RBCC Red Blood Cell Collection

KRT10 (KPP) [Confidence: low (only semi-automatic identification from reviews)]
Keratin, type I cytoskeletal 10 (Cytokeratin-10; CK-10; Keratin-10; K10)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P13645
ID K1C10_HUMAN Reviewed; 584 AA.
AC P13645; Q14664; Q8N175;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 24-NOV-2009, sequence version 6.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Keratin, type I cytoskeletal 10;
DE AltName: Full=Cytokeratin-10;
DE Short=CK-10;
DE AltName: Full=Keratin-10;
DE Short=K10;
GN Name=KRT10; Synonyms=KPP;
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], AND VARIANTS SER-101 AND TYR-487.
RC TISSUE=Foreskin;
RX PubMed=2459124;
RA Zhou X.M., Idler W.W., Steven A.C., Roop D.R., Steinert P.M.;
RT "The complete sequence of the human intermediate filament chain
RT keratin 10. Subdomainal divisions and model for folding of end domain
RT sequences.";
RL J. Biol. Chem. 263:15584-15589(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT TYR-487.
RX PubMed=2464696; DOI=10.1016/0022-2836(88)90045-9;
RA Rieger M., Franke W.W.;
RT "Identification of an orthologous mammalian cytokeratin gene. High
RT degree of intron sequence conservation during evolution of human
RT cytokeratin 10.";
RL J. Mol. Biol. 204:841-856(1988).
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS SER-101 AND
RP TYR-487.
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 130-584, AND VARIANT TYR-487.
RX PubMed=2448602; DOI=10.1007/BF00444680;
RA Darmon M.Y., Semat A., Darmon M.C., Vasseur M.;
RT "Sequence of a cDNA encoding human keratin No 10 selected according to
RT structural homologies of keratins and their tissue-specific
RT expression.";
RL Mol. Biol. Rep. 12:277-283(1987).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 147-161, AND VARIANTS EHK HIS-156
RP AND ASN-160.
RX PubMed=7507150; DOI=10.1111/1523-1747.ep12371723;
RA Rothnagel J.A., Longley M.A., Holder R.A., Kuster W., Roop D.R.;
RT "Prenatal diagnosis of epidermolytic hyperkeratosis by direct gene
RT sequencing.";
RL J. Invest. Dermatol. 102:13-16(1994).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 147-161, AND VARIANT EHK CYS-156.
RA Rothnagel J.J., Dominey A., Fisher M., Axtell S., Pittelkow M.,
RA Anton-Lamprecht I., Hohl D., Roop D.;
RT "Identification of mutational hot spots in the suprabasal keratin
RT genes from patients with epidermolytic hyperkeratosis.";
RL Submitted (JUN-1993) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 197-584.
RX PubMed=1378806; DOI=10.1016/0378-1119(92)90521-P;
RA Tkachenko A.V., Buchman V.L., Bliskovsky V.V., Shvets Y.P.,
RA Kisselev L.L.;
RT "Exons I and VII of the gene (Ker10) encoding human keratin 10 undergo
RT structural rearrangements within repeats.";
RL Gene 116:245-251(1992).
RN [9]
RP PROTEIN SEQUENCE OF 180-184 AND 568-580.
RC TISSUE=Keratinocyte;
RX PubMed=1286667; DOI=10.1002/elps.11501301199;
RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E.,
RA Vandekerckhove J.;
RT "Microsequences of 145 proteins recorded in the two-dimensional gel
RT protein database of normal human epidermal keratinocytes.";
RL Electrophoresis 13:960-969(1992).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-16 AND SER-42, 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 [11]
RP INVOLVEMENT IN CRIE.
RX PubMed=20798280; DOI=10.1126/science.1192280;
RA Choate K.A., Lu Y., Zhou J., Choi M., Elias P.M., Farhi A.,
RA Nelson-Williams C., Crumrine D., Williams M.L., Nopper A.J., Bree A.,
RA Milstone L.M., Lifton R.P.;
RT "Mitotic recombination in patients with ichthyosis causes reversion of
RT dominant mutations in KRT10.";
RL Science 330:94-97(2010).
RN [12]
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 [13]
RP VARIANT EHK HIS-156.
RX PubMed=1381287; DOI=10.1016/0092-8674(92)90314-3;
RA Cheng J., Syder A.J., Yu Q.-C., Letai A., Paller A.S., Fuchs E.;
RT "The genetic basis of epidermolytic hyperkeratosis: a disorder of
RT differentiation-specific epidermal keratin genes.";
RL Cell 70:811-819(1992).
RN [14]
RP VARIANTS.
RX PubMed=1371013; DOI=10.1073/pnas.89.3.910;
RA Korge B.P., Gan S.-Q., McBridge O.W., Mischke D., Steinert P.M.;
RT "Extensive size polymorphism of the human keratin 10 chain resides in
RT the C-terminal V2 subdomain due to variable numbers and sizes of
RT glycine loops.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:910-914(1992).
RN [15]
RP VARIANTS EHK HIS-156 AND SER-161.
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 [16]
RP VARIANTS EHK HIS-154; CYS-156; HIS-156; ASP-160 AND GLN-442.
RX PubMed=7508181;
RA Chipev C.C., Yang J.-M., Digiovanna J.J., Steinert P.M., Marekov L.,
RA Compton J.G., Bale S.J.;
RT "Preferential sites in keratin 10 that are mutated in epidermolytic
RT hyperkeratosis.";
RL Am. J. Hum. Genet. 54:179-190(1994).
RN [17]
RP VARIANTS EHK ARG-150; CYS-156 AND GLU-439, AND VARIANT SER-126.
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 [18]
RP VARIANTS EHK PRO-156 AND SER-156.
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 [19]
RP VARIANT THR-150.
