTION, AND MUTAGENESIS OF ARG-163.
RX PubMed=10218578; DOI=10.1016/S0014-5793(99)00233-1;
RA Kobayashi S., Kore-eda S., Tanaka T.;
RT "Demonstration of the pathogenic effect of point mutated keratin 9 in
RT vivo.";
RL FEBS Lett. 447:39-43(1999).
RN [9]
RP INDUCTION.
RX PubMed=10201533; DOI=10.1046/j.1523-1747.1999.00544.x;
RA Yamaguchi Y., Itami S., Tarutani M., Hosokawa K., Miura H.,
RA Yoshikawa K.;
RT "Regulation of keratin 9 in nonpalmoplantar keratinocytes by
RT palmoplantar fibroblasts through epithelial-mesenchymal
RT interactions.";
RL J. Invest. Dermatol. 112:483-488(1999).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
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 [12]
RP VARIANTS EPPK VAL-157 AND PRO-172.
RX PubMed=7516304; DOI=10.1007/BF00201564;
RA Hennies H.-C., Zehender D., Kunze J., Kuester W., Reis A.;
RT "Keratin 9 gene mutational heterogeneity in patients with
RT epidermolytic palmoplantar keratoderma.";
RL Hum. Genet. 93:649-654(1994).
RN [13]
RP VARIANT EPPK SER-161.
RX PubMed=7523529; DOI=10.1111/1523-1747.ep12395570;
RA Bonifas J.M., Matsumura K., Chen M.A., Berth-Jones J.,
RA Hutchinson P.E., Zloczower M., Fritsch P.O., Epstein E.H. Jr.;
RT "Mutations of keratin 9 in two families with palmoplantar
RT epidermolytic hyperkeratosis.";
RL J. Invest. Dermatol. 103:474-477(1994).
RN [14]
RP VARIANT EPPK TYR-161.
RX PubMed=7511021; DOI=10.1038/ng0194-106;
RA Torchard D., Blanchet-Bardon C., Serova O., Langbein L., Narod S.,
RA Janin N., Goguel A.F., Bernheim A., Franke W.W., Lenoir G.M.,
RA Feunteun J.;
RT "Epidermolytic palmoplantar keratoderma cosegregates with a keratin 9
RT mutation in a pedigree with breast and ovarian cancer.";
RL Nat. Genet. 6:106-110(1994).
RN [15]
RP VARIANTS EPPK TRP-163 AND SER-168.
RX PubMed=7532199; DOI=10.1111/1523-1747.ep12666018;
RA Rothnagel J.A., Wojcik S., Liefer K.M., Dominey A.M., Huber M.,
RA Hohl D., Roop D.R.;
RT "Mutations in the 1A domain of keratin 9 in patients with
RT epidermolytic palmoplantar keratoderma.";
RL J. Invest. Dermatol. 104:430-433(1995).
RN [16]
RP VARIANT EPPK VAL-160.
RX PubMed=9204965; DOI=10.1111/1523-1747.ep12276751;
RA Endo H., Hatamochi A., Shinkai H.;
RT "A novel mutation of a leucine residue in coil 1A of keratin 9 in
RT epidermolytic palmoplantar keratoderma.";
RL J. Invest. Dermatol. 109:113-115(1997).
RN [17]
RP VARIANTS EPPK THR-157; VAL-157 AND GLN-163.
RX PubMed=9856842; DOI=10.1046/j.1523-1747.1998.00445.x;
RA Covello S.P., Irvine A.D., McKenna K.E., Munro C.S., Nevin N.C.,
RA Smith F.J.D., Uitto J., McLean W.H.I.;
RT "Mutations in keratin K9 in kindreds with epidermolytic palmoplantar
RT keratoderma and epidemiology in Northern Ireland.";
RL J. Invest. Dermatol. 111:1207-1209(1998).
RN [18]
RP VARIANTS EPPK GLN-163 AND STOP-170.
RX PubMed=10632938; DOI=10.1046/j.1525-1470.1999.00111.x;
RA Szalai S., Szalai C., Becker K., Torok E.;
RT "Keratin 9 mutations in the coil 1A region in epidermolytic
RT palmoplantar keratoderma.";
RL Pediatr. Dermatol. 16:430-435(1999).
RN [19]
RP VARIANT EPPK TRP-163.
RX PubMed=10844507; DOI=10.1046/j.1365-2230.2000.00626.x;
RA Warmuth I., Cserhalmi-Friedman P.B., Schneiderman P., Grossman M.E.,
RA Christiano A.M.;
RT "Epidermolytic palmoplantar keratoderma in a Hispanic kindred
RT resulting from a mutation in the keratin 9 gene.";
RL Clin. Exp. Dermatol. 25:244-246(2000).
RN [20]
RP VARIANT EPPK ILE-161.
RX PubMed=12192490; DOI=10.1007/s00403-002-0328-9;
RA Kuster W., Reis A., Hennies H.C.;
RT "Epidermolytic palmoplantar keratoderma of Vorner: re-evaluation of
RT Vorner's original family and identification of a novel keratin 9
RT mutation.";
RL Arch. Dermatol. Res. 294:268-272(2002).
RN [21]
RP VARIANTS EPPK VAL-157; TRP-163; GLN-163 AND MET-171.
RX PubMed=12072061; DOI=10.1046/j.1365-2133.2002.04764.x;
RA Rugg E.L., Common J.E., Wilgoss A., Stevens H.P., Buchan J.,
RA Leigh I.M., Kelsell D.P.;
RT "Diagnosis and confirmation of epidermolytic palmoplantar keratoderma
RT by the identification of mutations in keratin 9 using denaturing high-
RT performance liquid chromatography.";
RL Br. J. Dermatol. 146:952-957(2002).
RN [22]
RP VARIANT EPPK ILE-161.
RX PubMed=12926810; DOI=10.1080/00015550310016652;
RA Csikos M., Hollo P., Becker K., Racz E., Horvath A., Karpati S.;
RT "Novel N160I mutation of keratin 9 in a large pedigree from Hungary
RT with epidermolytic palmoplantar keratoderma.";
RL Acta Derm. Venereol. 83:303-305(2003).
RN [23]
RP VARIANT EPPK PHE-160.
RX PubMed=12838553; DOI=10.1002/ajmg.a.20090;
RA Lu Y., Guo C., Liu Q., Zhang X., Cheng L., Li J., Chen B., Gao G.,
RA Zhou H., Guo Y., Li Y., Gong Y.;
RT "A novel mutation of keratin 9 in epidermolytic palmoplantar
RT keratoderma combined with knuckle pads.";
RL Am. J. Med. Genet. A 120:345-349(2003).
RN [24]
RP VARIANTS EPPK HIS-161; SER-161 AND TRP-163.
RX PubMed=14675368; DOI=10.1111/j.0906-6705.2003.00012.x;
RA Lee J.-H., Ahn K.-S., Lee C.-H., Youn S.-J., Kim J.-W., Lee D.-Y.,
RA Lee E.-S., Steinert P.M., Yang J.-M.;
RT "Keratin 9 gene mutations in five Korean families with epidermolytic
RT palmoplantar keratoderma.";
RL Exp. Dermatol. 12:876-881(2003).
RN [25]
RP VARIANT EPPK TYR-167 DEL TRP-LEU INS.
RX PubMed=15099359; DOI=10.1111/j.0007-0963.2004.05865.x;
RA He X.-H., Zhang X.-N., Mao W., Chen H.-P., Xu L.-R., Chen H.,
RA He X.-L., Le Y.-P.;
RT "A novel mutation of keratin 9 in a large Chinese family with
RT epidermolytic palmoplantar keratoderma.";
RL Br. J. Dermatol. 150:647-651(2004).
RN [26]
RP VARIANT EPPK HIS-161.
RX PubMed=15115518; DOI=10.1111/j.1365-2230.2004.01497.x;
RA Lin J.-H., Lin M.-H., Yang M.-H., Chao S.-C.;
RT "A novel keratin 9 gene mutation (Asn160His) in a Taiwanese family
RT with epidermolytic palmoplantar keratoderma.";
RL Clin. Exp. Dermatol. 29:308-310(2004).
RN [27]
RP VARIANT EPPK PRO-163.
RX PubMed=15605275; DOI=10.1007/s00403-004-0534-8;
RA Kon A., Itagaki K., Yoneda K., Takagaki K.;
RT "A novel mutation of keratin 9 gene (R162P) in a Japanese family with
RT epidermolytic palmoplantar keratoderma.";
RL Arch. Dermatol. Res. 296:375-378(2005).
RN [28]
RP VARIANT EPPK PHE-458.
RX PubMed=16911293; DOI=10.1111/j.1365-2133.2006.07358.x;
RA Kon A., Ito N., Kudo Y., Nomura K., Yoneda K., Hanada K.,
RA Hashimoto I., Takagaki K.;
RT "L457F missense mutation within the 2B rod domain of keratin 9 in a
RT Japanese family with epidermolytic palmoplantar keratoderma.";
RL Br. J. Dermatol. 155:624-626(2006).
RN [29]
RP VARIANT EPPK ARG-157.
RX PubMed=16961539; DOI=10.1111/j.1365-4632.2006.02910.x;
