RBCC Red Blood Cell Collection

KRT14 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Keratin, type I cytoskeletal 14 (Cytokeratin-14; CK-14; Keratin-14; K14)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P02533
ID K1C14_HUMAN Reviewed; 472 AA.
AC P02533; Q14715; Q53XY3; Q9BUE3; Q9UBN2; Q9UBN3; Q9UCY4;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-MAY-2009, sequence version 4.
DT 22-JAN-2014, entry version 159.
DE RecName: Full=Keratin, type I cytoskeletal 14;
DE AltName: Full=Cytokeratin-14;
DE Short=CK-14;
DE AltName: Full=Keratin-14;
DE Short=K14;
GN Name=KRT14;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6210150; DOI=10.1016/0092-8674(84)90456-2;
RA Marchuk D., McCrohon S., Fuchs E.;
RT "Remarkable conservation of structure among intermediate filament
RT genes.";
RL Cell 39:491-498(1984).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT TYR-63.
RX PubMed=2580298; DOI=10.1073/pnas.82.6.1609;
RA Marchuk D., McCrohon S., Fuchs E.;
RT "Complete sequence of a gene encoding a human type I keratin:
RT sequences homologous to enhancer elements in the regulatory region of
RT the gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:1609-1613(1985).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS TYR-63 AND
RP THR-94.
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS TYR-63 AND
RP THR-94.
RC TISSUE=Brain, Pancreas, and 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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 64-472.
RC TISSUE=Epidermis;
RX PubMed=6186381; DOI=10.1016/0092-8674(82)90424-X;
RA Hanukoglu I., Fuchs E.;
RT "The cDNA sequence of a human epidermal keratin: divergence of
RT sequence but conservation of structure among intermediate filament
RT proteins.";
RL Cell 31:243-252(1982).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 117-132, AND VARIANT DM-EBS
RP ASP-129.
RX PubMed=8601736; DOI=10.1111/1523-1747.ep12342985;
RA Chan Y.-M., Cheng J., Gedde-Dahl T. Jr., Niemi K.M., Fuchs E.;
RT "Genetic analysis of a severe case of Dowling-Meara epidermolysis
RT bullosa simplex.";
RL J. Invest. Dermatol. 106:327-334(1996).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 118-126, AND VARIANTS DM-EBS
RP PHE-122; CYS-125 AND HIS-125.
RX PubMed=1717157; DOI=10.1016/0092-8674(91)90051-Y;
RA Coulombe P.A., Hutton M.E., Letai A., Hebert A., Paller A.S.,
RA Fuchs E.;
RT "Point mutations in human keratin 14 genes of epidermolysis bullosa
RT simplex patients: genetic and functional analyses.";
RL Cell 66:1301-1311(1991).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 118-126, AND VARIANT K-EBS
RP PHE-122.
RX PubMed=7526926; DOI=10.1093/hmg/3.7.1171;
RA Yamanishi K., Matsuki M., Konishi K., Yasuno H.;
RT "A novel mutation of Leu122 to Phe at a highly conserved hydrophobic
RT residue in the helix initiation motif of keratin 14 in epidermolysis
RT bullosa simplex.";
RL Hum. Mol. Genet. 3:1171-1172(1994).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 352-424, AND VARIANT K-EBS
RP THR-413.
RA Fujiwara H.;
RT "A novel mutation of cytokeratin 14 in a Japanese epidermolysis
RT bullosa simplex family.";
RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP TISSUE SPECIFICITY.
RX PubMed=9457912; DOI=10.1046/j.1523-1747.1998.00097.x;
RA Bowden P.E., Hainey S.D., Parker G., Jones D.O., Zimonjic D.,
RA Popescu N., Hodgins M.B.;
RT "Characterization and chromosomal localization of human hair-specific
RT keratin genes and comparative expression during the hair growth
RT cycle.";
RL J. Invest. Dermatol. 110:158-164(1998).
RN [12]
RP INTERACTION WITH TRADD.
RX PubMed=11684708; DOI=10.1083/jcb.200103078;
RA Inada H., Izawa I., Nishizawa M., Fujita E., Kiyono T., Takahashi T.,
RA Momoi T., Inagaki M.;
RT "Keratin attenuates tumor necrosis factor-induced cytotoxicity through
RT association with TRADD.";
RL J. Cell Biol. 155:415-426(2001).
RN [13]
RP FUNCTION, INTERACTION WITH KERATIN FILAMENTS, AND SUBCELLULAR
RP LOCATION.
RX PubMed=11724817; DOI=10.1083/jcb.200104063;
RA Bousquet O., Ma L., Yamada S., Gu C., Idei T., Takahashi K., Wirtz D.,
RA Coulombe P.A.;
RT "The nonhelical tail domain of keratin 14 promotes filament bundling
RT and enhances the mechanical properties of keratin intermediate
RT filaments in vitro.";
RL J. Cell Biol. 155:747-754(2001).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [15]
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 [16]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 295-422 IN COMPLEX WITH KRT5,
RP DISULFIDE BOND, AND SUBCELLULAR LOCATION.
RX PubMed=22705788; DOI=10.1038/nsmb.2330;
RA Lee C.H., Kim M.S., Chung B.M., Leahy D.J., Coulombe P.A.;
RT "Structural basis for heteromeric assembly and perinuclear
RT organization of keratin filaments.";
RL Nat. Struct. Mol. Biol. 19:707-715(2012).
RN [17]
RP VARIANT K-EBS PRO-384.
RX PubMed=1720261; DOI=10.1126/science.1720261;
RA Bonifas J.M., Rothman A.L., Epstein E.H. Jr.;
RT "Epidermolysis bullosa simplex: evidence in two families for keratin
RT gene abnormalities.";
RL Science 254:1202-1205(1991).
RN [18]
RP VARIANT WC-EBS GLU-375 DEL.
RX PubMed=7506606; DOI=10.1093/hmg/2.11.1971;
RA Chen M.A., Bonifas J.M., Matsumura K., Blumenfeld A.,
RA Epstein E.H. Jr.;
RT "A novel three-nucleotide deletion in the helix 2B region of keratin
RT 14 in epidermolysis bullosa simplex: delta E375.";
RL Hum. Mol. Genet. 2:1971-1972(1993).
RN [19]
RP VARIANT K-EBS ARG-272.
RX PubMed=7682883; DOI=10.1002/humu.1380020107;
RA Humphries M.M., Sheils D.M., Farrar G.J., Kumar-Singh R., Kenna P.F.,
RA Mansergh F.C., Jordan S.A., Young M.M., Humphries P.;
RT "A mutation (Met-->Arg) in the type I keratin (K14) gene responsible
RT for autosomal dominant epidermolysis bullosa simplex.";
RL Hum. Mutat. 2:37-42(1993).
RN [20]
RP VARIANT DM-EBS HIS-125.
RX PubMed=7688405; DOI=10.1111/1523-1747.ep12365079;
RA Stephens K., Sybert V.P., Wijsman E.M., Ehrlich P., Spencer A.;
RT "A keratin 14 mutational hot spot for epidermolysis bullosa simplex,
RT Dowling-Meara: implications for diagnosis.";
RL J. Invest. Dermatol. 101:240-243(1993).
RN [21]
RP VARIANT EBSB1 ALA-144.
RX PubMed=7526933; DOI=10.1038/ng0493-327;
RA Hovnanian A., Pollack E., Hilal L., Rochat A., Prost C., Barrandon Y.,
RA Goossens M.;
RT "A missense mutation in the rod domain of keratin 14 associated with
RT recessive epidermolysis bullosa simplex.";
RL Nat. Genet. 3:327-331(1993).
RN [22]
RP VARIANT WC-EBS MET-270.
RX PubMed=7506097; DOI=10.1038/ng1193-294;
RA Rugg E.L., Morley S.M., Smith F.J.D., Boxer M., Tidman M.J.,
RA Navsaria H.A., Leigh I.M., Lane E.B.;
RT "Missing links: Weber-Cockayne keratin mutations implicate the L12
RT linker domain in effective cytoskeleton function.";
RL Nat. Genet. 5:294-300(1993).
RN [23]
RP VARIANTS WC-EBS ILE-119; ASP-274; ASN-377 AND CYS-388, AND VARIANTS
RP DM-EBS ARG-120; CYS-125 AND SER-125.
RX PubMed=7561171; DOI=10.1111/1523-1747.ep12323846;
RA Chen H., Bonifas J.M., Matsumura K., Ikeda S., Leyden W.A.,
RA Epstein E.H. Jr.;
RT "Keratin 14 gene mutations in patients with epidermolysis bullosa
RT simplex.";
RL J. Invest. Dermatol. 105:629-632(1995).
RN [24]
RP VARIANT WC-EBS ILE-119.
RX PubMed=9284105; DOI=10.1111/1523-1747.ep12336051;
RA Hu Z.L., Smith L., Martins S., Bonifas J.M., Chen H.,
RA Epstein E.H. Jr.;
RT "Partial dominance of a keratin 14 mutation in epidermolysis bullosa
RT simplex: increased severity of disease in a homozygote.";
RL J. Invest. Dermatol. 109:360-364(1997).
RN [25]
RP VARIANT DM-EBS THR-119.
RX PubMed=9804355; DOI=10.1046/j.1523-1747.1998.00388.x;
RA Shemanko C.S., Mellerio J.E., Tidman M.J., Lane E.B., Eady R.A.J.;
RT "Severe palmo-plantar hyperkeratosis in Dowling-Meara epidermolysis
RT bullosa simplex caused by a mutation in the keratin 14 gene (KRT14).";
RL J. Invest. Dermatol. 111:893-895(1998).
RN [26]
RP VARIANT WC-EBS GLY-273.
RX PubMed=9804357; DOI=10.1046/j.1523-1747.1998.00374.x;
RA Mueller F.B., Kuester W., Bruckner-Tuderman L., Korge B.P.;
RT "Novel K5 and K14 mutations in German patients with the Weber-Cockayne
RT variant of epidermolysis bullosa simplex.";
RL J. Invest. Dermatol. 111:900-902(1998).
RN [27]
RP VARIANT DM-EBS CYS-125.
RX PubMed=10583131; DOI=10.1046/j.1365-2133.1999.03124.x;
RA Sasaki Y., Shimizu H., Akiyama M., Hiraoka Y., Takizawa Y., Yamada S.,
RA Morishima Y., Yamanishi K., Aiso S., Nishikawa T.;
RT "A recurrent keratin 14 mutation in Dowling-Meara epidermolysis
RT bullosa simplex.";
RL Br. J. Dermatol. 141:747-748(1999).
RN [28]
RP VARIANT K-EBS HIS-415, AND VARIANT DM-EBS GLN-419.