RX PubMed=7526210; DOI=10.1056/NEJM199411243312103;
RA Paller A.S., Syder A.J., Chan Y.-M., Yu Q.-C., Hutton M.E., Tadini G.,
RA Fuchs E.;
RT "Genetic and clinical mosaicism in a type of epidermal nevus.";
RL N. Engl. J. Med. 331:1408-1415(1994).
RN [20]
RP VARIANT AEI GLU-422.
RX PubMed=9036939; DOI=10.1111/1523-1747.ep12286491;
RA Joh G.-Y., Traupe H., Metze D., Nashan D., Huber M., Hohl D.,
RA Longley M.A., Rothnagel J.A., Roop D.R.;
RT "A novel dinucleotide mutation in keratin 10 in the annular
RT epidermolytic ichthyosis variant of bullous congenital ichthyosiform
RT erythroderma.";
RL J. Invest. Dermatol. 108:357-361(1997).
RN [21]
RP VARIANT AEI THR-446.
RX PubMed=9856845; DOI=10.1046/j.1523-1747.1998.00451.x;
RA Suga Y., Duncan K.O., Heald P.W., Roop D.R.;
RT "A novel helix termination mutation in keratin 10 in annular
RT epidermolytic ichthyosis, a variant of bullous congenital
RT ichthyosiform erythroderma.";
RL J. Invest. Dermatol. 111:1220-1223(1998).
RN [22]
RP VARIANT EHK SER-160.
RX PubMed=10201536; DOI=10.1046/j.1523-1747.1999.00557.x;
RA Arin M.J., Longley M.A., Anton-Lamprecht I., Kurze G., Huber M.,
RA Hohl D., Rothnagel J.A., Roop D.R.;
RT "A novel substitution in keratin 10 in epidermolytic hyperkeratosis.";
RL J. Invest. Dermatol. 112:506-508(1999).
CC -!- SUBUNIT: Heterotetramer of two type I and two type II keratins.
CC keratin-10 is generally associated with keratin-1.
CC -!- TISSUE SPECIFICITY: Seen in all suprabasal cell layers including
CC stratum corneum.
CC -!- POLYMORPHISM: A number of alleles are known that mainly differ in
CC the Gly-rich region (positions 490-560).
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 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: Erythroderma, ichthyosiform, congenital reticular (CRIE)
CC [MIM:609165]: A rare skin condition characterized by slowly
CC enlarging islands of normal skin surrounded by erythematous
CC ichthyotic patches in a reticulated pattern. The condition starts
CC in infancy as a lamellar ichthyosis, with small islands of normal
CC skin resembling confetti appearing in late childhood and at
CC puberty. Histopathologic findings include band-like parakeratosis,
CC psoriasiform acanthosis, and vacuolization of keratinocytes with
CC binucleated cells in the upper epidermis, sometimes associated
CC with amyloid deposition in the dermis. Ultrastructural
CC abnormalities include perinuclear shells formed from a network of
CC fine filaments in the upper epidermis. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: There are two types of cytoskeletal and
CC microfibrillar keratin: I (acidic; 40-55 kDa) and II (neutral to
CC basic; 56-70 kDa).
CC -!- SIMILARITY: Belongs to the intermediate filament family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA59468.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
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/KRT10";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Keratin-10 entry;
CC URL="http://en.wikipedia.org/wiki/Keratin_10";
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DR EMBL; J04029; AAA60544.1; -; mRNA.
DR EMBL; X14487; CAA32649.1; -; Genomic_DNA.
DR EMBL; AC090283; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC034697; AAH34697.1; -; mRNA.
DR EMBL; M19156; AAA59468.1; ALT_INIT; mRNA.
DR EMBL; L20218; AAB59438.1; -; Genomic_DNA.
DR EMBL; L20219; AAB59439.1; -; Genomic_DNA.
DR EMBL; M77663; AAA59199.1; -; mRNA.
DR PIR; A31994; A31994.
DR PIR; S02158; KRHU0.
DR RefSeq; NP_000412.3; NM_000421.3.
DR UniGene; Hs.99936; -.
DR PDB; 3ASW; X-ray; 2.60 A; B=473-487.
DR PDB; 4F1Z; X-ray; 2.30 A; Q=473-486.
DR PDBsum; 3ASW; -.
DR PDBsum; 4F1Z; -.
DR ProteinModelPortal; P13645; -.
DR SMR; P13645; 145-287, 313-455.
DR IntAct; P13645; 19.
DR MINT; MINT-1132575; -.
DR STRING; 9606.ENSP00000269576; -.
DR PhosphoSite; P13645; -.
DR DMDM; 269849769; -.
DR REPRODUCTION-2DPAGE; P13645; -.
DR SWISS-2DPAGE; P13645; -.
DR PaxDb; P13645; -.
DR PeptideAtlas; P13645; -.
DR PRIDE; P13645; -.
DR ProMEX; P13645; -.
DR DNASU; 3858; -.
DR Ensembl; ENST00000269576; ENSP00000269576; ENSG00000186395.
DR GeneID; 3858; -.
DR KEGG; hsa:3858; -.
DR UCSC; uc002hvi.3; human.
DR CTD; 3858; -.
DR GeneCards; GC17M038974; -.
DR HGNC; HGNC:6413; KRT10.
DR HPA; CAB000132; -.
DR HPA; HPA012014; -.
DR MIM; 113800; phenotype.
DR MIM; 148080; gene.
DR MIM; 607602; phenotype.
DR MIM; 609165; phenotype.
DR neXtProt; NX_P13645; -.
DR Orphanet; 281139; Annular epidermolytic ichthyosis.
DR Orphanet; 281190; Congenital reticular ichthyosiform erythroderma.
DR Orphanet; 312; Epidermolytic ichthyosis.
DR PharmGKB; PA30200; -.
DR eggNOG; NOG147548; -.
DR HOGENOM; HOG000230975; -.
DR HOVERGEN; HBG013015; -.
DR InParanoid; P13645; -.
DR KO; K07604; -.
DR OMA; YSSSKHY; -.
DR OrthoDB; EOG7FV3Q8; -.
DR PhylomeDB; P13645; -.
DR GeneWiki; Keratin_10; -.
DR GenomeRNAi; 3858; -.
DR NextBio; 15181; -.
DR PRO; PR:P13645; -.
DR Bgee; P13645; -.
DR CleanEx; HS_KRT10; -.
DR Genevestigator; P13645; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005882; C:intermediate filament; NAS:UniProtKB.