RA Shimazu K., Tsunemi Y., Hattori N., Saeki H., Komine M., Adachi M.,
RA Tamaki K.;
RT "A novel keratin 9 gene mutation (Met156Arg) in a Japanese patient
RT with epidermolytic palmoplantar keratoderma.";
RL Int. J. Dermatol. 45:1128-1130(2006).
CC -!- FUNCTION: May serve an important special function either in the
CC mature palmar and plantar skin tissue or in the morphogenetic
CC program of the formation of these tissues. Plays a role in keratin
CC filament assembly.
CC -!- SUBUNIT: Heterotetramer of two type I and two type II keratins.
CC -!- TISSUE SPECIFICITY: Expressed in the terminally differentiated
CC epidermis of palms and soles.
CC -!- INDUCTION: Induced by intrinsic regulatory mechanisms and by
CC extrinsic signals from a subset of dermal palmoplantar
CC fibroblasts.
CC -!- DISEASE: Keratoderma, palmoplantar, epidermolytic (EPPK)
CC [MIM:144200]: A dermatological disorder characterized by diffuse
CC thickening of the epidermis on the entire surface of palms and
CC soles sharply bordered with erythematous margins. Some patients
CC may present knuckle pads, thick pads of skin appearing over the
CC proximal phalangeal joints. 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) and II (neutral to basic) (40-
CC 55 and 56-70 kDa, respectively).
CC -!- SIMILARITY: Belongs to the intermediate filament family.
CC -!- CAUTION: Was originally (PubMed:2140676) thought to be a 60 kDa
CC chain of placental scatter protein.
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/KRT9";
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DR EMBL; Z29074; CAA82315.1; -; mRNA.
DR EMBL; S69510; AAC60619.1; -; mRNA.
DR EMBL; X75015; CAA52924.1; -; Genomic_DNA.
DR EMBL; AC019349; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AB001594; BAA19418.1; -; mRNA.
DR EMBL; BC121170; AAI21171.1; -; mRNA.
DR PIR; I37984; I37984.
DR RefSeq; NP_000217.2; NM_000226.3.
DR UniGene; Hs.654569; -.
DR ProteinModelPortal; P35527; -.
DR SMR; P35527; 204-302, 318-460.
DR IntAct; P35527; 19.
DR MINT; MINT-4998976; -.
DR STRING; 9606.ENSP00000246662; -.
DR PhosphoSite; P35527; -.
DR DMDM; 239938886; -.
DR DOSAC-COBS-2DPAGE; P35527; -.
DR PaxDb; P35527; -.
DR PeptideAtlas; P35527; -.
DR PRIDE; P35527; -.
DR ProMEX; P35527; -.
DR DNASU; 3857; -.
DR Ensembl; ENST00000246662; ENSP00000246662; ENSG00000171403.
DR GeneID; 3857; -.
DR KEGG; hsa:3857; -.
DR UCSC; uc002hxe.4; human.
DR CTD; 3857; -.
DR GeneCards; GC17M039722; -.
DR H-InvDB; HIX0039018; -.
DR HGNC; HGNC:6447; KRT9.
DR HPA; HPA007261; -.
DR HPA; HPA009673; -.
DR MIM; 144200; phenotype.
DR MIM; 149100; phenotype.
DR MIM; 607606; gene.
DR neXtProt; NX_P35527; -.
DR Orphanet; 2199; Epidermolytic palmoplantar keratoderma.
DR PharmGKB; PA30235; -.
DR eggNOG; NOG148410; -.
DR HOGENOM; HOG000230975; -.
DR HOVERGEN; HBG013015; -.
DR InParanoid; P35527; -.
DR KO; K07604; -.
DR OMA; EMQYETL; -.
DR OrthoDB; EOG7FV3Q8; -.
DR PhylomeDB; P35527; -.
DR GeneWiki; Keratin_9; -.
DR GenomeRNAi; 3857; -.
DR NextBio; 15177; -.
DR PRO; PR:P35527; -.
DR ArrayExpress; P35527; -.
DR Bgee; P35527; -.
DR CleanEx; HS_KRT9; -.
DR Genevestigator; P35527; -.
DR GO; GO:0005882; C:intermediate filament; IEA:UniProtKB-KW.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:ProtInc.
DR GO; GO:0008544; P:epidermis development; TAS:ProtInc.
DR GO; GO:0045109; P:intermediate filament organization; IMP:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; IEA:Ensembl.
DR InterPro; IPR001664; IF.
DR InterPro; IPR018039; Intermediate_filament_CS.
DR InterPro; IPR002957; Keratin_I.
DR PANTHER; PTHR23239; PTHR23239; 1.
DR Pfam; PF00038; Filament; 1.
DR PRINTS; PR01248; TYPE1KERATIN.
DR PROSITE; PS00226; IF; 1.
PE 1: Evidence at protein level;
KW Coiled coil; Complete proteome; Direct protein sequencing;
KW Disease mutation; Intermediate filament; Keratin;
KW Palmoplantar keratoderma; Reference proteome.
FT CHAIN 1 623 Keratin, type I cytoskeletal 9.
FT /FTId=PRO_0000063640.
FT REGION 1 152 Head.
FT REGION 153 461 Rod.
FT REGION 153 188 Coil 1A.
FT REGION 189 207 Linker 1.
FT REGION 208 299 Coil 1B.
FT REGION 300 322 Linker 12.
FT REGION 323 461 Coil 2.
FT REGION 462 623 Tail.
FT COMPBIAS 15 26 Poly-Gly.
FT VARIANT 157 157 M -> R (in EPPK).
FT /FTId=VAR_036805.
FT VARIANT 157 157 M -> T (in EPPK; dbSNP:rs59510579).
FT /FTId=VAR_010499.
FT VARIANT 157 157 M -> V (in EPPK; dbSNP:rs58597584).
FT /FTId=VAR_010500.
FT VARIANT 160 160 L -> F (in EPPK; with knuckle pads;
FT dbSNP:rs28940896).
FT /FTId=VAR_035438.
FT VARIANT 160 160 L -> V (in EPPK).
FT /FTId=VAR_010501.
FT VARIANT 161 161 N -> H (in EPPK).
FT /FTId=VAR_036806.
FT VARIANT 161 161 N -> I (in EPPK).
FT /FTId=VAR_036807.
FT VARIANT 161 161 N -> K (in EPPK; dbSNP:rs57536312).
FT /FTId=VAR_003822.
FT VARIANT 161 161 N -> S (in EPPK; dbSNP:rs56707768).
FT /FTId=VAR_010502.
FT VARIANT 161 161 N -> Y (in EPPK; dbSNP:rs59296273).
FT /FTId=VAR_010503.
FT VARIANT 163 163 R -> P (in EPPK).
FT /FTId=VAR_036808.
FT VARIANT 163 163 R -> Q (in EPPK; dbSNP:rs57758262).
FT /FTId=VAR_003823.
FT VARIANT 163 163 R -> W (in EPPK; dbSNP:rs59616921).
FT /FTId=VAR_003824.
FT VARIANT 167 167 Y -> WL (in EPPK).
FT /FTId=VAR_036809.
FT VARIANT 168 168 L -> S (in EPPK; dbSNP:rs61157095).
FT /FTId=VAR_003825.
FT VARIANT 171 171 V -> M (in EPPK; dbSNP:rs57019720).
FT /FTId=VAR_035439.
FT VARIANT 172 172 Q -> P (in EPPK; dbSNP:rs59878153).
FT /FTId=VAR_010504.
FT VARIANT 458 458 L -> F (in EPPK; dbSNP:rs58120120).
FT /FTId=VAR_036810.
FT MUTAGEN 163 163 R->QHA: Leads to aggregate formation.
FT CONFLICT 12 13 SR -> T (in Ref. 1; AAC60619 and 2;
FT CAA52924).
FT CONFLICT 41 41 G -> R (in Ref. 1; AAC60619/CAA82315 and
FT 2; CAA52924).
FT CONFLICT 134 134 F -> L (in Ref. 1; AAC60619/CAA82315 and
FT 2; CAA52924).
FT CONFLICT 157 170 MQELNSRLASYLDK -> HLGAGSTPITASQP (in Ref.
FT 6; AAI21171).
SQ SEQUENCE 623 AA; 62064 MW; 45C833749B63873D CRC64;
MSCRQFSSSY LSRSGGGGGG GLGSGGSIRS SYSRFSSSGG GGGGGRFSSS SGYGGGSSRV
CGRGGGGSFG YSYGGGSGGG FSASSLGGGF GGGSRGFGGA SGGGYSSSGG FGGGFGGGSG
GGFGGGYGSG FGGFGGFGGG AGGGDGGILT ANEKSTMQEL NSRLASYLDK VQALEEANND
LENKIQDWYD KKGPAAIQKN YSPYYNTIDD LKDQIVDLTV GNNKTLLDID NTRMTLDDFR
IKFEMEQNLR QGVDADINGL RQVLDNLTME KSDLEMQYET LQEELMALKK NHKEEMSQLT
GQNSGDVNVE INVAPGKDLT KTLNDMRQEY EQLIAKNRKD IENQYETQIT QIEHEVSSSG
QEVQSSAKEV TQLRHGVQEL EIELQSQLSK KAALEKSLED TKNRYCGQLQ MIQEQISNLE
AQITDVRQEI ECQNQEYSLL LSIKMRLEKE IETYHNLLEG GQEDFESSGA GKIGLGGRGG
SGGSYGRGSR GGSGGSYGGG GSGGGYGGGS GSRGGSGGSY GGGSGSGGGS GGGYGGGSGG
GHSGGSGGGH SGGSGGNYGG GSGSGGGSGG GYGGGSGSRG GSGGSHGGGS GFGGESGGSY
GGGEEASGSG GGYGGGSGKS SHS
//