RA Hut P.H.L., van der Vlies P., Jonkman M.F., Shimizu H., Buys C.H.C.M.,
RA Scheffer H.;
RT "Genomic keratin 14 mutation detection in epidermolysis bullosa
RT simplex.";
RL Eur. J. Hum. Genet. Suppl. 7:121-121(1999).
RN [29]
RP VARIANT WC-EBS ASN-116, VARIANT DM-EBS SER-123, VARIANT K-EBS PRO-143,
RP VARIANT THR-94, AND SEQUENCE REVISION TO 25 AND 43.
RX PubMed=9989794; DOI=10.1046/j.1523-1747.1999.00495.x;
RA Soerensen C.B., Ladekjaer-Mikkelsen A.-S., Andresen B.S., Brandrup F.,
RA Veien N.K., Buus S.K., Anton-Lamprecht I., Kruse T.A., Jensen P.K.A.,
RA Eiberg H., Bolund L., Gregersen N.;
RT "Identification of novel and known mutations in the genes for keratin
RT 5 and 14 in Danish patients with epidermolysis bullosa simplex:
RT correlation between genotype and phenotype.";
RL J. Invest. Dermatol. 112:184-190(1999).
RN [30]
RP VARIANT DM-EBS HIS-125.
RX PubMed=10730767; DOI=10.1046/j.1365-2133.2000.03304.x;
RA Shemanko C.S., Horn H.M., Keohane S.G., Hepburn N., Kerr A.I.G.,
RA Atherton D.J., Tidman M.J., Lane E.B.;
RT "Laryngeal involvement in the Dowling-Meara variant of epidermolysis
RT bullosa simplex with keratin mutations of severely disruptive
RT potential.";
RL Br. J. Dermatol. 142:315-320(2000).
RN [31]
RP VARIANTS DM-EBS CYS-125; HIS-125 AND GLN-419, VARIANTS K-EBS ASP-247
RP AND HIS-415, AND VARIANT WC-EBS LYS-422.
RX PubMed=10733662; DOI=10.1046/j.1523-1747.2000.00928.x;
RA Hut P.H.L., van der Vlies P., Jonkman M.F., Verlind E., Shimizu H.,
RA Buys C.H.C.M., Scheffer H.;
RT "Exempting homologous pseudogene sequences from polymerase chain
RT reaction amplification allows genomic keratin 14 hotspot analysis.";
RL J. Invest. Dermatol. 114:616-619(2000).
RN [32]
RP VARIANTS DM-EBS CYS-125 AND HIS-415, AND VARIANT K-EBS PRO-134.
RX PubMed=10820403;
RX DOI=10.1002/(SICI)1097-0223(200005)20:5<371::AID-PD818>3.0.CO;2-5;
RA Rugg E.L., Baty D., Shemanko C.S., Magee G., Polak S., Bergman R.,
RA Kadar T., Boxer M., Falik-Zaccai T., Borochowitz Z., Lane E.B.;
RT "DNA based prenatal testing for the skin blistering disorder
RT epidermolysis bullosa simplex.";
RL Prenat. Diagn. 20:371-377(2000).
RN [33]
RP VARIANT DM-EBS THR-119, AND VARIANT K-EBS VAL-119.
RX PubMed=11710919; DOI=10.1046/j.0022-202x.2001.01508.x;
RA Cummins R.E., Klingberg S., Wesley J., Rogers M., Zhao Y.,
RA Murrell D.F.;
RT "Keratin 14 point mutations at codon 119 of helix 1A resulting in
RT different epidermolysis bullosa simplex phenotypes.";
RL J. Invest. Dermatol. 117:1103-1107(2001).
RN [34]
RP VARIANTS WC-EBS HIS-388 AND CYS-415, AND VARIANT DM-EBS HIS-125.
RX PubMed=12707098; DOI=10.1001/archderm.139.4.498;
RA Ciubotaru D., Bergman R., Baty D., Indelman M., Pfendner E.,
RA Petronius D., Moualem H., Kanaan M., Ben Amitai D., McLean W.H.I.,
RA Uitto J., Sprecher E.;
RT "Epidermolysis bullosa simplex in Israel: clinical and genetic
RT features.";
RL Arch. Dermatol. 139:498-505(2003).
RN [35]
RP ERRATUM.
RA Ciubotaru D., Bergman R., Baty D., Indelman M., Pfendner E.,
RA Petronius D., Moualem H., Kanaan M., Ben Amitai D., McLean W.H.I.,
RA Uitto J., Sprecher E.;
RL Arch. Dermatol. 139:1084-1084(2003).
RN [36]
RP VARIANTS DM-EBS PRO-130 AND GLN-419, AND VARIANT WC-EBS MET-408.
RX PubMed=12655565; DOI=10.1002/humu.9124;
RA Schuilenga-Hut P.H.L., Vlies P., Jonkman M.F., Waanders E.,
RA Buys C.H.C.M., Scheffer H.;
RT "Mutation analysis of the entire keratin 5 and 14 genes in patients
RT with epidermolysis bullosa simplex and identification of novel
RT mutations.";
RL Hum. Mutat. 21:447-447(2003).
RN [37]
RP VARIANTS DM-EBS SER-128 DEL AND PRO-416, AND VARIANT WC-EBS CYS-148.
RX PubMed=12603865; DOI=10.1046/j.1523-1747.2003.12052.x;
RA Wood P., Baty D.U., Lane E.B., McLean W.H.I.;
RT "Long-range polymerase chain reaction for specific full-length
RT amplification of the human keratin 14 gene and novel keratin 14
RT mutations in epidermolysis bullosa simplex patients.";
RL J. Invest. Dermatol. 120:495-497(2003).
RN [38]
RP VARIANTS DM-EBS LYS-123 AND GLY-125, AND VARIANT WC-EBS LEU-133.
RX PubMed=14987259; DOI=10.1111/j.0906-6705.2004.0120.x;
RA Csikos M., Szalai Z., Becker K., Sebok B., Schneider I., Horvath A.,
RA Karpati S.;
RT "Novel keratin 14 gene mutations in patients from Hungary with
RT epidermolysis bullosa simplex.";
RL Exp. Dermatol. 13:185-191(2004).
RN [39]
RP INVOLVEMENT IN NFJS, AND INVOLVEMENT IN DPR.
RX PubMed=16960809; DOI=10.1086/507792;
RA Lugassy J., Itin P., Ishida-Yamamoto A., Holland K., Huson S.,
RA Geiger D., Hennies H.C., Indelman M., Bercovich D., Uitto J.,
RA Bergman R., McGrath J.A., Richard G., Sprecher E.;
RT "Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa
RT reticularis: two allelic ectodermal dysplasias caused by dominant
RT mutations in KRT14.";
RL Am. J. Hum. Genet. 79:724-730(2006).
RN [40]
RP VARIANT WC-EBS VAL-119, AND VARIANTS DM-EBS HIS-125 AND CYS-125.
RX PubMed=16882168; DOI=10.1111/j.1365-2133.2006.07285.x;
RA Yasukawa K., Sawamura D., Goto M., Nakamura H., Jung S.-Y., Kim S.-C.,
RA Shimizu H.;
RT "Epidermolysis bullosa simplex in Japanese and Korean patients:
RT genetic studies in 19 cases.";
RL Br. J. Dermatol. 155:313-317(2006).
RN [41]
RP VARIANTS DM-EBS LYS-123; CYS-125; HIS-125 AND PRO-417, VARIANTS K-EBS
RP LEU-133; THR-272 AND PRO-384, AND VARIANTS WC-EBS PRO-211 AND GLU-411
RP DEL.
RX PubMed=16786515; DOI=10.1002/humu.9437;
RA Mueller F.B., Kuester W., Wodecki K., Almeida H. Jr.,
RA Bruckner-Tuderman L., Krieg T., Korge B.P., Arin M.J.;
RT "Novel and recurrent mutations in keratin KRT5 and KRT14 genes in
RT epidermolysis bullosa simplex: implications for disease phenotype and
RT keratin filament assembly.";
RL Hum. Mutat. 27:719-720(2006).
CC -!- FUNCTION: The nonhelical tail domain is involved in promoting
CC KRT5-KRT14 filaments to self-organize into large bundles and
CC enhances the mechanical properties involved in resilience of
CC keratin intermediate filaments in vitro.
CC -!- SUBUNIT: Heterotetramer of two type I and two type II keratins.
CC disulfide-linked keratin-14 associates with keratin-5. Interacts
CC with TRADD and with keratin filaments. Associates with other type
CC I keratins.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Expressed in both
CC as a filamentous pattern.
CC -!- TISSUE SPECIFICITY: Detected in the basal layer, lowered within
CC the more apically located layers specifically in the stratum
CC spinosum, stratum granulosum but is not detected in stratum
CC corneum. Strongly expressed in the outer root sheath of anagen
CC follicles but not in the germinative matrix, inner root sheath or
CC hair. Found in keratinocytes surrounding the club hair during
CC telogen.
CC -!- PTM: A disulfide bond is formed between rather than within
CC filaments and promotes the formation of a keratin filament cage
CC around the nucleus.
CC -!- DISEASE: Epidermolysis bullosa simplex, Dowling-Meara type (DM-
CC EBS) [MIM:131760]: A severe form of intraepidermal epidermolysis
CC bullosa characterized by generalized herpetiform blistering, milia
CC formation, dystrophic nails, and mucous membrane involvement.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Epidermolysis bullosa simplex, Weber-Cockayne type (WC-
CC EBS) [MIM:131800]: A form of intraepidermal epidermolysis bullosa
CC characterized by blistering limited to palmar and plantar areas of
CC the skin. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Epidermolysis bullosa simplex, Koebner type (K-EBS)
CC [MIM:131900]: A form of intraepidermal epidermolysis bullosa
CC characterized by generalized skin blistering. The phenotype is not
CC fundamentally distinct from the Dowling-Meara type, although it is
CC less severe. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Epidermolysis bullosa simplex, autosomal recessive 1
CC (EBSB1) [MIM:601001]: An intraepidermal epidermolysis bullosa
CC characterized by localized blistering on the dorsal, lateral and
CC plantar surfaces of the feet. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Naegeli-Franceschetti-Jadassohn syndrome (NFJS)
CC [MIM:161000]: A rare autosomal dominant form of ectodermal
CC dysplasia. The cardinal features are absence of dermatoglyphics
CC (fingerprints), reticular cutaneous hyperpigmentation (starting at
CC about the age of 2 years without a preceding inflammatory stage),
CC palmoplantar keratoderma, hypohidrosis with diminished sweat gland
CC function and discomfort provoked by heat, nail dystrophy, and
CC tooth enamel defects. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Dermatopathia pigmentosa reticularis (DPR) [MIM:125595]:
CC A rare ectodermal dysplasia characterized by lifelong persistent
CC reticulate hyperpigmentation, non-cicatricial alopecia, and nail
CC dystrophy. Variable features include adermatoglyphia, hypohidrosis
CC or hyperhidrosis, and palmoplantar hyperkeratosis. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- MISCELLANEOUS: There are two types of cytoskeletal and
CC microfibrillar keratin: I (acidic; 40-55 kDa) and II (neutral to
CC basic; 56-70 kDa).
CC -!- SIMILARITY: Belongs to the intermediate filament family.
CC -!- WEB RESOURCE: Name=Human Intermediate Filament Mutation Database;
CC URL="http://www.interfil.org";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/KRT14";
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DR EMBL; J00124; AAB59562.1; -; Genomic_DNA.
DR EMBL; BT007186; AAP35850.1; -; mRNA.
DR EMBL; AC019349; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC002690; AAH02690.1; -; mRNA.
DR EMBL; BC019097; AAH19097.1; -; mRNA.
DR EMBL; BC042437; AAH42437.1; -; mRNA.
DR EMBL; BC094830; AAH94830.1; -; mRNA.
DR EMBL; D28807; BAA05967.1; -; Genomic_DNA.
DR EMBL; AF186085; AAF04034.1; -; Genomic_DNA.
DR EMBL; AF186086; AAF04035.1; -; Genomic_DNA.
DR EMBL; AF186087; AAF04036.1; -; Genomic_DNA.
DR EMBL; AF186088; AAF04037.1; -; Genomic_DNA.
DR EMBL; AF186089; AAF04038.1; -; Genomic_DNA.
DR EMBL; AF186090; AAF04039.1; -; Genomic_DNA.
DR PIR; A26763; KRHUE.
DR RefSeq; NP_000517.2; NM_000526.4.
DR UniGene; Hs.654380; -.
DR PDB; 3TNU; X-ray; 3.00 A; A=295-422.
DR PDBsum; 3TNU; -.
DR ProteinModelPortal; P02533; -.
DR SMR; P02533; 165-263, 279-421.
DR DIP; DIP-33874N; -.
DR IntAct; P02533; 16.
DR STRING; 9606.ENSP00000167586; -.
DR PhosphoSite; P02533; -.
DR DMDM; 229463044; -.
DR PaxDb; P02533; -.
DR PRIDE; P02533; -.
DR ProMEX; P02533; -.
DR DNASU; 3861; -.
DR Ensembl; ENST00000167586; ENSP00000167586; ENSG00000186847.
DR GeneID; 3861; -.
DR KEGG; hsa:3861; -.
DR UCSC; uc002hxf.2; human.
DR CTD; 3861; -.
DR GeneCards; GC17M039738; -.
DR HGNC; HGNC:6416; KRT14.
DR HPA; CAB000134; -.
DR HPA; HPA000452; -.
DR HPA; HPA000453; -.
DR HPA; HPA023040; -.
DR MIM; 125595; phenotype.
DR MIM; 131760; phenotype.
DR MIM; 131800; phenotype.
DR MIM; 131900; phenotype.
DR MIM; 148066; gene.
DR MIM; 161000; phenotype.
DR MIM; 601001; phenotype.
DR neXtProt; NX_P02533; -.
DR Orphanet; 89838; Autosomal recessive epidermolysis bullosa simplex.
DR Orphanet; 86920; Dermatopathia pigmentosa reticularis.
DR Orphanet; 79397; Epidermolysis bullosa simplex with mottled pigmentation.
DR Orphanet; 79396; Epidermolysis bullosa simplex, Dowling-Meara type.
DR Orphanet; 79399; Generalized epidermolysis bullosa simplex, non-Dowling-Meara type.
DR Orphanet; 79400; Localized epidermolysis bullosa simplex.
DR Orphanet; 69087; Naegeli-Franceschetti-Jadassohn syndrome.
DR PharmGKB; PA30203; -.
DR eggNOG; NOG148784; -.
DR HOVERGEN; HBG013015; -.
DR InParanoid; P02533; -.
DR KO; K07604; -.
DR OMA; RQVRTKV; -.
DR OrthoDB; EOG7FV3Q8; -.
DR PhylomeDB; P02533; -.
DR Reactome; REACT_111155; Cell-Cell communication.
DR GeneWiki; Keratin_14; -.
DR GenomeRNAi; 3861; -.
DR NextBio; 15195; -.
DR PRO; PR:P02533; -.
DR ArrayExpress; P02533; -.
DR Bgee; P02533; -.
DR CleanEx; HS_KRT14; -.
DR Genevestigator; P02533; -.
DR GO; GO:0071944; C:cell periphery; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0045095; C:keratin filament; IDA:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:ProtInc.
DR GO; GO:0008544; P:epidermis development; TAS:ProtInc.
DR GO; GO:0030855; P:epithelial cell differentiation; IEA:Ensembl.
DR GO; GO:0031581; P:hemidesmosome assembly; TAS:Reactome.
DR GO; GO:0045110; P:intermediate filament bundle assembly; IMP:UniProtKB.
DR GO; GO:0010212; P:response to ionizing radiation; IEA:Ensembl.
DR GO; GO:0010043; P:response to zinc ion; IEA:Ensembl.
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; Cytoplasm;
KW Disease mutation; Disulfide bond; Ectodermal dysplasia;
KW Epidermolysis bullosa; Intermediate filament; Keratin; Nucleus;
KW Palmoplantar keratoderma; Polymorphism; Reference proteome.
FT CHAIN 1 472 Keratin, type I cytoskeletal 14.
FT /FTId=PRO_0000063653.
FT REGION 1 114 Head.
FT REGION 115 422 Rod.
FT REGION 115 150 Coil 1A.
FT REGION 151 168 Linker 1.
FT REGION 169 260 Coil 1B.
FT REGION 261 283 Linker 12.
FT REGION 284 422 Coil 2.
FT REGION 423 472 Tail.
FT REGION 425 472 Interaction with Type I keratins and
FT keratin filaments.
FT SITE 364 364 Stutter.
FT DISULFID 367 367 Interchain.
FT VARIANT 63 63 C -> Y (in dbSNP:rs6503640).
FT /FTId=VAR_055347.
FT VARIANT 94 94 A -> T (in dbSNP:rs3826550).
FT /FTId=VAR_010437.
FT VARIANT 116 116 K -> N (in WC-EBS; dbSNP:rs59271739).
FT /FTId=VAR_010438.
FT VARIANT 119 119 M -> I (in WC-EBS at heterozygosity; more
FT severe phenotype is associated with
FT homozygosity; dbSNP:rs57358989).
FT /FTId=VAR_010439.
FT VARIANT 119 119 M -> T (in DM-EBS; dbSNP:rs28928893).
FT /FTId=VAR_010440.
FT VARIANT 119 119 M -> V (in K-EBS and WC-EBS;
FT dbSNP:rs61263401).
FT /FTId=VAR_023719.
FT VARIANT 120 120 Q -> R (in DM-EBS; dbSNP:rs60993843).
FT /FTId=VAR_010441.
FT VARIANT 122 122 L -> F (in DM-EBS and K-EBS;
FT dbSNP:rs59110575).
FT /FTId=VAR_010442.
FT VARIANT 123 123 N -> K (in DM-EBS; dbSNP:rs3826549).
FT /FTId=VAR_023720.
FT VARIANT 123 123 N -> S (in DM-EBS; dbSNP:rs60171927).
FT /FTId=VAR_010443.
FT VARIANT 125 125 R -> C (in DM-EBS; dbSNP:rs60399023).
FT /FTId=VAR_003837.
FT VARIANT 125 125 R -> G (in DM-EBS).
FT /FTId=VAR_023721.
FT VARIANT 125 125 R -> H (in DM-EBS; dbSNP:rs58330629).
FT /FTId=VAR_003838.
FT VARIANT 125 125 R -> S (in DM-EBS).
FT /FTId=VAR_010444.
FT VARIANT 128 128 Missing (in DM-EBS).
FT /FTId=VAR_031634.
FT VARIANT 129 129 Y -> D (in DM-EBS; dbSNP:rs60470268).
FT /FTId=VAR_010445.
FT VARIANT 130 130 L -> P (in DM-EBS; dbSNP:rs57522245).
FT /FTId=VAR_023722.
FT VARIANT 133 133 V -> A (in dbSNP:rs642601).
FT /FTId=VAR_033496.
FT VARIANT 133 133 V -> L (in WC-EBS and K-EBS;
FT dbSNP:rs61027685).
FT /FTId=VAR_023723.
FT VARIANT 134 134 R -> P (in K-EBS; dbSNP:rs61540016).
FT /FTId=VAR_031635.
FT VARIANT 143 143 L -> P (in K-EBS; dbSNP:rs61326242).
FT /FTId=VAR_010446.
FT VARIANT 144 144 E -> A (in EBSB1; dbSNP:rs57121345).
FT /FTId=VAR_003839.
FT VARIANT 148 148 R -> C (in WC-EBS; dbSNP:rs58378809).
FT /FTId=VAR_031636.
FT VARIANT 211 211 R -> P (in WC-EBS; dbSNP:rs60589227).
FT /FTId=VAR_027718.
FT VARIANT 215 215 E -> K (in dbSNP:rs11551755).
FT /FTId=VAR_049784.
FT VARIANT 247 247 A -> D (in K-EBS).
FT /FTId=VAR_010447.
FT VARIANT 270 270 V -> M (in WC-EBS; dbSNP:rs58560979).
FT /FTId=VAR_003840.
FT VARIANT 272 272 M -> R (in K-EBS; dbSNP:rs61371557).
FT /FTId=VAR_003841.
FT VARIANT 272 272 M -> T (in K-EBS).
FT /FTId=VAR_027719.
FT VARIANT 273 273 D -> G (in WC-EBS; dbSNP:rs59375065).
FT /FTId=VAR_010448.
FT VARIANT 274 274 A -> D (in WC-EBS; dbSNP:rs58785777).
FT /FTId=VAR_010449.
FT VARIANT 375 375 Missing (in WC-EBS).
FT /FTId=VAR_003842.
FT VARIANT 377 377 I -> N (in WC-EBS; dbSNP:rs61536893).
FT /FTId=VAR_010450.
FT VARIANT 384 384 L -> P (in K-EBS; dbSNP:rs59629244).
FT /FTId=VAR_003843.
FT VARIANT 388 388 R -> C (in WC-EBS; dbSNP:rs59966597).
FT /FTId=VAR_010451.
FT VARIANT 388 388 R -> H (in WC-EBS; dbSNP:rs58645163).
FT /FTId=VAR_031637.
FT VARIANT 408 408 L -> M (in WC-EBS; dbSNP:rs57200223).
FT /FTId=VAR_023724.
FT VARIANT 411 411 Missing (in WC-EBS).
FT /FTId=VAR_027720.
FT VARIANT 413 413 A -> T (in K-EBS; dbSNP:rs59780231).
FT /FTId=VAR_023725.
FT VARIANT 415 415 Y -> C (in WC-EBS).
FT /FTId=VAR_031638.
FT VARIANT 415 415 Y -> H (in K-EBS).
FT /FTId=VAR_003844.
FT VARIANT 416 416 R -> P (in DM-EBS).
FT /FTId=VAR_031639.
FT VARIANT 417 417 R -> P (in DM-EBS).
FT /FTId=VAR_027721.
FT VARIANT 419 419 L -> Q (in DM-EBS).
FT /FTId=VAR_003845.
FT VARIANT 422 422 E -> K (in WC-EBS).
FT /FTId=VAR_010452.
FT CONFLICT 26 26 G -> A (in Ref. 1 and 2; AAB59562).
FT CONFLICT 44 44 S -> N (in Ref. 1 and 2; AAB59562).
FT HELIX 333 418
SQ SEQUENCE 472 AA; 51561 MW; 120BA30BA2F8E397 CRC64;
MTTCSRQFTS SSSMKGSCGI GGGIGGGSSR ISSVLAGGSC RAPSTYGGGL SVSSSRFSSG
GACGLGGGYG GGFSSSSSSF GSGFGGGYGG GLGAGLGGGF GGGFAGGDGL LVGSEKVTMQ
NLNDRLASYL DKVRALEEAN ADLEVKIRDW YQRQRPAEIK DYSPYFKTIE DLRNKILTAT
VDNANVLLQI DNARLAADDF RTKYETELNL RMSVEADING LRRVLDELTL ARADLEMQIE
SLKEELAYLK KNHEEEMNAL RGQVGGDVNV EMDAAPGVDL SRILNEMRDQ YEKMAEKNRK
DAEEWFFTKT EELNREVATN SELVQSGKSE ISELRRTMQN LEIELQSQLS MKASLENSLE
ETKGRYCMQL AQIQEMIGSV EEQLAQLRCE MEQQNQEYKI LLDVKTRLEQ EIATYRRLLE
GEDAHLSSSQ FSSGSQSSRD VTSSSRQIRT KVMDVHDGKV VSTHEQVLRT KN
//