DR GO; GO:0045095; C:keratin filament; IEA:Ensembl.
DR GO; GO:0030280; F:structural constituent of epidermis; NAS:UniProtKB.
DR GO; GO:0071277; P:cellular response to calcium ion; IEA:Ensembl.
DR GO; GO:0030216; P:keratinocyte differentiation; IEP:UniProtKB.
DR InterPro; IPR001664; IF.
DR InterPro; IPR018039; Intermediate_filament_CS.
DR InterPro; IPR002957; Keratin_I.
DR InterPro; IPR009053; Prefoldin.
DR PANTHER; PTHR23239; PTHR23239; 1.
DR Pfam; PF00038; Filament; 1.
DR PRINTS; PR01248; TYPE1KERATIN.
DR SUPFAM; SSF46579; SSF46579; 1.
DR PROSITE; PS00226; IF; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Coiled coil; Complete proteome;
KW Direct protein sequencing; Disease mutation; Ichthyosis;
KW Intermediate filament; Keratin; Phosphoprotein; Polymorphism;
KW Reference proteome.
FT CHAIN 1 584 Keratin, type I cytoskeletal 10.
FT /FTId=PRO_0000063642.
FT REGION 1 145 Head.
FT REGION 146 456 Rod.
FT REGION 146 181 Coil 1A.
FT REGION 182 202 Linker 1.
FT REGION 203 294 Coil 1B.
FT REGION 295 317 Linker 12.
FT REGION 318 456 Coil 2.
FT REGION 457 584 Tail.
FT COMPBIAS 17 575 Gly-rich.
FT COMPBIAS 477 579 Ser-rich.
FT MOD_RES 16 16 Phosphoserine.
FT MOD_RES 42 42 Phosphoserine.
FT VARIANT 101 101 I -> S (in dbSNP:rs4261597).
FT /FTId=VAR_058202.
FT VARIANT 126 126 G -> S (in dbSNP:rs77919366).
FT /FTId=VAR_010505.
FT VARIANT 150 150 M -> R (in EHK; dbSNP:rs58901407).
FT /FTId=VAR_010506.
FT VARIANT 150 150 M -> T (in a patient with epidermal nevi
FT hyperkeratotic type due to genetic
FT mosaicism).
FT /FTId=VAR_010507.
FT VARIANT 154 154 N -> H (in EHK; dbSNP:rs57784225).
FT /FTId=VAR_003826.
FT VARIANT 156 156 R -> C (in EHK).
FT /FTId=VAR_003828.
FT VARIANT 156 156 R -> H (in EHK; dbSNP:rs58075662).
FT /FTId=VAR_003827.
FT VARIANT 156 156 R -> P (in EHK).
FT /FTId=VAR_003829.
FT VARIANT 156 156 R -> S (in EHK; dbSNP:rs58852768).
FT /FTId=VAR_003830.
FT VARIANT 160 160 Y -> D (in EHK; severe phenotype;
FT dbSNP:rs58414354).
FT /FTId=VAR_003831.
FT VARIANT 160 160 Y -> N (in EHK; severe phenotype).
FT /FTId=VAR_010508.
FT VARIANT 160 160 Y -> S (in EHK; severe phenotype;
FT dbSNP:rs58735429).
FT /FTId=VAR_010509.
FT VARIANT 161 161 L -> S (in EHK; dbSNP:rs60118264).
FT /FTId=VAR_003832.
FT VARIANT 422 422 R -> E (in AEI; requires 2 nucleotide
FT substitutions; dbSNP:rs59075499).
FT /FTId=VAR_033145.
FT VARIANT 439 439 K -> E (in EHK; mild phenotype;
FT dbSNP:rs61434181).
FT /FTId=VAR_010510.
FT VARIANT 442 442 L -> Q (in EHK; dbSNP:rs58026994).
FT /FTId=VAR_003833.
FT VARIANT 446 446 I -> T (in AEI).
FT /FTId=VAR_010511.
FT VARIANT 487 487 H -> Y (in dbSNP:rs17855579).
FT /FTId=VAR_060723.
FT CONFLICT 9 11 KHY -> SKQF (in Ref. 1; AAA60544).
FT CONFLICT 24 31 Missing (in Ref. 1; AAA60544).
FT CONFLICT 86 86 R -> H (in Ref. 2; CAA32649).
FT CONFLICT 106 106 S -> N (in Ref. 2; CAA32649).
FT CONFLICT 181 184 WYEK -> RYDQ (in Ref. 1; AAA60544).
FT CONFLICT 189 189 H -> R (in Ref. 1; AAA60544).
FT CONFLICT 197 197 S -> G (in Ref. 8; AAA59199).
FT CONFLICT 266 266 K -> Q (in Ref. 1; AAA60544).
FT CONFLICT 279 280 EL -> YV (in Ref. 5; AAA59468).
FT CONFLICT 287 287 H -> R (in Ref. 1; AAA60544).
FT CONFLICT 293 293 D -> H (in Ref. 1; AAA60544).
FT CONFLICT 312 312 V -> I (in Ref. 5; AAA59468).
FT CONFLICT 323 323 S -> N (in Ref. 1; AAA60544).
FT CONFLICT 340 340 F -> V (in Ref. 5; AAA59468).
FT CONFLICT 374 374 A -> R (in Ref. 5; AAA59468).
FT CONFLICT 408 408 Q -> H (in Ref. 2; CAA32649).
FT CONFLICT 420 420 Q -> E (in Ref. 1; AAA60544).
FT CONFLICT 436 436 L -> T (in Ref. 1; AAA60544).
FT CONFLICT 451 451 S -> G (in Ref. 8; AAA59199).
FT CONFLICT 460 461 GG -> RS (in Ref. 5; AAA59468).
FT CONFLICT 477 477 S -> T (in Ref. 5; AAA59468).
FT CONFLICT 482 482 S -> T (in Ref. 5; AAA59468).
FT CONFLICT 487 490 Missing (in Ref. 8; AAA59199).
FT CONFLICT 491 516 Missing (in Ref. 1; AAA60544).
FT CONFLICT 503 503 S -> T (in Ref. 5; AAA59468).
FT CONFLICT 508 508 S -> T (in Ref. 5; AAA59468).
FT CONFLICT 513 519 YGGGSSS -> LRGELH (in Ref. 5; AAA59468).
FT CONFLICT 523 527 GGSSS -> AHST (in Ref. 5; AAA59468).
FT CONFLICT 524 524 G -> GGSSSGGHGG (in Ref. 2; CAA32649).
FT CONFLICT 534 534 S -> N (in Ref. 5; AAA59468).
FT CONFLICT 535 535 S -> F (in Ref. 1; AAA60544).
FT CONFLICT 542 546 YGGGS -> LRGRH (in Ref. 5; AAA59468).
FT CONFLICT 565 565 G -> GGYGGGSSSGG (in Ref. 1; AAA60544).
FT STRAND 479 481
FT STRAND 483 486
FT STRAND 500 508
SQ SEQUENCE 584 AA; 58827 MW; 4941ECD2AE46D417 CRC64;
MSVRYSSSKH YSSSRSGGGG GGGGCGGGGG VSSLRISSSK GSLGGGFSSG GFSGGSFSRG
SSGGGCFGGS SGGYGGLGGF GGGSFRGSYG SSSFGGSYGG IFGGGSFGGG SFGGGSFGGG
GFGGGGFGGG FGGGFGGDGG LLSGNEKVTM QNLNDRLASY LDKVRALEES NYELEGKIKE
WYEKHGNSHQ GEPRDYSKYY KTIDDLKNQI LNLTTDNANI LLQIDNARLA ADDFRLKYEN
EVALRQSVEA DINGLRRVLD ELTLTKADLE MQIESLTEEL AYLKKNHEEE MKDLRNVSTG
DVNVEMNAAP GVDLTQLLNN MRSQYEQLAE QNRKDAEAWF NEKSKELTTE IDNNIEQISS
YKSEITELRR NVQALEIELQ SQLALKQSLE ASLAETEGRY CVQLSQIQAQ ISALEEQLQQ
IRAETECQNT EYQQLLDIKI RLENEIQTYR SLLEGEGSSG GGGRGGGSFG GGYGGGSSGG
GSSGGGHGGG HGGSSGGGYG GGSSGGGSSG GGYGGGSSSG GHGGSSSGGY GGGSSGGGGG
GYGGGSSGGG SSSGGGYGGG SSSGGHKSSS SGSVGESSSK GPRY
//