MIM 144200
*RECORD*
*FIELD* NO
144200
*FIELD* TI
#144200 PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC; EPPK
;;KERATODERMA, EPIDERMOLYTIC PALMOPLANTAR;;
read morePALMOPLANTAR KERATODERMA, VORNER TYPE;;
HYPERKERATOSIS, LOCALIZED EPIDERMOLYTIC;;
KERATOSIS PALMARIS ET PLANTARIS FAMILIARIS;;
TYLOSIS;;
KERATOSIS OF GREITHER
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC, WITH KNUCKLE PADS, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because epidermolytic
palmoplantar keratoderma is caused by heterozygous mutation in the
keratin-9 gene (KRT9; 607606) on chromosome 17q12. A mild form of
epidermolytic palmoplantar keratoderma is caused by mutation in the
keratin-1 gene (KRT1; 139350) on chromosome 12q.

DESCRIPTION

Palmoplantar keratoderma (PPK) is a common hereditary cutaneous disorder
characterized by marked hyperkeratosis on the surface of palms and soles
(Hennies et al., 1995). PPK has been classified into diffuse, focal, and
punctate forms according to the pattern of hyperkeratosis on the palms
and soles (Lucker et al., 1994). Diffuse PPK develops at birth or
shortly thereafter and involves the entire palm and sole with a sharp
cutoff at an erythematous border; there are no lesions outside the volar
skin, and, in particular, no follicular or oral lesions. In contrast,
focal PPK is a late-onset form in which focal hyperkeratotic lesions
develop in response to mechanical trauma; an important distinguishing
feature is the presence of lesions at other body sites, e.g., oral and
follicular hyperkeratosis (Stevens et al., 1996). Palmoplantar
keratodermas can be further subdivided histologically into epidermolytic
and nonepidermolytic PPK (Risk et al., 1994).

- Genetic Heterogeneity of Palmoplantar Keratoderma

Nonepidermolytic palmoplantar keratoderma (NEPPK; 600962) is caused by
mutation in the KRT1 gene. A focal form of NEPPK (FNEPPK; 613000) is
caused by mutation in the KRT16 gene (148067). The diffuse Bothnian form
of NEPPK (PPKB; 600231) is caused by mutation in the AQP5 gene (600442).
The Nagashima type of nonepidermolytic diffuse PPK (PPKN; 615598) is
caused by mutation in the SERPINB7 gene (603357).

A generalized form of epidermolytic hyperkeratosis (EHK; 113800), also
designated bullous congenital ichthyosiform erythroderma (BCIE), is
caused by mutation in the keratin genes KRT1 and KRT10 (148080).

For a discussion of punctate PPK, see 148600; for a discussion of
striate PPK, see 148700.

NOMENCLATURE

Vorner (1901) provided an early description of epidermolytic
hyperkeratosis limited to the palms and soles, whereas Thost (1880) and
Unna (1883) reported what appeared to be a nonepidermolytic 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 several descendants; Lind et al.
(1994) stated that the designation 'Unna-Thost' is misleading and should
be avoided.

CLINICAL FEATURES

Localized epidermolytic hyperkeratosis was first described by Vorner
(1901). Blasik et al. (1981), Fritsch et al. (1978), and Camisa and
Williams (1985) reported affected families. In an affected father and
daughter, Moriwaki et al. (1988) noted a decrease in 67-kD keratin
(KRT1; 139350) in the involved epidermis and the appearance of 48-kD
keratin. Southern blot analysis using 67-kD keratin cDNA showed no
abnormality in the gene for 67-kD keratin.

Kanitakis et al. (1987) reported a Greek family with EPPK in which 21
individuals over 6 generations were affected, all of whom developed
diffuse PPK before 2 months of age and had no other cutaneous or
systemic disease. Kanitakis et al. (1987) reviewed 27 published families
or cases of EPPK, which in all instances appeared to be inherited as an
autosomal dominant trait. The disease was present at birth or developed
during the first weeks of life as a palmoplantar erythema which
subsequently became covered with a thick horny layer. The clinical
features were almost invariable from one patient to another, with
disease involving the entire volar surface and sometimes extending to
the lateral aspects of the fingers and toes. The hyperkeratosis was
diffuse, thick, and uniform, but in some cases demonstrated deep
fissures or pits, and a thin, erythematous rim was sometimes present. In
rare cases, small hyperkeratotic plaques were present over the dorsa of
the hands. Some patients had hyperhidrosis; palmoplantar blistering was
exceptional. Mucous membrane, adnexal, or tooth abnormalities were not
present.

Keratosis palmaris et plantaris as described by Thost (1880) and Unna
(1883) and later delineated by Greither (1952) is characterized by
diffuse hyperkeratosis of the palms and soles which usually becomes
evident between the ages of 3 and 12 months. Low serum vitamin A has
been found in some cases. Goette (1974) described successful use of
topical vitamin A. A PPK family reported by Anderson and Klintworth
(1961) had clinodactyly also, possibly as an independent trait (see
148520).