MIM 125595
*RECORD*
*FIELD* NO
125595
*FIELD* TI
#125595 DERMATOPATHIA PIGMENTOSA RETICULARIS; DPR
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moredermatopathia pigmentosa reticularis (DPR), like
Naegeli-Franceschetti-Jadassohn syndrome (NFJS; 161000), is caused by
mutations in the keratin-14 gene (KRT14; 148066).

CLINICAL FEATURES

Dermatopathia pigmentosa reticularis (DPR) is a rare heritable disorder
consisting of a triad of cutaneous findings including reticulate
hyperpigmentation, noncicatricial alopecia, and onychodystrophy.
Variable features include adermatoglyphia, hypohidrosis or
hyperhidrosis, and palmoplantar hyperkeratosis. Heimer et al. (1992)
described a family with 9 cases distributed through 6 sibships of 4
generations. The diagnosis was confirmed by the authors in the
30-year-old proband and her son and daughter. In addition to the triad,
the proposita had adermatoglyphia, hypohidrosis, and punctate
hyperkeratosis of the palms and soles. The family contained no instance
of male-to-male transmission. Heimer et al. (1992) presented a figure
demonstrating the lack of fingerprint patterns.

Dermatopathia pigmentosa reticularis is closely related to another
autosomal dominant ectodermal dysplasia syndrome,
Naegeli-Franceschetti-Jadassohn syndrome (NFJS; 161000) (Lugassy et al.,
2006). Among the most distinctive characteristics of these syndromes is
the complete absence of dermatoglyphics. Other shared features include a
reticulate pattern of skin hyperpigmentation, thickening of the palms
and soles (palmoplantar keratoderma), abnormal sweating, and other
subtle developmental anomalies of the teeth, hair, and skin. DPR has
been distinguished from NFJS by lifelong persistence of the skin
hyperpigmentation, partial alopecia, and absence of dental anomalies
(Heimer et al., 1992).