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
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*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 148080
*RECORD*
*FIELD* NO
148080
*FIELD* TI
*148080 KERATIN 10; KRT10
;;K10
*FIELD* TX

CLONING

Keratin-10 is an intermediate filament (IF) chain which belongs to the
read moreacidic type I family and is expressed in terminally differentiated
epidermal cells. Epithelial cells almost always coexpress pairs of type
I and type II keratins, and the pairs that are coexpressed are highly
characteristic of a given epithelial tissue. For example, in human
epidermis, 3 different pairs of keratins are expressed: keratins 5 (type
II) and 14 (type I), characteristic of basal or proliferative cells;
keratins 1 (type II) and 10 (type I), characteristic of suprabasal
terminally differentiating cells; and keratins 6 (type II) and 16 (type
I) (and keratin 17 [type I]), characteristic of cells induced to
hyperproliferate by disease or injury, and epithelial cells grown in
cell culture. Darmon et al. (1987) presented the nucleotide sequence of
a 1,700 bp cDNA encoding human epidermal keratin-10 (56.5 kD). Zhou et
al. (1988) presented the complete amino acid sequence of human
keratin-10. Korge et al. (1992) described extensive polymorphism of the
KRT10 gene, restricted to insertions and deletions of the glycine-rich
quasipeptide repeats that form the glycine-loop motif in the C-terminal
domain.

Langbein et al. (2005) examined the expression of several keratins in
eccrine sweat gland and in plantar epidermis. In the sweat gland, KRT10
was expressed throughout the duct region but not in the deeper secretory
portion of the gland. In plantar epidermis, KRT10 was expressed in the
stratum cornium through to the lower suprabasal layer, but not in the
basal layer.

MAPPING

By use of specific cDNA clones in conjunction with somatic cell hybrid
analysis and in situ hybridization, Lessin et al. (1988) mapped the
KRT10 gene to 17q12-q21 in a region proximal to the breakpoint at 17q21
that is involved in a t(17;21)(q21;q22) translocation associated with a
form of acute leukemia. KRT10 appeared to be telomeric to 3 other loci
that map in the same region: CSF3 (138970), ERBA1 (190120), and HER2
(164870). NGFR (162010) and HOX2 (142960) are distal to K9. Romano et
al. (1991) demonstrated that the KRT10, KRT13, and KRT15 genes are
located in the same large pulsed field gel electrophoresis fragment. A
correlation of assignments of the 3 genes makes 17q21-q22 the likely
location of the cluster.

MOLECULAR GENETICS

- Epidermolytic Hyperkeratosis

Heterozygous mutations in the KRT10 gene as the cause of epidermolytic
hyperkeratosis (EHK; 113800) were described by Rothnagel et al. (1992),
Cheng et al. (1992), and Chipev et al. (1994). Heterozygous mutations in
the KRT1 gene (139350) 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.

In a consanguineous family segregating autosomal recessive EHK, Muller
et al. (2006) identified homozygosity for a nonsense mutation in the
KRT10 gene (148080.0019) in 2 affected sibs. The clinically unaffected
parents and 5 other unaffected relatives were heterozygous for the
mutation, which was not found in 50 controls. Semiquantitative RT-PCR
and Western blot analysis demonstrated degradation of the KRT10
transcript, resulting in complete absence of keratin-10 protein in the
epidermis and cultured keratinocytes of the homozygous individuals.
Muller et al. (2006) noted strong induction of the wound-healing
keratins KRT6 (see 148041), KRT16 (148067), and KRT17 (148069) in the
suprabasal dermis, which was unable to compensate for lack of KRT10.

In a 3-year-old Turkish girl with mild EHK, born of first-cousin
parents, Tsubota et al. (2008) identified homozygosity for a nonsense
mutation in the KRT10 gene (148080.0020). Immunohistochemical labeling
of suprabasal epidermal layers by antibodies to KRT5 (148040), KRT6, and
KRT14 (148066) suggested compensatory expression of 1 or more of these
keratins by suprabasal keratinocytes.

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). KRT6, KRT16, and KRT17 were
upregulated in the proband, with maximal expression at the sites of
cytolysis. Terheyden et al. (2009) noted that the 3 mutations reported
to that time in recessive EHK were all located in exon 6 of the KRT10
gene, near the end of the 2B domain and just upstream of the highly
conserved helix termination peptide.

In an infant with severe 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). Immunohistology of the patient's skin showed
loss of keratin-10 expression in the suprabasal epidermis, with
induction of KRT5, KRT14, KRT16, and KRT17. The authors stated that
their study confirmed that in humans, the compensatory upregulation of
other cytokeratins in the suprabasal layers elicited by complete absence
of KRT10 is not sufficient for phenotypic rescue.

- Ichthyosis with Confetti

In 7 kindreds with ichthyosis with confetti (609165), Choate et al.
(2010) identified heterozygous mutations resulting in frameshifts that
create an arginine-rich C terminus that redirects keratin-10 from the
cytokeratin filament network to the nucleolus. None of the mutations was
found in control chromosomes or in the revertant spots (clones of normal
skin that arise from loss of heterozygosity on chromosome 17q via
mitotic recombination) that comprise the 'confetti' for which the
disorder is named.