Gamborg Nielsen (1985) did a follow-up study on hereditary palmoplantar
keratoderma originally surveyed in the northernmost county of Sweden
(Norrbotten) by Bergstrom (1967). Two clinical types were found: a
common form with the usual autosomal dominant inheritance and a severe
form thought to have autosomal recessive inheritance (see 244850). Mal
de Meleda (248300) is a recessive form of keratosis palmoplantaris in
which the phenotype includes hyperhidrosis and perioral erythema.

Alsaleh and Teebi (1990) described 2 affected sons of phenotypically
normal, consanguineous Arab parents. They presented with patchy
eczematous skin lesions followed by palmoplantar keratoderma and raised
serum levels of IgE. Nogita et al. (1991) described the disorder in a
32-year-old Japanese man who had knuckle-pad-like lesions over the
dorsal aspect of the proximal interphalangeal joints since the age of 3
or 4 months and whose father had had the same skin disease.

Reis et al. (1994) studied multiple unrelated German pedigrees with
marked hyperkeratosis restricted to the palms and soles, including the
family originally described by Thost (1880) and the family studied by
Reis et al. (1992). Histopathologic analysis in at least 1 patient from
each family revealed typical signs of epidermolytic hyperkeratosis,
consisting of a thickened granular layer with large irregularly shaped
keratohyalin granules located in the granular layer of the epidermis and
perinuclear vacuolization of the keratinocytes. The thickness of the
scales varied among patients between and within families.

Torchard et al. (1994) studied a large 4-generation French kindred with
EPPK, originally reported by Blanchet-Bardon et al. (1987), in which 8
of 10 affected females over 40 years of age also developed breast or
ovarian cancer (1 underwent prophylactic bilateral mastectomy at 38
years of age). The male founder of the family had EPPK and was reported
to have died of colon cancer; there was 1 unaffected female in the
family who developed breast cancer at 67 years of age. In the fourth
generation of the family, 21 of 33 children of affected parents had EPPK
and were cancer-free, except for 1 woman who developed cervical cancer
at 31 years of age. The EPPK lesions in this family appear on the entire
surface of the palms and soles, demarcated from normal skin by a
distinct band of erythema, and display the typical histopathologic
features of epidermolytic hyperkeratosis resulting from abnormal
tonofilament aggregations.

Hatsell et al. (2001) studied 3 Scottish kindreds segregating autosomal
dominant PPK in which affected members displayed palmoplantar
hyperkeratosis that varied in severity and had been present since
childhood. In the most severely affected cases, there was confluent
plantar keratoderma on weight-bearing surfaces, sparing the instep, and
normal skin bordering the keratoderma displayed a violaceous erythema.
In milder cases, there was patchy plantar keratoderma in weight-bearing
areas, resembling focal keratoderma. There was no generalized
transgradient keratoderma, but several individuals had developed marked
local callosities on dorsal toes or fingers at sites of rubbing. The
remaining skin looked entirely normal except for mild hyperkeratosis of
the knees in 1 man, and nails, hair, and teeth were normal. Although
epidermolysis was not identified by light microscopy in biopsies from 3
patients, electron microscopy revealed that a minority of keratinocytes
in the spinous and granular layers appeared to be undergoing cytolysis,
with tonofilaments forming tight clumps or aggregates at the cell
surface, often adjacent to desmosomes. These changes did not appear to
affect clusters of adjacent cells and were thus less disruptive than
those typically seen in epidermolytic hyperkeratosis (113800) where
blistering is associated with extensive cell lysis.

Kuster et al. (2002) performed a follow-up study of the now 8-generation
pedigree with EPPK, originally described by Vorner (1901), involving 32
affected individuals (17 males and 15 females). Examination of an
affected 42-year-old man and his affected 15-year-old daughter and
9-year-old son showed the typical diffuse yellow-grayish keratoses over
the entire surface of the palms and soles, sharply bordered by red
margins; all had clubbing of the nails and knuckle pad-like keratoses on
the finger joints with variable expression. The father and son showed
slightly increased palmoplantar hidrosis, but this was not observed in
the daughter. Mycotic infection of the plantar scales was also found in
the father and son. Histopathologic examination confirmed epidermolytic
hyperkeratosis.

- Unilateral Palmoplantar Verrucous Nevus

Terrinoni et al. (2000) described a patient with a localized thickening
of the skin in parts of the right palm and the right sole, following the
Blaschko lines. Light microscopy showed hyperkeratosis, vacuolar
degeneration of keratinocytes in the upper spinosum and granular layer,
pyknotic nuclei, and a thickened granular layer containing an increased
number of keratohyaline granules. Histologic findings were consistent
with the diagnosis of disease similar to localized palmoplantar
epidermolytic hyperkeratosis, or focal EPPK, and ultrastructural
analysis suggested a keratin defect. The authors proposed that this
clinical entity be referred to as 'unilateral palmoplantar verrucous
nevus,' rather than localized or focal epidermolytic palmoplantar
keratoderma, as the lesions are present only on one side of the body and
follow the lines of Blaschko.

- Epidermolytic Palmoplantar Keratoderma Associated With Knuckle
Pads

Lu et al. (2003) studied a family from Shandong, China, with autosomal
dominant EPPK associated with knuckle pads. Both the hyperkeratosis and
knuckle pads were friction-related. Lu et al. (2003) stated that
aggravation of the hyperkeratosis by friction had not previously been
reported. The right hand of each right-handed affected member showed
more severe hyperkeratosis than the less frequently used left hand. The
knuckle pads on the right hand were likewise more prominent than those
on the left hand. Furthermore, the knuckle pad on the more frequently
used proximal interphalangeal joint of the index finger was more
severely affected than that on the less frequently used interphalangeal
joint of the thumb. One patient showed EPPK symptoms approximately 5
months after birth, whereas another showed EPPK symptoms at a little
more than 1 year after birth.

Chiu et al. (2007) reported a large 5-generation Taiwanese family with
EPPK in which 13 affected members had severe epidermolytic
hyperkeratosis, surrounded by a characteristic erythematous border on
the palmoplantar surface. In addition, 6 adults among the 13 affected
individuals had prominent knuckle pads on the dorsal aspect of the
fingers and to a lesser extent the toes. For each right-handed patient,
both the hyperkeratosis and knuckle pads were more severe on the right
hand than on the left. The age of onset of palmoplantar hyperkeratosis
was in the early months of life. Skin biopsies showed the characteristic
features of epidermolytic hyperkeratosis.

Codispoti et al. (2009) studied a 4-generation southern Italian family
in which 11 of 24 members had EPPK. In all patients, the lesions
initially appeared around 2 months of age, presenting a diffuse PPK with
a well-demarcated erythematous border; none had any involvement of hair,
teeth, or nails. One patient showed hyperkeratotic pad-like plaques on
the metacarpophalangeal and proximal interphalangeal joints, which were
more severe on the more frequently used right hand. Histologic analysis
of a knuckle-pad biopsy showed hyperkeratosis and epidermolysis, with
vacuolar degeneration of keratinocytes in the upper spinous and granular
layers, pyknotic nuclei, and a thickened granular layer containing an
increased number of keratohyalin granules.

INHERITANCE

Klaus et al. (1970) demonstrated dominant inheritance and male-to-male
transmission.

Alsaleh and Teebi (1990) suggested the existence of an autosomal
recessive form, but because of the high background frequency of
consanguinity in Kuwait where the patients were observed, and because of
the possibility of gonadal mosaicism, the evidence for recessive
inheritance was not strong in the small family studied by them.

POPULATION GENETICS

Covello et al. (1998) found the point prevalence of EPPK in Northern
Ireland to be 4.4 per 100,000.