MAPPING

Both dermatopathia pigmentosa reticularis and
Naegeli-Franceschetti-Jadassohn syndrome map to a common 6-cM interval
on 17q11.2-q21 (Whittock et al., 2000; Sprecher et al., 2002),
supporting the suggestion that NFJS and DPR are allelic disorders (Itin
and Lautenschlager, 1998). Lugassy et al. (2006) refined the location of
the NFJS/DPR locus on 17q11.2-q21, with demonstration of a maximal lod
score of 8.3 at marker D17S800 at a recombination fraction of 0.0.

MOLECULAR GENETICS

Lugassy et al. (2006) found that the NFJS/DPR locus harbored 230 genes,
including a large cluster of keratin genes. They found heterozygous
nonsense or frameshift mutations in the KRT14 gene (148066) that
segregated with the disease traits in all 5 families, 4 with NFJS and
the 1 previously reported as DPR by Heimer et al. (1992).

*FIELD* RF
1. Heimer, W. L., II; Brauner, G.; James, W. D.: Dermatopathia pigmentosa
reticularis: a report of a family demonstrating autosomal dominant
inheritance. J. Am. Acad. Derm. 26: 298-301, 1992.

2. Itin, P. H.; Lautenschlager, S.: Genodermatosis with reticulate,
patchy and mottled pigmentation of the neck--a clue to rare dermatologic
disorders. Dermatology 197: 281-290, 1998.

3. Lugassy, J.; Itin, P.; Ishida-Yamamoto, A.; Holland, K.; Huson,
S.; Geiger, D.; Hennies, H. C.; Indelman, M.; Bercovich, D.; Uitto,
J.; Bergman, R.; McGrath, J. A.; Richard, G.; Sprecher, E.: Naegeli-Franceschetti-Jadassohn
syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal
dysplasias caused by dominant mutations in KRT14. Am. J. Hum. Genet. 79:
724-730, 2006.

4. Sprecher, E.; Itin, P.; Whittock, N. V.; McGrath, J. A.; Meyer,
R.; DiGiovanna, J. J.; Bale, S. J.; Uitto, J.; Richard, G.: Refined
mapping of Naegeli-Franceschetti-Jadassohn syndrome to a 6 cM interval
on chromosome 17q11.2-q21 and investigation of candidate genes. J.
Invest. Derm. 119: 692-698, 2002.

5. Whittock, N. V.; Coleman, C. M.; McLean, W. H. I.; Ashton, G. H.
S.; Acland, K. M.; Eady, R. A. J.; McGrath, J. A.: The gene for Naegeli-Franceschetti-Jadassohn
syndrome maps to 17q21. J. Invest. Derm. 115: 694-698, 2000.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Reticulate pigmentation (bulbar conjunctiva);
[Mouth];
Reticulate pigmentation (oral mucosa)

SKIN, NAILS, HAIR:
[Skin];
Reticulate hyperpigmentation (primarily trunk);
Adermatoglyphia;
Hypohidrosis/hyperhidrosis;
Palmoplantar hyperkeratosis;
Nonscarring blisters (hand, feet, forearms);
[Nails];
Onychodystrophy;
[Hair];
Noncicatricial alopecia (scalp, eyebrows, axillary hair)

MISCELLANEOUS:
Reticulate hyperpigmentation onset birth - 2 years

MOLECULAR BASIS:
Caused by mutation in the keratin-14 gene (KRT14, 148066.0016)

*FIELD* CN
Kelly A. Przylepa - revised: 02/27/2007

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

*FIELD* ED
joanna: 02/27/2007
alopez: 9/27/2006
alopez: 5/1/2003

*FIELD* CN
Victor A. McKusick - updated: 9/22/2006

*FIELD* CD
Victor A. McKusick: 3/25/1992

*FIELD* ED
alopez: 09/27/2006
terry: 9/22/2006
alopez: 3/18/2004
alopez: 5/1/2003
mimadm: 6/25/1994
carol: 3/30/1992
carol: 3/25/1992

MIM 131760
*RECORD*
*FIELD* NO
131760
*FIELD* TI
#131760 EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
;;EPIDERMOLYSIS BULLOSA HERPETIFORMIS, DOWLING-MEARA TYPE;;
read moreEBS-DM
*FIELD* TX
A number sign (#) is used with this entry because the Dowling-Meara type
of epidermolysis bullosa simplex (EBS-DM) can be caused by mutation in
either the keratin-5 (KRT5; 148040) or the keratin-14 (KRT14; 148066)
gene.

DESCRIPTION

Epidermolysis bullosa simplex (EBS) is a clinically and genetically
heterogeneous skin disorder characterized by recurrent blistering of the
skin following minor physical trauma as a result of cytolysis within
basal epidermal cells. Most forms show autosomal dominant inheritance.
The Dowling-Meara type of EBS is the most severe form, with generalized
blistering that often occurs in clusters (herpetiform), is often
associated with hyperkeratosis of the palms and soles, and shows
clumping of keratin filaments in basal epidermal cells. The other 2 main
types of EBS include the milder generalized Koebner type (131900) and
the milder and localized Weber-Cockayne type (131800) (Fine et al.,
2008). All 3 forms can be caused by mutation in the KRT5 or the KRT14
gene. See 601001 for a rare autosomal recessive form caused by mutation
in the KRT14 gene.

CLINICAL FEATURES

Dowling and Meara (1954) first described a form of epidermolysis bullosa
simplex that resembled dermatitis herpetiformis (601230). Onset of
generalized bullae in a herpetiform (arciform) arrangement occurred
during the first 3 months of life. Serous and hemorrhagic blisters could
occur on any part of the body, but most frequently on the palms and
soles, around the mouth, and on the trunk and neck. In general, the
lesions healed without scarring, but pronounced inflammatory reactions,
especially seen in hemorrhagic blisters, was accompanied by milia and
occasional scar formation.

Anton-Lamprecht and Schnyder (1982) reported a 2-year-old girl of
Turkish origin with congenital generalized blister formation in a
herpetiform arrangement. Direct immunofluorescence ruled out juvenile
dermatitis herpetiformis. Ultrastructural investigation of a fresh
blister and clinically intact preblistering skin revealed intraepidermal
blister formation via cytolysis of basal cells, preceded by clumping of
tonofilaments and partial attachment to the hemidesmosomes at the
dermo-epidermal junction. This type of blister formation was
significantly different from all other epidermolysis bullosa types and
was a characteristic feature of the Dowling-Meara type of EBS.

McGrath et al. (1992) reviewed the clinicopathologic features of 22
cases varying in age from 5 days to 46 years. All cases presented
clinically within the first 5 days of life. Early blisters were often
large (up to 5 cm in diameter), and were mostly acral and particularly
periungual. Some patients presented with more widespread erosive skin
changes, and 2 neonates with extensive skin involvement died as a result
of overwhelming sepsis. After the neonatal period, the pattern of
blistering became more proximal, with hemorrhagic, herpetiform clusters
of blisters. Central healing with recurrent blistering at the margins of
these areas was frequent. Other physical signs included varying degrees
of intraoral blistering, nail shedding, nail dystrophy, minor scarring,
palmoplantar keratoderma, a lack of seasonal variation, and improvement
during later childhood. Basal cell cytolysis in association with
clumping of tonofilaments was the underlying pathologic mechanism. The
clumping was found even in some nonlesional skin, suggesting that it is
of primary pathogenetic significance. The disease was occasionally so
severe, especially during the neonatal period, as to be confused with
junctional (see, e.g., 226700) or severe recessive dystrophic EB (see,
e.g., 226600).

Kitajima et al. (1993) described 2 cases of the Dowling-Meara type of
EBS with severe blistering at birth that improved gradually with age.
Both had vesicles and small bullae clustering in a herpetiform fashion.
In 1, there was a mild pincer deformity of the nails, whereas in the
other, the nail plates shed after subungual blistering but regrew
without deformity. Both had histopathologic and ultrastructural evidence
of cytolysis of the basal cells, but with ultrastructural differences in
the form of the tonofilament clumps present in epidermal keratinocytes.
One case had typical round clumping of tonofilaments, while the other
had whisk-type clumping of tonofilaments. The same difference in form
was observed in cultured keratinocytes. The authors suggested possible
subgrouping of this disorder.

Although laryngeal involvement is generally associated with junctional
forms of EB, Shemanko et al. (2000) reported 2 unrelated infants with no
family history of skin disease who presented within hours of birth with
extensive blistering of the skin and oral mucosa and subsequently
developed hoarse cries, consistent with a diagnosis of Dowling-Meara
EBS. DNA analysis revealed a heterozygous KRT5 mutation (S181P;
148040.0012) in 1 infant and a heterozygous KRT14 mutation (R125H;
148066.0003) in the other.

DIAGNOSIS

- Prenatal Diagnosis

Holbrook et al. (1992) made a diagnosis of this disorder by in utero
fetal skin biopsy. Two earlier-born sibs had been affected. The mother,
who had been thought to be normal, was found to have had blistering of
the skin as a child and hyperkeratotic palms and soles.

MOLECULAR GENETICS

In a large family with Dowling-Meara EBS, Lane et al. (1992) identified
a heterozygous mutation in the KRT5 gene (E475G; 148040.0001) that
segregated with the disorder in an autosomal dominant pattern.