- Nonepidermolytic Keratosis Palmaris et Plantaris

In a 5-generation Uzbek family with nonepidermolytic keratosis palmaris
et plantaris (NEPPK; 600962), Rogaev et al. (1993) found tight linkage
to an insertion-deletion polymorphism in the C-terminal coding region of
the KRT10 gene (maximum lod score = 8.36 at theta = 0.00). It is
noteworthy that it was a rare, high molecular weight allele of the KRT10
polymorphism that segregated with the disorder. The allele was observed
once in 96 independent chromosomes from unaffected Caucasians. The KRT10
polymorphism arose from the insertion/deletion of imperfect (CCG)n
repeats within the coding region and gave rise to a variable glycine
loop motif in the C-terminal tail of the keratin-10 protein. It is
possible that there was a pathogenic role for the expansion of the
imperfect trinucleotide repeat.

ANIMAL MODEL

Fuchs et al. (1992) discovered that transgenic mice expressing a mutant
keratin-10 gene have the phenotype of epidermolytic hyperkeratosis (EHK;
113800), thus suggesting that a genetic basis for the human disorder
resides in mutations in genes encoding suprabasal keratins KRT1 (139350)
or KRT10. They also showed that stimulation of basal cell proliferation
can result from a defect in suprabasal cells and that distortion of
nuclear shape or aberrations in cytokinesis can occur when an
intermediate filament network is perturbed.

*FIELD* AV
.0001
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, ARG10HIS

Rothnagel et al. (1992) demonstrated heterozygosity for an R10H mutation
(due to G-to-A transition) in an isolated case of epidermolytic
hyperkeratosis (113800). The patient, aged 17 at the time of report,
still exhibited frequent blistering in addition to hyperkeratotic
lesions on his limbs, trunk, and face. Chipev et al. (1994) found the
arg10-to-his mutation in 2 families with epidermolytic hyperkeratosis.

.0002
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, LEU15SER

In a mother and son with epidermolytic hyperkeratosis (113800),
Rothnagel et al. (1992) demonstrated a T-to-C transition in codon 15
resulting in substitution of serine for leucine in the keratin-10
protein. Both affected persons showed widespread hyperkeratosis and
palmoplantar keratoderma.

.0003
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, ARG156HIS

In 2 out of 6 unrelated cases of EHK (113800), Cheng et al. (1992) found
a CGC-to-CAC transition at codon 156 resulting in substitution of
histidine for arginine. By genetic engineering, gene transfection, and
10-nm filament assembly, Cheng et al. (1992) demonstrated that this
mutation is functionally responsible for the keratin filament clumping
that occurs in basal cells in epidermolysis bullosa simplex and
suprabasal cells in EHK. An explanation may be provided for the
seemingly binucleate cells typical of EHK. They commented on the fact
that the arg156-to-his mutation of the KRT10 gene in the EHK patients is
in exactly the same position of the rod as the arg125-to-his mutation of
the KRT14 gene leading to Dowling-Meara epidermolysis bullosa simplex
(148066.0003).

In a family with EHK in which Cheng et al. (1992) had identified an
R156H mutation in the KRT10 gene, 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.
From these findings, Paller et al. (1994) reasoned that the
epidermolytic hyperkeratotic form of epidermal nevus arises from a
postzygotic KRT1 or KRT10 mutation in a cell destined to become an
epidermal keratinocyte. They showed that 50% of the KRT10 alleles of
epidermal cells carried the point mutation in keratinocytes from
lesional skin of the grandmother, whereas no mutations were detected in
normal skin. The mutation was present in 50% of the KRT10 alleles from
all cell types examined in her daughter and granddaughter, both of whom
had generalized epidermolytic hyperkeratosis.

.0004
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, ARG10CYS

Rothnagel et al. (1993) concluded that there is a mutation hotspot
within the 1A alpha-helical segment of KRT10 responsible for
epidermolytic hyperkeratosis (113800). Mutations at residue 10 of the
rod domain involved arginine to histidine (148080.0001), arginine to
cysteine, and arginine to leucine (148080.0005). (It should be noted
that arginine-125 in the KRT14 gene seems to be a similar mutation
hotspot; in that case, epidermolysis bullosa simplex results from
mutation in arginine-125 to histidine, cysteine, or leucine.)

In a family with epidermolytic hyperkeratosis, Chipev et al. (1994) also
identified an arg10-to-cys mutation in the beginning of the 1A rod
domain of keratin-10.

.0005
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, ARG10LEU

See 148080.0004 and Rothnagel et al. (1993).

.0006
MOVED TO 148080.0004
.0007
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, ASN8HIS

In a family with epidermolytic hyperkeratosis (113800), Chipev et al.
(1994) identified an asn8-to-his mutation in the beginning of the 1A rod
domain of keratin-10.

.0008
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, TYR14ASP

In a family with epidermolytic hyperkeratosis (113800), Chipev et al.
(1994) identified a tyr14-to-asp mutation in the beginning of the 1A rod
domain of keratin-10.

.0009
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, LEU103GLN

In a family with epidermolytic hyperkeratosis (113800), Chipev et al.
(1994) identified a leu103-to-gln mutation in the conserved region late
in the 2B rod domain of keratin-10.

.0010
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, ARG156CYS

In 2 severe cases of epidermolytic hyperkeratosis (113800), Syder et al.
(1994) found an arg156-to-cys mutation located at a conserved arginine
that had previously been shown to be mutated to a histidine
(148080.0003) in 2 unrelated EHK families.

Paller et al. (1994) studied a woman with epidermal nevi who had a
daughter with epidermolytic hyperkeratosis. In the mother, 50% of the
KRT10 alleles carried the arg156-to-cys mutation in lesional skin,
whereas the mutation was not detected in normal skin. In the case of the
daughter, the mutation was present in 50% of the KRT10 alleles from all
cell types examined.

.0011
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, MET150ARG

In a case of severe epidermolytic hyperkeratosis (113800), Syder et al.
(1994) found a mutation from methionine to arginine at codon 150. This
mutation was 6 residues from the site of the R156H (148080.0003) and
R156C (148080.0010) mutations which were also associated with severe
epidermolysis bullosa. All are within the amino end of the alpha-helical
rod domain of KRT10. In contrast, affected members of an atypically mild
family had a mutation just proximal to the conserved carboxy end of the
KRT10 rod (148080.0012). By genetic engineering and gene transfection,
Syder et al. (1994) demonstrated that each mutation was functionally
responsible for the keratin filament aberrations that were typical of
keratinocytes cultured from the patients. Moreover, they showed that the
mild EHK mutation affected filament network formation less severely.