MAPPING

In a large family with epidermolytic palmoplantar keratoderma, Reis et
al. (1992) mapped the disease locus to 17q11-q23 by linkage analysis
using microsatellite DNA polymorphisms; maximum lod score = 6.66 with
D17S579 at theta = 0.00. Thus, the disease mutation maps to the same
region as the type I (acidic) keratin gene cluster (e.g., 148080). One
acidic keratin, keratin-9 (KRT9; 607606), is expressed only in the
terminally differentiated epidermis of palms and soles; thus, the KRT9
gene was considered a candidate for the site of the mutation in
epidermolytic palmoplantar keratoderma.

In a large 4-generation French kindred with EPPK, originally reported by
Blanchet-Bardon et al. (1987), in which 8 of 10 affected females over 40
years of age also developed breast or ovarian cancer, Torchard et al.
(1994) obtained a maximum 2-point lod score for EPPK of 6.62 between
markers THRA1 and D17S8000 on chromosome 17q21. Linkage between EPPK and
breast/ovarian cancer yielded a maximum lod score of 0.92 at theta =
0.08.

- Heterogeneity

Hatsell et al. (2001) screened 6 affected individuals from a
6-generation Scottish family segregating a mild form of EPPK in an
autosomal dominant fashion and identified a common haplotype for
microsatellite markers spanning the type II keratin cluster on
chromosome 12q13; no linkage was seen for markers mapping to 17q12-q21.

MOLECULAR GENETICS

In 5 unrelated German pedigrees with epidermolytic PPK, including the
family originally described by Thost (1880) and the family previously
studied by Reis et al. (1992) with linkage to chromosome 17q11-q23, Reis
et al. (1994) identified heterozygosity for a missense mutation in the
KRT9 gene (R162W; 607606.0001). Two other missense mutations were also
detected in 1 EPPK kindred each, N160K (607606.0004) and R162Q
(607606.0005), respectively. All 3 mutations involved highly conserved
residues in coil 1A of KRT9.

In 4 affected members of a large 4-generation French kindred with EPPK
originally reported by Blanchet-Bardon et al. (1987), in which 8 of 10
affected females over 40 years of age also developed breast or ovarian
cancer, Torchard et al. (1994) identified a missense mutation in the
KRT9 gene (N160Y; 607606.0003). The mutation was not found in unaffected
family members or in 20 unrelated controls. Noting that the KRT9 gene is
not expressed in the mammary gland, Torchard et al. (1994) stated that
the most likely explanation for the association of EPPK with hereditary
breast/ovarian cancer syndrome is that the 2 conditions resulted from
distinct genetic events on chromosome 17q in linked genes.

Covello et al. (1998) studied 4 Northern Irish EPPK kindreds and
identified heterozygosity for missense mutations in exon 1 of KRT9 in
all of the families: R162Q and M156T (607606.0010) in 1 family each, and
M156V (607606.0006) in 2 families.

In a patient with unilateral palmoplantar verrucous nevus, Terrinoni et
al. (2000) reported somatic mosaicism for a 12-bp deletion in the KRT16
gene in a biopsy from lesional epidermis.

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).

Kuster et al. (2002) analyzed the KRT9 gene in members of the EPPK
pedigree originally described by Vorner (1901) and identified
heterozygosity for a missense mutation in affected individuals
(607606.0013).

In a family from Shandong, China, with autosomal dominant epidermolytic
palmoplantar keratoderma associated with knuckle pads, Lu et al. (2003)
identified a heterozygous missense mutation in the KRT9 gene (L160F;
607606.0012).

In affected members a 5-generation Taiwanese family with EPPK associated
with knuckle pads, Chiu et al. (2007) identified heterozygosity for the
common R163W mutation in the KRT9 gene (607606.0001), previously
designated R162W.

In a 4-generation southern Italian family in which 11 of 24 members had
EPPK, 1 of whom also had knuckle pads, Codispoti et al. (2009)
identified heterozygosity for the R163W mutation. Quantitative RT-PCR
analysis of a knuckle-pad skin biopsy revealed an almost 90-fold
increase in KRT9 expression compared to control.

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 (139350.0004) that Kimonis et al. (1994) found in
association with nonepidermolytic PPK (600962) was located in the
amino-terminal variable end region, which may be involved in
supramolecular interactions of keratin filaments rather than stability.

*FIELD* SA
Chung (1937); Klintworth and Anderson (1961); Torchard et al. (1994)
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*FIELD* CS
INHERITANCE:
Autosomal dominant

SKIN, NAILS, HAIR:
[Skin];
Localized epidermolytic hyperkeratosis;
Thick, waxy skin of palms and soles with well-defined erythematous
border;
Keratosis palmaris;
Keratosis plantaris;
Hyperkeratosis on dorsal surface of fingers and toes (knuckle pads;
in some patients);
Palmoplantar epidermolytic hyperkeratosis along Blaschko lines (rare);
HISTOLOGY:;
Thickened granular layer of epidermis;
Large irregularly shaped keratohyalin granules;
Perinuclear vacuolization of keratinocytes;
ELECTRON MICROSCOPY:;
Cytolysis of keratinocytes in spinous and granular layers;
Aggregated tonofilaments at cell surface

MOLECULAR BASIS:
Caused by mutation in the keratin 1 gene (KRT1, 139350.0014);
Caused by mutation in the keratin 9 gene (KRT9, 607606.0001)

*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: 01/09/2014
Marla J. F. O'Neill - updated: 9/27/2013
Marla J. F. O'Neill - updated: 4/14/2011
Marla J. F. O'Neill - updated: 8/12/2009
Marla J. F. O'Neill - updated: 7/28/2009
Marla J. F. O'Neill - reorganized: 7/10/2009
Marla J. F. O'Neill - updated: 7/9/2009
Victor A. McKusick - updated: 2/25/1999
Victor A. McKusick - updated: 9/8/1997
Iosif W. Lurie - updated: 8/11/1996
Perseveranda M. Cagas - updated: 7/4/1996

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

*FIELD* ED
mcolton: 01/09/2014
carol: 9/27/2013
wwang: 4/27/2011
terry: 4/14/2011
wwang: 9/3/2009
terry: 8/12/2009
wwang: 7/31/2009
terry: 7/28/2009
carol: 7/27/2009
terry: 7/10/2009
carol: 7/10/2009
carol: 7/9/2009
terry: 11/10/2005
tkritzer: 8/12/2003
alopez: 3/28/2003
alopez: 3/10/2003
alopez: 3/7/2003
carol: 3/22/1999
terry: 2/25/1999
terry: 7/24/1998
alopez: 5/14/1998
jenny: 9/18/1997
terry: 9/8/1997
terry: 7/7/1997
carol: 6/3/1997
carol: 8/11/1996
mark: 7/4/1996
mark: 2/20/1996
terry: 2/15/1996
mark: 1/12/1996
carol: 3/19/1995
terry: 1/27/1995
mimadm: 9/24/1994
pfoster: 8/16/1994
warfield: 3/31/1994
carol: 12/13/1993

MIM 149100
*RECORD*
*FIELD* NO
149100
*FIELD* TI
#149100 KNUCKLE PADS
*FIELD* TX
A number sign (#) is used with this entry because knuckle pads are
read moreassociated with certain genetic disorders such as epidermolytis
palmoplantar keratoderma (144200) or Dupuytren contractures (126900),
both of which are autosomal dominant.

Knuckle pads are sometimes associated with Dupuytren contractures and it
is not completely certain that a different gene is involved.
Camptodactyly (114200) also has an uncertain relationship. Skoog (1948)
defined knuckle pads as 'subcutaneous nodules on the dorsal aspect of
the proximal interphalangeal joints.'

Lu et al. (2003) reported association of knuckle pads with epidermolytic
palmoplantar keratoderma in a Chinese family and identified a novel
leu160-to-phe mutation in the keratin-9 gene (L160F; 607606.0012) as the
presumed cause. They presented evidence that both the hyperkeratosis and
the knuckle pads were friction-related.

*FIELD* SA
Allison and Allison (1966); Garrod (1904); Weber (1938); White
(1908)
*FIELD* RF
1. Allison, J. R., Jr.; Allison, J. R., Sr.: Knuckle pads. Arch.
Derm. 93: 311-316, 1966.