In affected members of a large French family with Dowling-Meara EBS,
Rugg et al. (1999) identified a heterozygous splice site mutation in the
KRT5 gene (148040.0011), resulting in a deletion of the last 5 amino
acids of the H1 head domain and the first 17 amino acids of the
conserved N-terminal end of the 1A rod domain, including the first 2
heptad repeats and the helix initiation peptide.

In 2 unrelated patients with Dowling-Meara EBS, Coulombe et al. (1991)
identified 2 different heterozygous mutations in the KRT14 gene
(148066.0002; 148066.0003).

Hut et al. (2000) identified 3 different mutations in the KRT14 gene
(148066.0011-148066.0013) in patients with EBS-DM.

In 4 unrelated probands with Dowling-Meara EBS, Pfendner et al. (2005)
identified a heterozygous mutation in the KRT14 gene (N123S;
148066.0018). All of the patients had a de novo mutation and severe
generalized blistering with oral mucous membrane involvement. The
mutation was predicted to severely perturb the intermediate filament
network.

Among 18 families with various forms of EBS, Pfendner et al. (2005)
identified KRT5 mutations in 7 probands and KRT14 mutations in 11
probands, indicating that mutations in either gene can result in EBS at
approximately equal frequencies. A large number (15 of 18) were de novo
mutations. The clinical spectrum was highly variable.

GENOTYPE/PHENOTYPE CORRELATIONS

Letai et al. (1993) reported that clinical severity of EBS and
epidermolytic hyperkeratosis (EHK; 113800) is related to the location of
point mutations within the keratin polypeptides and the degree to which
these mutations perturb keratin intermediate filament (IF) structure.
Point mutations in the most severe forms have been clustered in the
highly conserved ends of the K5 or K14 rod domains in EBS-DM (e.g.,
148066.0002) and in the corresponding regions of the K10 (e.g.,
148080.0003) and K1 rod in EHK. Mutations in milder cases have been
found in less-conserved regions, either within or outside the rod
domain. Of 11 known Dowling-Meara 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 arg125
of K14 and arg156 of K10 must play a special role in maintaining keratin
network integrity.

ANIMAL MODEL

Roth et al. (2009) found that skin from Krt5-null mice showed increased
levels of the inflammatory cytokines MCP1 (CCL2; 158105), CCL19
(602227), and CCL20 (601960), all of which are regulated by NFKB (see
164011) and involved in the recruitment, maturation, and migration of
Langerhans cells in the epidermis. These changes were not observed in
Krt14-null mice. The number of Langerhans cells were increased 2-fold in
epidermis of neonatal Krt5-null mice. In contrast, TNFA (191160) was not
changed, demonstrating the specificity of that process. The basal
epidermis from Krt5-null mice also showed decreased p120-catenin
(CTNND1; 601045). Enhanced Langerhans cell recruitment within the
epidermis was found in 5 patients with various forms of EBS due to KRT5
mutations, but not in EBS patients with KRT14 gene mutations. These data
provided an explanation for distinct, keratin-type-specific
genotype-phenotype correlations in EBS, and suggested that the
pathophysiology of EBS involves more than mutant keratins.

*FIELD* RF
1. Anton-Lamprecht, I.; Schnyder, U. W.: Epidermolysis bullosa herpetiformis
Dowling Meara: report of a case and pathomorphogenesis. Dermatologica 164:
221-235, 1982.

2. Coulombe, P. A.; Hutton, M. E.; Letai, A.; Hebert, A.; Paller,
A. S.; Fuchs, E.: Point mutations in human keratin 14 genes of epidermolysis
bullosa simplex patients: genetic and functional analyses. Cell 66:
1301-1311, 1991.

3. Dowling, G. B.; Meara, R. H.: Epidermolysis bullosa dermatitis
herpetiformis. Brit. J. Derm. 66: 139-143, 1954.

4. Fine, J.-D.; Eady, R. A. J.; Bauer, E. A.; Bauer, J. W.; Bruckner-Tuderman,
L.; Heagerty, A.; Hintner, H.; Hovnanian, A.; Jonkman, M. F.; Leigh,
I.; McGrath, J. A.; Mellerio, J. E.; Murrell, D. F.; Shimizu, H.;
Uitto, J.; Vahlquist, A.; Woodley, D.; Zambruno, G.: The classification
of inherited epidermolysis bullosa (EB): report of the Third International
Consensus Meeting on diagnosis and classification of EB. J. Am. Acad.
Derm. 58: 931-950, 2008.

5. Holbrook, K. A.; Wapner, R.; Jackson, L.; Zaeri, N.: Diagnosis
and prenatal diagnosis of epidermolysis bullosa herpetiformis (Dowling-Meara)
in a mother, two affected children, and an affected fetus. Prenatal
Diag. 12: 725-739, 1992.

6. Hut, P. H. L.; Vlies, P. V. D.; Jonkman, M. F.; Verlind, E.; Shimizu,
H.; Buys, C. H. C. M.; Scheffer, H.: Exempting homologous pseudogene
sequences from polymerase chain reaction amplification allows genomic
keratin 14 hotspot analysis. J. Invest. Derm. 114: 616-619, 2000.

7. Kitajima, Y.; Jokura, Y.; Yaoita, H.: Epidermolysis bullosa simplex,
Dowling-Meara type: a report of two cases with different types of
tonofilament clumping. Brit. J. Derm. 128: 79-85, 1993.

8. Lane, E. B.; Rugg, E. L.; Navsaria, H.; Leigh, I. M.; Heagerty,
A. H. M.; Ishida-Yamamoto, A.; Eady, R. A. J.: A mutation in the
conserved helix termination peptide of keratin 5 in hereditary skin
blistering. Nature 356: 244-246, 1992.

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

10. McGrath, J. A.; Ishida-Yamamoto, A.; Tidman, M. J.; Heagerty,
A. H. M.; Schofield, O. M. V.; Eady, R. A. J.: Epidermolysis bullosa
simplex (Dowling-Meara): a clinicopathological review. Brit. J. Derm. 126:
421-430, 1992.

11. Pfendner, E. G.; Sadowski, S. G.; Uitto, J.: Epidermolysis bullosa
simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes,
phenotype/genotype correlations, and implications for genetic counseling
and prenatal diagnosis. J. Invest. Derm. 125: 239-243, 2005.

12. Roth, W.; Reuter, U.; Wohlenberg, C.; Bruckner-Tuderman, L.; Magin,
T. M.: Cytokines as genetic modifiers in K5-/- mice and in human
epidermolysis bullosa simplex. Hum. Mutat. 30: 832-841, 2009.

13. Rugg, E. L.; Rachet-Prehu, M.-O.; Rochat, A.; Barrandon, Y.; Goossens,
M.; Lane, E. B.; Hovnanian, A.: Donor splice site mutation in keratin
5 causes in-frame removal of 22 amino acids of H1 and 1A rod domains
in Dowling-Meara epidermolysis bullosa simplex. Europ. J. Hum. Genet. 7:
293-300, 1999.

14. Shemanko, C. S.; Horn, H. M.; Keohane, S. G.; Hepburn, N.; Kerr,
A. I. G.; Atherton, D. J.; Tidman, M. J.; Lane, E. B.: Laryngeal
involvement in the Dowling-Meara variant of epidermolysis bullosa
simplex with keratin mutations of severely disruptive potential. Brit.
J. Derm. 142: 315-320, 2000.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Other];
Growth retardation

HEAD AND NECK:
[Mouth];
Oral blistering

SKIN, NAILS, HAIR:
[Skin];
Blistering, generalized, recurrent, severe (occurs after mild physical
trauma);
Blistering occurs in clusters ('herpetiform', 'arcuate');
Blistering of hands, elbows, feet, knees;
Hemorrhagic blisters;
Hyperkeratosis of the palms and soles;
Milia;
Atrophic scarring (less common);
ELECTRON MICROSCOPY:;
Cleavage within basal keratinocytes;
Clumping of keratin filaments in basal epidermal cells;
[Nails];
Dystrophic nails;
Nail shedding

MISCELLANEOUS:
Onset at birth or in early infancy;
Infant death may occur secondary to sepsis;
Disease exacerbation during summer due to heat;
Some patients show improvement during summer or with fever;
Improvement with age

MOLECULAR BASIS:
Caused by mutation in the keratin 5 gene (KRT5, 148040.0001);
Caused by mutation in the keratin 14 gene (KRT14, 148066.0002)

*FIELD* CN
Cassandra L. Kniffin - revised: 8/25/2009

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

*FIELD* ED
joanna: 01/07/2010
ckniffin: 8/25/2009

*FIELD* CN
Cassandra L. Kniffin - reorganized: 9/14/2009
Cassandra L. Kniffin - updated: 8/25/2009
Gary A. Bellus - updated: 6/13/2000
Wilson H. Y. Lo - updated: 9/9/1999

*FIELD* CD
Victor A. McKusick: 6/23/1988

*FIELD* ED
carol: 09/14/2009
ckniffin: 8/25/2009
alopez: 6/13/2000
carol: 9/9/1999
alopez: 5/14/1998
mimadm: 9/24/1994
davew: 7/5/1994
carol: 12/14/1993
carol: 10/26/1993
carol: 7/6/1993
carol: 6/30/1993

MIM 131800
*RECORD*
*FIELD* NO
131800
*FIELD* TI
#131800 EPIDERMOLYSIS BULLOSA SIMPLEX, LOCALIZED
;;EPIDERMOLYSIS BULLOSA SIMPLEX, WEBER-COCKAYNE TYPE;;
read moreEPIDERMOLYSIS BULLOSA OF HANDS AND FEET;;
EBS, ACRAL FORM
*FIELD* TX
A number sign (#) is used with this entry because localized
epidermolysis bullosa simplex (EBS), previously known as Weber-Cockayne
EBS, is caused by heterozygous mutation in either the keratin-5 (KRT5;
148040) or keratin-14 (KRT14; 148066) gene.