.0012
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, LYS439GLU

In affected members of a family with atypically mild epidermolytic
hyperkeratosis (113800), Syder et al. (1994) found a lys439-to-glu
mutation which was located just proximal to the conserved carboxy end of
the KRT10 rod. The location of the mutation was thought to account for
the fact that clinical manifestations were mild compared with those in
families with mutations in the amino end of the alpha-helical rod domain
of KRT10 (e.g., 148080.0011). In general, epidermolytic hyperkeratosis
shows marked clinical heterogeneity with respect to severity of
blistering, keratoderma, and erythroderma, and with respect to the
extent of body involvement.

.0013
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, MET150THR

Paller et al. (1994) studied a family reported by Nazzaro et al. (1990)
in which the generalized form of epidermolytic hyperkeratosis (EHK;
113800) was observed in children of parents with the linear form of EHK.
They found that the mutation was absent or underrepresented in blood and
skin fibroblasts of the parent with the nevus, was present in 50% of the
KRT10 alleles of keratinocytes from lesional skin, and was absent in
normal skin. The mutation in one family was found to be a substitution
of thr for met150. In a second family of this type, they found the
arg156-to-cys mutation (148080.0010), and in a third family, they found
the arg156-to-his mutation (148080.0003).

.0014
ICHTHYOSIS, CYCLIC, WITH EPIDERMOLYTIC HYPERKERATOSIS
KRT10, ARG83GLU

In a family with cyclic ichthyosis with epidermolytic hyperkeratosis
(607602), Joh et al. (1997) found a novel tandem CG-to-GA mutation of
the KRT10 gene, resulting in an arg-to-glu substitution at residue 83
(R83E) of the 2B helical segment.

.0015
ICHTHYOSIS WITH CONFETTI
KRT10, IVS6AS, A-G, -2

In a patient with ichthyosis with confetti (609165), Choate et al.
(2010) identified a heterozygous splice site mutation in the intron 6
splice acceptor site of the KRT10 gene. The mutation created a new
splice acceptor site leading to an 8-bp deletion resulting in frameshift
(S458RfsX120). This mutation generated a protein with an arginine-rich C
terminus that redirected keratin-10 from the cytokeratin filament
network to the nucleolus. This mutation was not identified in this
patient's parents or in control chromosomes. Two similar mutations
affecting the intron 6 splice acceptor were identified in 2 other de
novo cases.

.0016
ICHTHYOSIS WITH CONFETTI
KRT10, IVS6DS, +2, G-A

In a mother and 2 of her offspring, all affected with ichthyosis with
confetti (609165), Choate et al. (2010) identified a G-to-A transition
at the +2 position of the intron 6 splice donor site of KRT10. The
mutation resulted in skipping of exon 6 with a junction between exons 5
and 7 (delK386-S458, G459FfsX122). This mutation generated a protein
with an arginine-rich C terminus that redirected keratin-10 from the
cytokeratin filament network to the nucleolus.

.0017
ICHTHYOSIS WITH CONFETTI
KRT10, 1-BP INS, 1450C

In a patient with de novo ichthyosis with confetti (609165), Choate et
al. (2010) identified a single-basepair insertion at position 1450 in
exon 7 of the KRT10 gene that resulted in a frameshift at codon 484
(G484RfsX97). This mutation generated a protein with an arginine-rich C
terminus that redirected keratin-10 from the cytokeratin filament
network to the nucleolus.

.0018
ICHTHYOSIS WITH CONFETTI
KRT10, 2-BP DEL, 1560CG

In a father and daughter with ichthyosis with confetti (609165), Choate
et al. (2010) identified a 2-bp deletion at position 1560 in exon 7 of
the KRT10 gene resulting in a frameshift at codon 521 (G521PfsX59). This
mutation generated a protein with an arginine-rich C terminus that
redirected keratin-10 from the cytokeratin filament network to the
nucleolus.

.0019
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, GLN434TER

In a brother and sister with epidermolytic hyperkeratosis (EHK; 113800),
born of first-cousin parents, Muller et al. (2006) identified
homozygosity for a 1300C-T transition in exon 6 of the KRT10 gene,
resulting in a gln434-to-ter (Q434X) substitution causing a premature
termination codon 25 amino acids prior to the end of the 2B domain of
keratin-10. The unaffected parents, 2 unaffected sibs, and 3 other
unaffected relatives were heterozygous for the mutation, which was not
found in 50 controls. Semiquantitative RT-PCR of RNA from cultured
keratinocytes indicated massive reduction of specific KRT10 mRNA levels
in the homozygous children, and immunofluorescence and Western blot
analysis demonstrated complete absence of keratin-10 protein in their
epidermis and keratinocytes, respectively.

.0020
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, CYS427TER

In a 3-year-old Turkish girl with mild epidermolytic hyperkeratosis
(EHK; 113800), born of first-cousin parents, Tsubota et al. (2008)
identified homozygosity for a 2-bp transversion (1281CC-AA) in exon 6 of
the KRT10 gene, resulting in a cys427-to-ter (C427X) substitution
causing a premature termination codon 34 amino acids prior to the end of
the 2B domain of keratin-10. The unaffected parents were heterozygous
carriers of the mutation, which was not found in 50 controls.
Immunohistochemical analysis demonstrated complete lack of keratin-10
protein in the patient's epidermis.

.0021
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, 1-BP INS, 1325C

In a girl with severe epidermolytic hyperkeratosis (EHK; 113800) from a
consanguineous family of Sudanese descent, Terheyden et al. (2009)
identified homozygosity for a 1-bp insertion (1325insC) in exon 6 of the
KRT10 gene, causing a frameshift that results in a premature termination
codon 6 amino acids downstream. Her unaffected parents and brother were
heterozygous carriers of the mutation, which was not found in 50
controls. Quantitative RT-PCR showed a significant decrease of specific
KRT10 mRNA in the skin of the patient, whereas levels in the
heterozygous father were approximately 50% of wildtype.

.0022
EPIDERMOLYTIC HYPERKERATOSIS
KRT10, IVS5DS, G-A, +5

In an infant with severe epidermolytic hyperkeratosis (EHK; 113800),
born of consanguineous North African parents, Covaciu et al. (2010)
identified heterozygosity for a G-A transition (1155+5G-A) in intron 5
of the KRT10 gene. The unaffected parents were heterozygous for the
mutation. RT-PCR analysis of total RNA from the patient's cultured
keratinocytes revealed that the splice site mutation results in a
premature termination codon that truncates KRT10 in the proximal portion
of the 2B helical domain. Immunohistology of the patient's skin showed
loss of keratin-10 expression in the suprabasal epidermis. The infant
became septic with hypernatremic dehydration soon after birth and died
at 3 days of age.