2. Garrod, A. E.: Concerning pads upon the finger joints and their
clinical relationship. Brit. Med. J. 2: 8 only, 1904.

3. Lu, Y.; Guo, C.; Liu, Q.; Zhang, X.; Cheng, L.; Li, J.; Chen, B.;
Gao, G.; Zhou, H.; Guo, Y.; Li, Y.; Gong, Y.: A novel mutation of
keratin 9 in epidermolytic palmoplantar keratoderma combined with
knuckle pads. Am. J. Med. Genet. 120A: 345-349, 2003.

4. Skoog, T.: Dupuytren's contraction with special references to
aetiology and improved surgical treatment: its occurrence in epileptics:
note on knuckle-pads. Acta Chir. Scand. 96 (suppl. 139): 1-190,
1948. Note: P. 173.

5. Weber, F. P.: A note on Dupuytren's contraction, camptodactylia
and knuckle-pads. Brit. J. Derm. Syph. 50: 26-31, 1938.

6. White, W. H.: On pads on the finger joints. Quart. J. Med. 1:
479-480, 1908.

*FIELD* CS

Limbs:
Knuckle pads;
Subcutaneous nodules on the dorsum of proximal interphalangeal joints

Inheritance:
Autosomal dominant

*FIELD* CN
Victor A. McKusick - updated: 8/5/2003

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

*FIELD* ED
carol: 06/24/2004
tkritzer: 8/6/2003
tkritzer: 8/5/2003
mimadm: 11/5/1994
davew: 7/13/1994
warfield: 4/21/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989

MIM 607606
*RECORD*
*FIELD* NO
607606
*FIELD* TI
*607606 KERATIN 9; KRT9
;;K9
*FIELD* TX

CLONING

Langbein et al. (1993) reported the cloning and sequence of the KRT9
read moregene. The amino acid sequence showed the typical structure of type I
cytokeratins, with a head (153 residues), alpha-helical
coiled-coil-forming rod (306 residues), and tail (163 residues) domains.
(In an erratum, the authors stated that the polypeptide has 623
residues, 154 in the head domain, with a calculated molecular mass of 63
kD.) The keratin 9 protein displayed highest homology to human keratin
10 (148080), not only in the highly conserved rod domain but also in
large parts of the head and tail domains. Expression was confined to
palmar and plantar epidermis. In situ hybridization and
immunolocalization showed expression in subrabasal cell layers.

MAPPING

Hennies et al. (1994) mapped the KRT9 gene to chromosome 17 by PCR
amplification from a chromosome 17-only hybrid. Reis et al. (1994)
refined the assignment of the KRT9 gene to 17q21.1-q21.2 by fluorescence
in situ hybridization.

MOLECULAR GENETICS

In 5 unrelated German pedigrees with epidermolytic palmoplantar
keratoderma (EPPK; 144200), including the family originally described by
Thost (1880) and the family previously studied by Reis et al. (1992)
that showed linkage to chromosome 17q11-q23, Reis et al. (1994)
identified heterozygosity for a missense mutation in the KRT9 gene
(R162W; 607606.0001). Two other missense mutations were also detected in
1 EPPK kindred each, N160K (607606.0004) and R162Q (607606.0005),
respectively. All 3 mutations involved highly conserved residues in coil
1A of KRT9, thought to be important for dimer formation in intermediate
filaments. Reis et al. (1994) noted that the R162W and R162Q mutations
are in the residue corresponding to the arginine that is altered in
KRT14 (R125, see 148066.0002 and 148066.0003) and KRT10 (R156, see
148080.0003 and 148080.0010) in epidermolysis bullosa simplex and
epidermolytic hyperkeratosis, respectively.

In a large 4-generation German EPPK kindred, Hennies et al. (1993, 1994)
identified a missense mutation in the KRT9 gene (Q171P; 607606.0002).

In affected members of a large 4-generation French kindred with EPPK
originally reported by Blanchet-Bardon et al. (1987), in which 8 of 10
affected females over 40 years of age also developed breast or ovarian
cancer, Torchard et al. (1994) identified a missense mutation in the
KRT9 gene (N160Y; 607606.0003). Noting that the KRT9 gene is not
expressed in the mammary gland, Torchard et al. (1994) stated that the
most likely explanation for the association of EPPK with hereditary
breast/ovarian cancer syndrome is that the 2 conditions resulted from
distinct genetic events on chromosome 17q in linked genes.

Kobayashi et al. (1996) obtained experimental evidence that the
arg162-to-gln point mutation (607606.0005) observed in patients with
epidermolytic hereditary palmoplantar keratoderma (Reis et al., 1994)
has a dominant-negative effect on keratin network formation. Transient
transfection of KRT9 cDNA into both epithelial- and epidermal-derived
cell lines showed normal keratin network formation in cells transfected
with normal KRT9 cDNA and disrupted keratin filaments with droplet
formation in cells transfected with the mutant KRT9 cDNA. Kobayashi et
al. (1996) also summarized published reports of mutations in KRT9
associated with EPPK (their Figure 3) and commented that amino acid
residues 156-171, which correspond to the head of the keratin 9
alpha-helical domain, may be crucial for keratin filament assembly and
intermediate filament network formation. (Allelic variants 607606.0001
through 607606.0008 are within the same region of the KRT9 polypeptide
cited by the authors. PMC.)

Covello et al. (1998) studied 4 Northern Irish kindreds with
epidermolytic palmoplantar keratoderma. Heterozygous missense mutations
in exon 1 of KRT9 were detected in all of the families: met156 to thr
(607606.0010) in 1 family; met156 to val (607606.0006) in 2 kindreds;
and arg162 to gln (607606.0005) in 1 family. Covello et al. (1998) noted
that all reported EPPK mutations had occurred in the helix initiation
motif at the start of the central coiled-coil rod domain of K9.

Kuster et al. (2002) analyzed the KRT9 gene in members of the EPPK
pedigree originally described by Vorner (1901) and identified
heterozygosity for a missense mutation in affected individuals
(607606.0013).

In a family from Shandong Province, China, with autosomal dominant
epidermolytic palmoplantar keratoderma associated with knuckle pads (see
144200), Lu et al. (2003) identified a heterozygous missense mutation in
the KRT9 gene (L160F; 607606.0012).

In a 5-generation Taiwanese family with EPPK in which 6 of 13 affected
individuals had knuckle pads, Chiu et al. (2007) identified
heterozygosity for the R163W mutation in the KRT9 gene. The authors
stated that because of renumbering of the KRT9 gene, this mutation was
identical to that previously designated R162W.

In a 4-generation southern Italian family in which 11 of 24 members had
EPPK, 1 of whom also had knuckle pads, Codispoti et al. (2009)
identified the common R163W mutation in the KRT9 gene. Expression of
KRT9 from a knuckle-pad biopsy was found to be increased almost 90-fold
compared to control.

*FIELD* AV
.0001
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC, WITH KNUCKLE PADS, INCLUDED
KRT9, ARG163TRP

The numbering of this KRT9 mutation (R163W) is based on the numbering
system used by Lu et al. (2003). Early reports designated this mutation
ARG162TRP.

In 5 unrelated German pedigrees with epidermolytic palmoplantar
keratoderma (EPPK; 144200), including the family originally described by
Thost (1880) and the family previously studied by Reis et al. (1992)
with linkage to chromosome 17q11-q23, Hennies et al. (1993) and Reis et
al. (1994) identified heterozygosity for a C-T transition in exon 1 of
the KRT9 gene, resulting in an arg162-to-trp substitution at a highly
conserved residue in coil 1A of KRT9. The mutation cosegregated
completely with disease in a large 6-generation EPPK family and was not
found in 42 unrelated controls. Haplotype analysis showed that in 3
large EPPK families, the mutation cosegregated with the same haplotype,
whereas the 2 other families carried different mutant haplotypes at the
KRT9 locus, suggesting that the mutation occurred independently on
different haplotypes, or, more probably, that the mutation is not of
recent origin.