A mutation in the ITGB4 gene (147557) has been identified in a single
patient with a similar phenotype.

DESCRIPTION

Epidermolysis bullosa simplex is a clinically and genetically
heterogeneous skin disorder characterized by blistering of the skin
following minor physical trauma as a result of cytolysis within the
basal epidermal cells. Most forms show autosomal dominant inheritance.
The localized form is characterized by localized blistering primarily on
the hands and feet (Pfendner et al., 2005). The other 2 main types of
EBS include the milder generalized Koebner type (131900) and the more
severe Dowling-Meara type (131760). All 3 forms can be caused by
mutation in the KRT5 or KRT14 genes (summary by Fine et al., 2008).

CLINICAL FEATURES

Readett (1961) described a family in which 14 members in 5 generations
had localized epidermolysis bullosa of the hands and feet inherited in
an autosomal dominant pattern. Treatment with adrenosteroid depressed
bulla formation, but recurrence occurred with the end of therapy. An
enormous pedigree with many affected persons was reported from West
Virginia by Cartledge and Myers (1943). The affected persons were
descendants of one Zachariah Piles, born in 1762. The blistering
occurred only on the hands and feet, and mainly in warm weather after
unusual walking or labor with hand tools. Friction-induced blisters in
the Weber-Cockayne type of EBS are temperature-dependent. Lesions can be
prevented by cooling the skin with ice before friction (Pearson, 1967).
This is thus an example in man of a temperature-sensitive mutant.

INHERITANCE

Yasukawa et al. (2002) reported an unusual Japanese family with both
autosomal recessive and dominant inheritance of KRT5 mutations resulting
in phenotypic variability. The proband was a man with classic
generalized EBS, manifest as blistering of the trunk and extremities,
improvement with age, and cytolysis within basal keratinocytes on
biopsy. Genetic analysis identified compound heterozygosity for the
E170K (148040.0020) and E418K (148040.0021) mutations in the KRT5 gene,
consistent with recessive inheritance (601001). His paternal uncle, who
had blisters restricted to the palms and soles consistent with localized
EBS was heterozygous for the E170K mutation. The proband's deceased
father and paternal grandmother, who were putatively heterozygous for
the E170K mutation, also reportedly had localized blistering of the
hands and feet. In contrast, 2 unaffected family members were
heterozygous for the E418K substitution, implying that it is not
pathogenic in isolation. In vitro functional expression studies showed
that cells transfected with either mutation developed small ball-like
filament aggregates, indicating a disruption of the keratin network,
although the effect was more pronounced for the E170K mutation.
Expression of both mutant proteins exacerbated the clumping and resulted
in significantly more disruption than either alone. These findings were
consistent with the marked phenotypic and genotypic variability observed
in this family.

MAPPING

Bonifas et al. (1991) found linkage of the Weber-Cockayne form to
markers D12S14 and D12S17, loci that map physically very near the
keratin-5 gene on chromosome 12.

The genetic heterogeneity of the Weber-Cockayne form of EBS was
indicated by the findings of McKenna et al. (1992) in 2 families: 1
family showed linkage to markers on chromosome 17 flanking the
keratin-14 gene and was excluded from linkage to markers on chromosome
12 flanking the keratin-5 gene. A second family showed linkage to the
region containing the keratin 5 gene and was excluded from linkage to
the keratin-14 gene.

MOLECULAR GENETICS

In affected members of 2 unrelated families with Weber-Cockayne EBS,
Chan et al. (1993) identified a heterozygous mutation in the K5 gene
(I161S; 148040.0003). Ehrlich et al. (1995) identified the I161S
mutation in 6 of 13 cases of the Weber-Cockayne type of EB simplex. The
high frequency of this mutation suggested either a hotspot or founder
effect.

Chan et al. (1994) identified mutations in the K5 gene (148040.0004;
148040.0005) in patients with Weber-Cockayne EBS.

In a family with at least 16 affected individuals in 5 generations with
Weber-Cockayne type EBS, Chen et al. (1993) identified a heterozygous
mutation in the KRT14 gene (148066.0005).

Pfendner et al. (2005) identified a heterozygous KRT5 mutation (I161S;
148040.0003) in a patient with blistering of the hands and feet. The
patient's affected mother carried the same mutation.

Among 18 families with various forms of EBS, Pfendner et al. (2005)
identified KRT5 mutations in 7 probands and KRT14 mutations in 11
probands, indicating that mutations in either gene can result in EBS at
approximately equal frequencies. A large number (15 of 18) were de novo
mutations. The clinical spectrum was highly variable.

In a 49-year-old woman with mild blistering of hands and feet from
birth, dystrophy of the nails with onychogryposis, and enamel
hypoplasia, Jonkman et al. (2002) identified a heterozygous 2-bp
deletion in the ITGB4 gene (147557.0013). She had no alopecia and no
history of pyloric atresia. Electron microscopy and antigen mapping of a
skin blister revealed that the level of separation was intraepidermal,
low in the basal keratinocytes through the attachment plaque of the
hemidesmosome. Immunofluorescence microscopy revealed absent binding of
monoclonal antibody 450-11 A against the third fibronectin III repeat on
the intracellular domain of integrin beta-4, whereas binding was reduced
with monoclonal antibodies recognizing epitopes on amino-terminal and
carboxy-terminal ends of the polypeptide. The patient was also expected
to be heterozygous for a null allele, as no full-size protein was
detected in vitro and the epitope 450-11 A was absent in vivo. These
data showed that deletion of the third fibronectin type III repeat in
the cytoplasmic domain of integrin beta-4, which is thought to interact
with BP180/type XVII collagen (113811), is clinically pathogenic and
results in a mild phenotype with predominant features of epidermolysis
bullosa simplex.

ANIMAL MODEL

Roth et al. (2009) found that skin from Krt5-null mice showed increased
levels of the inflammatory cytokines MCP1 (CCL2; 158105), CCL19
(602227), and CCL20 (601960), all of which are regulated by NFKB (see
164011) and involved in the recruitment, maturation, and migration of
Langerhans cells in the epidermis. These changes were not observed in
Krt14-null mice. The number of Langerhans cells were increased 2-fold in
epidermis of neonatal Krt5-null mice. In contrast, TNFA (191160) was not
changed, demonstrating the specificity of that process. The basal
epidermis from Krt5-null mice also showed decreased p120-catenin
(CTNND1; 601045). Enhanced Langerhans cell recruitment within the
epidermis was found in 5 patients with various forms of EBS due to KRT5
mutations, but not in EBS patients with KRT14 gene mutations. These data
provided an explanation for distinct, keratin-type-specific
genotype-phenotype correlations in EBS, and suggested that the
pathophysiology of EBS involves more than mutant keratins.

*FIELD* SA
Bonifas et al. (1991); Cockayne (1938); Fine et al. (1989); Haldane
and Poole (1942)
*FIELD* RF
1. Bonifas, J. M.; Rothman, A. L.; Epstein, E., Jr.: Linkage of epidermolysis
bullosa simplex to probes in the region of keratin gene clusters on
chromosomes 12q and 17q. (Abstract) Clin. Res. 39: 503A only, 1991.

2. Bonifas, J. M.; Rothman, A. L.; Epstein, E. H., Jr.: Epidermolysis
bullosa simplex: evidence in two families for keratin gene abnormalities. Science 254:
1202-1205, 1991.

3. Cartledge, J. L.; Myers, V. W.: Inherited foot blistering in an
American family. J. Hered. 34: 24 only, 1943.

4. Chan, Y.; Yu, Q.-C.; LeBlanc-Straceski, J.; Christiano, A.; Pulkkinen,
L.; Kucherlapati, R. S.; Uitto, J.; Fuchs, E.: Mutations in the non-helical
linker segment L1-2 of keratin 5 in patients with Weber-Cockayne epidermolysis
bullosa simplex. J. Cell Sci. 107: 765-774, 1994.

5. Chan, Y.-M.; Yu, Q.-C.; Fine, J.-D.; Fuchs, E.: The genetic basis
of Weber-Cockayne epidermolysis bullosa simplex. Proc. Nat. Acad.
Sci. 90: 7414-7418, 1993.