*FIELD* RF
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4. Covaciu, C.; Castori, M.; De Luca, N.; Ghirri, P.; Nannipieri,
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7. Joh, G.-Y.; Traupe, H.; Metze, D.; Nashan, D.; Huber, M.; Hohl,
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15. Romano, V.; Bosco, P.; Raimondi, E.; Feo, S.; Leube, R.; Franke,
W.; Ceratto, N.: Chromosomal mapping and physical linkage analysis
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16. Rothnagel, J. A.; Dominey, A. M.; Dempsey, L. D.; Longley, M.
A.; Greenhalgh, D. A.; Gagne, T. A.; Huber, M.; Frenk, E.; Hohl, D.;
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17. Rothnagel, J. A.; Fisher, M. P.; Axtell, S. M.; Pittelkow, M.
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18. 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
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19. 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.

20. 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.

21. Zhou, X.-M.; Idler, W. W.; Steven, A. C.; Roop, D. R.; Steinert,
P. M.: The complete sequence of the human intermediate filament chain
keratin 10: subdomainal divisions and model for folding of end domain
sequences. J. Biol. Chem. 263: 15584-15589, 1988.

*FIELD* CN
Marla J. F. O'Neill - updated: 4/15/2011
Ada Hamosh - updated: 11/2/2010
Marla J. F. O'Neill - updated: 7/10/2009
Patricia A. Hartz - updated: 6/22/2007
Anne M. Stumpf - updated: 3/6/2003

*FIELD* CD
Victor A. McKusick: 5/17/1989

*FIELD* ED
terry: 07/15/2011
carol: 7/6/2011
wwang: 4/27/2011
terry: 4/15/2011
carol: 4/8/2011
alopez: 11/10/2010
alopez: 11/9/2010
terry: 11/2/2010
carol: 8/5/2009
carol: 7/10/2009
wwang: 7/2/2007
terry: 6/22/2007
terry: 8/3/2005
alopez: 3/6/2003
alopez: 3/13/2001
alopez: 5/14/1998
mark: 12/20/1995
terry: 11/17/1995
mark: 7/12/1995
carol: 12/6/1994
warfield: 3/31/1994
carol: 10/12/1993
carol: 1/15/1993

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 609165
*RECORD*
*FIELD* NO
609165
*FIELD* TI
#609165 ERYTHRODERMA, ICHTHYOSIFORM, CONGENITAL RETICULAR; CRIE
;;ICHTHYOSIS WITH CONFETTI; IWC;;
read moreICHTHYOSIS VARIEGATA
ERYTHROKERATODERMA, RETICULAR, INCLUDED;;
AARAU DISEASE, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
ichthyosis with confetti is caused by heterozygous frameshift mutations
in the KRT10 gene (148080) on chromosome 17q21-q22.

DESCRIPTION

Congenital reticular ichthyosiform erythroderma (CRIE) is a rare skin
condition characterized by slowly enlarging islands of normal skin
surrounded by erythematous ichthyotic patches in a reticulated pattern.
The condition starts in infancy as a lamellar ichthyosis, with small
islands of normal skin resembling confetti appearing in late childhood
and at puberty. Histopathologic findings include band-like
parakeratosis, psoriasiform acanthosis, and vacuolization of
keratinocytes with binucleated cells in the upper epidermis, sometimes
associated with amyloid deposition in the dermis. Ultrastructural
abnormalities include perinuclear shells formed from a network of fine
filaments in the upper epidermis (summary by Krunic et al., 2003).

CLINICAL FEATURES

Krunic et al. (2003) reported a 32-year-old white man with a history of
red, scaly skin since birth. At age 10 years, he developed enlarging
white spots on the trunk and extremities. Physical examination showed
diffuse intense erythema on the face, trunk, and extremities, with fine
scaling and discrete hyperkeratotic patches on the upper trunk and back.
There were patches of apparently normal skin on the abdomen, upper
chest, and back. On the limbs, the areas of normal unaffected skin were
interspersed with erythematous scaly patches forming a reticulated
pattern. Histopathologic study of the affected erythematous skin showed
hyperkeratosis, a thick granular layer, acanthosis, and paranuclear
vacuolization in some keratinocytes. Ultrastructural study showed
binuclear cells and granular filamentous paranuclear material within the
vacuolized keratinocytes.

Choate et al. (2010) summarized the clinical features of ichthyosis with
confetti (IWC), a very rare, sporadic severe skin disease in which
affected subjects are born with erythroderma owing to defective skin
barrier function, prominent scale, and palmoplantar keratoderma. Poor
skin integrity leads to bacterial infections and, frequently, impaired
growth and development. Early in life, hundreds to thousands of pale
confetti-like spots appear across the body surface and increase in
number and size with time. Histology of ichthyotic skin shows epidermal
thickening and disordered differentiation above the basal layer, with
perinuclear vacuolization, lack of a granular layer, and hyperkeratosis
with retained nuclei in the stratum corneum. Choate et al. (2010)
studied 7 kindreds with characteristic IWC. Biopsy of confetti spots in
different kindreds revealed that these have normal histology, consistent
with each representing a revertant from clonal expansion of a normal
stem cell.

- Clinical Variability

Brusasco et al. (1998) reported an 18-year-old woman with congenital
reticular ichthyosiform erythroderma who developed several
hyperpigmented 3- to 5-mm macules on the extensor surfaces of her limbs.
These lesions were almost black in color and had a tendency to coalesce
into dark irregular areas. They were localized on the red ichthyotic
skin only, and not on the small patches of normal skin. This feature had
not been observed in the other patients with this disorder or in other
ichthyotic disorders. Light microscopy showed typical features of CRIE,
as well as a perivascular lymphohistiocytic infiltrate in the
superficial dermis. Electron microscopy and immunohistochemistry
demonstrated that the lesions were strictly related to the ichthyotic
skin, and that the dark color was due to melanosome accumulation in
activated dendritic melanocytes. No amyloid deposits were observed.
Brusasco et al. (1998) postulated an unusual postinflammatory
hyperpigmentation reaction in response to a continuous inflammatory
process in CRIE. The lack of pigment deposition in the keratinocytes may
have resulted from a transfer defect, or the finding may have reflected
hyperplastic stimulation of the epidermis.