Bonifas et al. (1994) found the same R162W mutation in a family with
EPPK previously reported by Berth-Jones and Hutchinson (1989). These
were, however, independent mutations because the R162W mutation reported
by Reis et al. (1994) occurred on an allele with 23 CA repeats in the
microsatellite in intron 4 of the KRT9 gene, whereas the mutant allele
reported by Bonifas et al. (1994) contained 24 CA repeats.

In 13 affected members of a 5-generation Taiwanese family with EPPK, 6
of whom also had knuckle pads (see 144200), Chiu et al. (2007)
identified heterozygosity for the R163W mutation.

In a 4-generation southern Italian family in which 11 of 24 members had
EPPK, 1 of whom also had knuckle pads, Codispoti et al. (2009)
identified heterozygosity for the R163W mutation. Quantitative RT-PCR
analysis of a knuckle-pad skin biopsy revealed an almost 90-fold
increase in KRT9 expression compared to control.

.0002
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC
KRT9, GLN172PRO

The numbering of this KRT9 mutation (Q172P) is based on the numbering
system used by Lu et al. (2003). Early reports designated this mutation
GLN171PRO.

In a large German EPPK (144200) kindred, Hennies et al. (1993, 1994)
demonstrated a gln171-to-pro (Q171P) mutation in the KRT9 gene.

.0003
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC
KRT9, ASN161TYR

The numbering of this KRT9 mutation (N161Y) is based on the numbering
system used by Lu et al. (2003). Early reports designated this mutation
ASN160TYR.

In 4 affected members of a large 4-generation French kindred with
epidermolytic palmoplantar keratoderma (144200), originally reported by
Blanchet-Bardon et al. (1987) and in which 8 of 10 affected females over
40 years of age also developed breast or ovarian cancer, Torchard et al.
(1994) identified an A-T transversion resulting in an asn160-to-tyr
(N160Y) substitution at a conserved residue at the beginning of the rod
domain in the KRT9 gene. The mutation was not found in unaffected family
members or in 20 unrelated controls. Noting that the KRT9 gene is not
expressed in the mammary gland, Torchard et al. (1994) stated that the
most likely explanation for the association of EPPK with hereditary
breast/ovarian cancer syndrome is that the 2 conditions resulted from
distinct genetic events on chromosome 17q in linked genes.

.0004
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC
KRT9, ASN161LYS

The numbering of this KRT9 mutation (N161K) is based on the numbering
system used by Lu et al. (2003). Early reports designated this mutation
ASN160LYS.

In a family with epidermolytic palmoplantar keratoderma (144200), Reis
et al. (1994) identified a T-A transversion in exon 1 of the KRT9 gene,
resulting in an asn160-to-lys (N160K) substitution at a highly conserved
residue in coil 1A of KRT9. The mutation was not found in 64 unrelated
controls.

.0005
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC
KRT9, ARG163GLN

The numbering of this KRT9 mutation (R163Q) is based on the numbering
system used by Lu et al. (2003). Early reports designated this mutation
ARG162GLN.

In a family with epidermolytic palmoplantar keratoderma (144200), Reis
et al. (1994) identified a G-A transition in exon 1 of the KRT9 gene,
resulting in an arg161-to-gln (R161Q) substitution at a highly conserved
residue in coil 1A of KRT9. The mutation was not found in 64 unrelated
controls.

Kobayashi et al. (1996) obtained experimental evidence that the
arg162-to-gln point mutation observed in patients with EPPK has a
dominant-negative effect on keratin network formation. Transient
transfection of KRT9 cDNA into both epithelial- and epidermal-derived
cell lines showed normal keratin network formation in cells transfected
with normal KRT9 cDNA and disrupted keratin filaments with droplet
formation in cells transfected with the mutant KRT9 cDNA.

In a Northern Irish EPPK kindred, Covello et al. (1998) identified
heterozygosity for the R162Q mutation in the KRT9 gene.

.0006
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC
KRT9, MET157VAL

The numbering of this KRT9 mutation (M157V) is based on the numbering
system used by Lu et al. (2003). Early reports designated this mutation
MET156VAL.

In 2 unrelated German patients with EPPK (144200), Hennies et al. (1994)
found an A-to-G transition at nucleotide 532 leading to a substitution
of methionine by valine at codon 156 of the KRT9 gene.

In 2 Northern Irish EPPK kindreds, Covello et al. (1998) identified
heterozygosity for the M156V mutation in the KRT9 gene.

.0007
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC
KRT9, ASN161SER

The numbering of this KRT9 mutation (N161S) is based on the numbering
system used by Lu et al. (2003). Early reports designated this mutation
ASN160SER.

In a family with EPPK (144200) reported by Fritsch et al. (1978),
Bonifas et al. (1994) identified a substitution of serine for
asparagine-160. Two other mutations of the same codon had been
described: asn160-to-tyr (607606.0003) and asn160-to-lys (607606.0004).

.0008
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC
KRT9, LEU168SER

The numbering of this KRT9 mutation (L168S) is based on the numbering
system used by Lu et al. (2003). Early reports designated this mutation
LEU167SER. The mutation has also been referred to as L15S.

Rothnagel et al. (1995) searched for mutations in the KRT9 gene in 6
unrelated patients with epidermolytic palmoplantar keratoderma (144200).
In 2 of these, they found mutations that altered critical residues
within the highly conserved helix initiation motif at the beginning of
the rod domain of keratin 9. In a 3-generation Middle Eastern kindred,
they found a C-to-T transition at codon 162 that resulted in an arginine
to tryptophan substitution at position 10 of the 1A alpha-helical
domain, thus confirming this codon as a hotspot for mutation in keratin
9 (see 607606.0001). The other mutation they found involved a T-to-C
transition at codon 167 that resulted in the expression of a serine
residue in place of the normal leucine at position 15 of the 1A segment.

.0009
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC
KRT9, LEU160VAL

The numbering of this KRT9 mutation (L160V) is based on the numbering
system used by Lu et al. (2003). Early reports designated this mutation
LEU159VAL.

In a Japanese kindred with epidermolytic palmoplantar keratoderma
(144200), Endo et al. (1997) identified a C-to-G transversion in
nucleotide 541 of the keratin 9 gene that converted a leucine residue
(CTC) to a valine (GTC) at codon 159. As in all other reported cases of
keratin 9 mutations in EPPK, this mutation was found within the highly
conserved coil 1A of the rod domain, which is considered to play a role
in the correct alignment of the coiled-coil molecules. In this family,
diffuse yellowish hyperkeratosis was limited strictly to the palms and
soles. The first patient presented with symptoms during the first 6
months of life.

.0010
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC
KRT9, MET157THR

The numbering of this KRT9 mutation (M157T) is based on the numbering
system used by Lu et al. (2003). Early reports designated this mutation
MET156THR.

In a Northern Irish family with EPPK (144200), Covello et al. (1998)
identified a met156-to-thr mutation in the KRT9 gene.

.0011
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC
KRT9, VAL171MET

The numbering of this KRT9 mutation (V171M) is based on the numbering
system used by Lu et al. (2003). Early reports designated this mutation
VAL170MET.

In a British family with epidermolytic palmoplantar keratoderma
(144200), Rugg et al. (2002) detected by denaturing high performance
liquid chromatography a G-to-A transition at nucleotide 508 of the KRT9
gene that resulted in a val170-to-met (V170M) amino acid substitution.

.0012
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC, WITH KNUCKLE PADS
KRT9, LEU160PHE

In a family from Shandong Province, China, with autosomal dominant
epidermolytic palmoplantar keratoderma associated with knuckle pads (see
144200), Lu et al. (2003) identified a heterozygous 544C-T transition in
exon 1 of the KRT9 gene, resulting in a leu160-to-phe (L160F) mutation.
Both the hyperkeratosis and knuckle pads were friction-related. Lu et
al. (2003) stated that aggravation of the hyperkeratosis by friction had
not previously been reported. The right hand of each right-handed
affected member showed more severe hyperkeratosis than the less
frequently used left hand. The knuckle pads on the right hand were
likewise more prominent than those on the left hand. Furthermore, the
knuckle pad on the more frequently used proximal interphalangeal joint
of the index finger was more severely affected than that on the less
frequently used interphalangeal joint of the thumb. One patient showed
EPPK symptoms approximately 5 months after birth, whereas another showed
EPPK symptoms at a little more than 1 year after birth.