- Aarau Disease

In Aarau, Switzerland, Itin et al. (2003) described a 12-year-old girl
with what they considered to be a 'new' disorder of cornification. The
patient developed an ichthyosis vulgaris (146700)-like skin disorder 6
months after birth. Several years later, the clinical features changed
considerably. The patient had developed streaks of hyperkeratotic,
slightly scaling skin with underlying erythema distributed in a
reticulate, occasionally annular pattern on the trunk and extremities.
Lesions were stable and had not changed significantly in size or
distribution over the ensuing years. The initial generalized skin
lesions in this patient resolved, and erythrokeratodermic streaks and
plaques developed, which was considered distinct from patients with
CRIE. Histopathologic and ultrastructural findings were nonspecific, and
there was no evidence of a metabolic disorder. Specifically, the
pathognomonic features of CRIE, such as keratinocyte vacuolization,
binucleate cells, and perinuclear shells, were not observed. The parents
of the patient were nonconsanguineous, and no family members had this or
any similar skin disorder. Itin et al. (2003) noted that the disorder in
their patient shared several clinical features with CRIE (Marghescu et
al., 1984), but was nonetheless distinct. Because of partial clinical
overlap with erythrokeratodermia variabilis (EKV; 133200), Itin et al.
(2003) screened for mutations in several connexin genes but found none.
Itin et al. (2003) speculated that this disorder of cornification
represented a separate new entity, which they proposed to call 'Aarau
disease.'

INHERITANCE

In a review of CRIE, Krunic et al. (2003) noted that only a small number
of patients with sporadic occurrence have been documented, suggesting a
new dominant mutation as a cause of the condition.

MAPPING

Choate et al. (2010) compared genotypes of DNA from blood and cultured
keratinocytes from biopsies of diseased and revertant skin of 1 subject.
In contrast to blood and disease keratinocytes, revertant DNA showed a
single large segment of copy-neutral loss of heterozygosity on
chromosome 17q extending from 34.5 Mb to the telomere at 78.7 Mb. Three
additional revertant spots from this subject also showed copy-neutral
loss of heterozygosity extending from proximal 17q to the telomere, each
with different inferred start sites for loss of heterozygosity, which
excluded simple genetic mosaicism. In each revertant, the same parental
haplotype was lost, consistent with loss of dominant mutation. Choate et
al. (2010) then analyzed 28 revertant spots from 5 additional patients.
All revertants showed copy-number loss of heterozygosity on 17q
extending to the telomere. These observations confined the disease locus
to an interval on 17q containing a gene cluster encoding 28 type 1
keratins and 24 keratin-associated proteins.

MOLECULAR GENETICS

Choate et al. (2010) sequenced the entire critical interval for IWC in a
parent-child trio and identified a de novo mutation in the keratin-10
gene (KRT10; 148080) in the affected subject. The mutation abolished the
canonical splice acceptor site of intron 6 (148080.0015) and was absent
in revertant spots. Sequencing of KRT10 from genomic DNA and disease
keratinocyte cDNA in the 6 other IWC kindres identified de novo
mutations in all 4 simplex kindreds and transmitted mutations in the 2
multiplex kindreds. All mutations resulted in cDNAs encoding frameshifts
that entered the same alternative C-terminal reading frame. Mutations
included 2 additional intron 6 splice acceptor mutations, an intron 6
splice donor site mutation that results in skipping of exon 6, 2
frameshift mutations in exon 7, and an exon 6 mutation that creates a
premature splice donor site. All of these mutations were absent in
control chromosomes, and each was lost in revertant spots. On the basis
of these findings, Choate et al. (2010) concluded that mutations in
KRT10 cause ichthyosis with confetti.

*FIELD* RF
1. Brusasco, A.; Cambiaghi, S.; Tadini, G.; Berti, E.; Caputo, R.
: Unusual hyperpigmentation developing in congenital reticular ichthyosiform
erythroderma (ichthyosis variegata). Brit. J. Derm. 139: 893-896,
1998.

2. Choate, K. A.; Lu, Y.; Zhou, J.; Choi, M.; Elias, P. M.; Farhi,
A.; Nelson-Williams, C.; Crumrine, D.; Williams, M. L.; Nopper, A.
J.; Bree, A; Milstone, L. M.; Lifton, R. P.: Mitotic recombination
in patients with ichthyosis causes reversion of dominant mutations
in KRT10. Science 330: 94-97, 2010.

3. Itin, P. H.; Moschopulos, M.; Richard, G.: Reticular erythrokeratoderma:
a new disorder of cornification. Am. J. Med. Genet. 120A: 237-240,
2003.

4. Krunic, A. L.; Palcesky, D.; Busbey, S.; Medenica, M.: Congenital
reticular ichthyosiform erythroderma-ichthyosis variegata: a case
report and review of the literature. Acta Derm. Venereol. 83: 36-39,
2003.

5. Marghescu, S.; Anton-Lamprecht, I.; Rudolph, P.-O.; Kaste, R.:
Kongenitale retikulare ichthyosiforme erythrodermie. Der Hautarzt 35:
522-529, 1984.

*FIELD* CS
INHERITANCE:
Isolated cases

SKIN, NAILS, HAIR:
[Skin];
Erythematous ichthyotic patches;
Patches are surrounded by normal skin in a fine, reticular pattern;
HISTOLOGY:;
Band-like parakeratosis;
Hyperkeratosis;
Acanthosis;
Amyloid deposits in the dermis (less common);
Vacuolized keratinocytes;
ELECTRON MICROSCOPY:;
Binucleated cells in the upper epidermis;
Perinuclear 'shells' in vacuolated keratinocytes;
Perinuclear material is filamentous

MISCELLANEOUS:
At birth, there is generalized red scaly skin;
Enlarging patches of normal skin appear during childhood and adolescence

*FIELD* CD
Cassandra L. Kniffin: 10/25/2010

*FIELD* ED
joanna: 07/17/2012
ckniffin: 10/25/2010

*FIELD* CN
Cassandra L. Kniffin - updated: 10/25/2010

*FIELD* CD
Victor A. McKusick: 1/14/2005

*FIELD* ED
joanna: 02/04/2014
carol: 10/12/2011
alopez: 11/10/2010
alopez: 11/9/2010
wwang: 11/8/2010
ckniffin: 10/25/2010
carol: 4/21/2006
terry: 12/14/2005
wwang: 1/20/2005
wwang: 1/14/2005