.0013
PALMOPLANTAR KERATODERMA, EPIDERMOLYTIC, WITH KNUCKLE PADS
KRT9, ASN161ILE

The numbering of this KRT9 mutation (ASN161ILE) is based on the
numbering system used by Lu et al. (2003). Early reports designated this
mutation ASN160ILE.

In 3 affected members of the family with epidermolytic palmoplantar
keratoderma (EPPK; 144200), originally described by Vorner (1901),
Kuster et al. (2002) identified heterozygosity for a 545A-T transversion
in the KRT9 gene, resulting in an asn160-to-ile (N160I) substitution at
a highly conserved residue in the coil-1 A segment at the beginning of
the central rod domain. The mutation was not found in 2 unaffected
family members or in 100 control chromosomes.

*FIELD* SA
Rogaev et al. (1993)
*FIELD* RF
1. Berth-Jones, J.; Hutchinson, P. E.: A family with palmoplantar
epidermolytic hyperkeratosis. Clin. Exp. Derm. 14: 313-316, 1989.

2. Blanchet-Bardon, C.; Nazzaro, V.; Chevrant-Breton, J.; Espie, M.;
Kerbrat, P.; Le Marec, B.: Hereditary epidermolytic palmoplantar
keratoderma associated with breast and ovarian cancer in a large kindred. Brit.
J. Derm. 117: 363-370, 1987.

3. Bonifas, J. M.; Matsumura, K.; Chen, M. A.; Berth-Jones, J.; Hutchinson,
P. E.; Zloczower, M.; Fritsch, P. O.; Epstein, E. H., Jr.: Mutations
of keratin 9 in two families with palmoplantar epidermolytic hyperkeratosis. J.
Invest. Derm. 103: 474-477, 1994.

4. Chiu, H.-C.; Jee, S.-H.; Sheen, Y.-S.; Chu, C.-Y.; Lin, P.-J.;
Liaw, S.-H.: Mutation of keratin 9 (R163W) in a family with epidermolytic
palmoplantar keratoderma and knuckle pads. (Letter) J. Derm. Sci. 45:
63-65, 2007.

5. Codispoti, A.; Colombo, E.; Zocchi, L.; Serra, Y.; Pertusi, G.;
Leigheb, G.; Tiberio, R.; Bornacina, G.; Zuccoli, R.; Ramponi, A.;
Campione, E.; Melino, G.; Terrinoni, A.: Knuckle pads, in an epidermal
palmoplantar keratoderma patient with keratin 9 R163W transgrediens
expression. Europ. J. Derm. 19: 114-118, 2009.

6. Covello, S. P.; Irvine, A. D.; McKenna, K. E.; Munro, C. S.; Nevin,
N. C.; Smith, F. J. D.; Uitto, J.; McLean, W. H. I.: Mutations in
keratin K9 in kindreds with epidermolytic palmoplantar keratoderma
and epidemiology in Northern Ireland. J. Invest. Derm. 111: 1207-1209,
1998.

7. Endo, H.; Hatamochi, A.; Shinkai, H.: A novel mutation of a leucine
residue in coil 1A of keratin 9 in epidermolytic palmoplantar keratoderma. J.
Invest. Derm. 109: 113-115, 1997.

8. Fritsch, P.; Honigsmann, H.; Jaschke, E.: Epidermolytic hereditary
palmoplantar keratoderma. Brit. J. Derm. 99: 561-568, 1978.

9. Hennies, H.-C.; Zehender, D.; Kunze, J.; Kuster, W.; Reis, A.:
Keratin 9 gene mutational heterogeneity in patients with epidermolytic
palmoplantar keratoderma. Hum. Genet. 93: 649-654, 1994.

10. Hennies, H. C.; Kuster, W.; Langbein, L.; Digweed, M.; Mischke,
D.; Franke, W. W.; Sperling, K.; Reis, A.: Keratin 9 gene mutations
in epidermolytic palmoplantar keratoderma (EPPK). (Abstract) Am.
J. Hum. Genet. 53 (suppl.): A211, 1993.

11. Kobayashi, S.; Tanaka, T.; Matsuyoshi, N.; Imamura, S.: Keratin
9 point mutation in the pedigree of epidermolytic hereditary palmoplantar
keratoderma perturbs keratin intermediate filament network formation. FEBS
Lett. 386: 149-155, 1996.

12. 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.

13. Langbein, L.; Heid, H. W.; Moll, I.; Francke, W. W.: Molecular
characterization of the body site-specific human epidermal cytokeratin
9: cloning, amino acid sequence, and tissue specificity of gene expression. Differentiation 55:
57-71, 1993. Note: Erratum: Differentiation 55: 164 only, 1994.

14. Lu, Y.; Guo, C.; Liu, Q.; Zhang, X.; Cheng, L.; Li, J.; Chen,
B.; Gao, G.; Zhou, H.; Guo, Y.; Li, Y.; Gong, Y.: A novel mutation
of keratin 9 in epidermolytic palmoplantar keratoderma combined with
knuckle pads. Am. J. Med. Genet. 120A: 345-349, 2003.

15. Reis, A.; Hennies, H.-C.; Langbein, L.; Digweed, M.; Mischke,
D.; Drechsler, M.; Schrock, E.; Royer-Pokora, B.; Franke, W. W.; Sperling,
K.; Kuster, W.: Keratin 9 gene mutations in epidermolytic palmoplantar
keratoderma (EPPK). Nature Genet. 6: 174-179, 1994.

16. Reis, A.; Kuster, W.; Eckardt, R.; Sperling, K.: Mapping of a
gene for epidermolytic palmoplantar keratoderma to the region of the
acidic keratin gene cluster at 17q12-q21. Hum. Genet. 90: 113-116,
1992.

17. 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.

18. Rothnagel, J. A.; Wojcik, S.; Liefer, K. M.; Dominey, A. M.; Huber,
M.; Hohl, D.; Roop, D. R.: Mutations in the 1A domain of keratin
9 in patients with epidermolytic palmoplantar keratoderma. J. Invest.
Derm. 104: 430-433, 1995.

19. Rugg, E. L.; Common, J. E. A.; Wilgoss, A.; Stevens, H. P.,; Buchan,
J.,; Leigh, I. M.; Kelsell, D. P.: Diagnosis and confirmation of
epidermolytic palmoplantar keratoderma by the identification of mutations
in keratin 9 using denaturing high-performance liquid chromatography. Brit.
J. Derm. 146: 952-957, 2002.

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

21. Torchard, D.; Blanchet-Bardon, C.; Serova, O.; Langbein, L.; Narod,
S.; Janin, N.; Goguel, A. F.; Bernheim, A.; Franke, W. W.; Lenoir,
G. M.; Feunteun, J.: Epidermolytic palmoplantar keratoderma cosegregates
with a keratin 9 mutation in a pedigree with breast and ovarian cancer. Nature
Genet. 6: 106-110, 1994.

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

*FIELD* CN
Marla J. F. O'Neill - updated: 7/28/2009
Marla J. F. O'Neill - updated: 7/9/2009
Victor A. McKusick - updated: 8/5/2003
Gary A. Bellus - updated: 4/29/2003

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

*FIELD* ED
carol: 03/19/2013
carol: 6/17/2010
carol: 11/5/2009
wwang: 7/31/2009
terry: 7/28/2009
carol: 7/28/2009
carol: 7/27/2009
terry: 7/10/2009
carol: 7/10/2009
carol: 7/9/2009
wwang: 5/27/2005
tkritzer: 8/12/2003
tkritzer: 8/6/2003
tkritzer: 8/5/2003
alopez: 4/29/2003
alopez: 3/28/2003
alopez: 3/7/2003