6. Chen, M. A.; Bonifas, J. M.; Matsumura, K.; Blumenfeld, A.; Epstein,
E. H., Jr.: A novel three-nucleotide deletion in the helix 2B region
of keratin 14 in epidermolysis bullosa simplex: delE375. Hum. Molec.
Genet. 2: 1971-1972, 1993.

7. Cockayne, E. A.: Recurrent bullous eruption of the feet. Brit.
J. Derm. Syph. 50: 358-362, 1938.

8. Ehrlich, P.; Sybert, V. P.; Spencer, A.; Stephens, K.: A common
keratin 5 gene mutation in epidermolysis bullosa simplex: Weber-Cockayne. J.
Invest. Derm. 104: 877-879, 1995.

9. Fine, J.-D.; Eady, R. A. J.; Bauer, E. A.; Bauer, J. W.; Bruckner-Tuderman,
L.; Heagerty, A.; Hintner, H.; Hovnanian, A.; Jonkman, M. F.; Leigh,
I.; McGrath, J. A.; Mellerio, J. E.; Murrell, D. F.; Shimizu, H.;
Uitto, J.; Vahlquist, A.; Woodley, D.; Zambruno, G.: The classification
of inherited epidermolysis bullosa (EB): report of the Third International
Consensus Meeting on diagnosis and classification of EB. J. Am. Acad.
Derm. 58: 931-950, 2008.

10. Fine, J. D.; Johnson, L.; Wright, T.; Horiguchi, Y.: Epidermolysis
bullosa simplex: identification of a kindred with autosomal recessive
transmission of the Weber-Cockayne variety. Pediat. Derm. 6: 1-5,
1989.

11. Haldane, J. B. S.; Poole, R.: A new pedigree of recurrent bullous
eruption of the feet: four generations of foot blisters. J. Hered. 33:
17-18, 1942.

12. Jonkman, M. F.; Pas, H. H.; Nijenhuis, M.; Kloosterhuis, G.; van
der Steege, G.: Deletion of a cytoplasmic domain of integrin beta-4
causes epidermolysis bullosa simplex. J. Invest. Derm. 119: 1275-1281,
2002.

13. McKenna, K. E.; Hughes, A. E.; Bingham, E. A.; Nevin, N. C.:
Linkage of epidermolysis bullosa simplex to keratin gene loci. J.
Med. Genet. 29: 568-570, 1992.

14. Pearson, R. W.: Epidermolysis bullosa, porphyria cutanea tarda
and erythema multiforme.In: Zelickson, A. S.: Ultrastructure of Normal
and Abnormal Skin. Philadelphia: Lea and Febiger (pub.) 1967.
Pp. 320-334.

15. Pfendner, E. G.; Sadowski, S. G.; Uitto, J.: Epidermolysis bullosa
simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes,
phenotype/genotype correlations, and implications for genetic counseling
and prenatal diagnosis. J. Invest. Derm. 125: 239-243, 2005.

16. Readett, M. D.: Localized epidermolysis bullosa. Brit. Med.
J. 1: 1510-1511, 1961.

17. Roth, W.; Reuter, U.; Wohlenberg, C.; Bruckner-Tuderman, L.; Magin,
T. M.: Cytokines as genetic modifiers in K5-/- mice and in human
epidermolysis bullosa simplex. Hum. Mutat. 30: 832-841, 2009.

18. Yasukawa, K.; Sawamura, D.; McMillan, J. R.; Nakamura, H.; Shimizu,
H.: Dominant and recessive compound heterozygous mutations in epidermolysis
bullosa simplex demonstrate the role of the stutter region in keratin
intermediate filament assembly. J. Biol. Chem. 277: 23670-23674,
2002.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKIN, NAILS, HAIR:
[Skin];
Blistering, recurrent, of the palms and soles;
Atrophic scarring (rare);
Milia (rare);
Hyperkeratosis, focal, on the palms and soles (in adulthood in some);
ELECTRON MICROSCOPY:;
Cleavage within basal keratinocytes

MISCELLANEOUS:
Onset in early childhood or adolescence;
Early adult onset has been reported;
Disease exacerbation during summer due to heat

MOLECULAR BASIS:
Caused by mutation in the keratin 5 gene (KRT5, 148040.0003);
Caused by mutation in the keratin 14 gene (KRT14, 148066.0005)

*FIELD* CN
Cassandra L. Kniffin - revised: 08/25/2009

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

*FIELD* ED
ckniffin: 08/25/2009

*FIELD* CN
Cassandra L. Kniffin - updated: 8/25/2009
Gary A. Bellus - updated: 5/13/2003

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

*FIELD* ED
carol: 09/30/2013
ckniffin: 11/19/2010
carol: 9/14/2009
ckniffin: 8/25/2009
ckniffin: 6/27/2008
ckniffin: 5/23/2008
ckniffin: 5/9/2008
carol: 8/29/2006
alopez: 5/13/2003
alopez: 3/6/2003
alopez: 3/5/2003
terry: 4/30/1999
mimadm: 9/24/1994
davew: 6/27/1994
carol: 5/2/1994
pfoster: 2/16/1994
warfield: 2/15/1994
carol: 12/13/1993

MIM 131900
*RECORD*
*FIELD* NO
131900
*FIELD* TI
#131900 EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED
;;EBS, GENERALIZED;;
EPIDERMOLYSIS BULLOSA SIMPLEX, KOEBNER TYPE
read more*FIELD* TX
A number sign (#) is used with this entry because generalized
epidermolysis bullosa simplex (EBS) can be caused by heterozygous
mutation in either the keratin-5 gene (KRT5; 148040) on chromosome 12 or
the keratin-14 gene (KRT14; 148066) on chromosome 17.

DESCRIPTION

Epidermolysis bullosa simplex (EBS) is a clinically and genetically
heterogeneous skin disorder characterized by recurrent blistering of the
skin following minor physical trauma as a result of cytolysis within
basal epidermal cells. Most forms show autosomal dominant inheritance.
The 3 main types include the generalized Koebner form, the more severe
generalized Dowling-Meara form (131760), and the localized, mild
Weber-Cockayne form (131800) (Fine et al., 2008). All 3 forms can be
caused by mutation in the KRT5 or the KRT14 gene. See 601001 for a rare
autosomal recessive form caused by mutation in the KRT14 gene.

Davison (1965) referred to generalized distribution of bullous vesicles
as epidermolysis simplex bullosa. The condition in which bullae were
limited to the hands and feet was referred to as the Cockayne type of
epidermolysis bullosa (131800).

On the basis of an extensive study in Norway and review of the
literature, Gedde-Dahl (1971) arrived at a classification of
epidermolysis bullosa. EB simplex in this classification encompassed
disorders characterized by bulla formation within the epidermis, basal
cell vacuolization, and dissolution of tonofibrils on electron
microscopy. The generalized Koebner form and the localized
Weber-Cockayne type were believed to be allelic. Gedde-Dahl (1981)
recognized at least 16 varieties of epidermolysis bullosa and suggested
that dominant EB simplex can be clinically and genetically divided into
at least 4 types: the generalized Koebner type, the localized
Weber-Cockayne type, the mild Ogna type with fragile skin (131950), and
a form with mottled pigmentation (131960).

Fine et al. (1991) provided a revised classification of the subtypes of
inherited epidermolysis bullosa based on clinical and laboratory
criteria.

CLINICAL FEATURES

Passarge (1965) observed 21 affected persons in 4 generations of a
family with generalized epidermolysis bullosa simplex. The inheritance
pattern was autosomal dominant.

Hacham-Zadeh et al. (1988) described a large Arab family originating
from Jerusalem in which 38 affected individuals spanning 4 generations
had EBS. Onset occurred between birth and 2 weeks of age. The main
clinical features were bullae, generalized, solitary, and in groups,
with predilection to the skin of the palms and soles. Mild to moderate
patchy hyperkeratosis of the palms and soles was found in 5 affected
members of the family. Blisters in oral mucous membranes were noted and
found in summer and in periods of fever. Hair, teeth, and nails were
normal. Improvement was noted by progression of age from 5 to 23 years,
and by some in summer and by others in winter. Ultrastructural studies
from a fresh blister disclosed intraepidermal blister via cytolysis of
basal cell cytoplasm. The pedigree indicated transmission of an
autosomal dominant gene. However, in 1 instance, affected first cousins
were married and all 6 of their offspring were affected. There was
marked intrafamilial variability. Although the family was originally
thought to have the Dowling-Meara form of EBS, Stephens et al. (1995)
reclassified the phenotype as the Koebner type based on the lack of
keratin filament clumping on electron microscopy.

MAPPING

Epstein (1991) cited evidence that linkage to the keratin gene cluster
on chromosome 12 had been demonstrated in at least 1 family with
generalized epidermolysis bullosa simplex.

In a large family with 14 affected members in 3 generations with
generalized EBS, Ryynanen et al. (1991) found linkage to DNA marker
D12S17, which is located on 12q (maximum lod score of 4.65 at theta =
0.0). In the full report (Ryynanen et al., 1991), the maximum lod score
for linkage to D12S17 was given as 5.55 at theta = 0.0.

MOLECULAR GENETICS

In a family with the generalized form of epidermolysis bullosa simplex,
Bonifas et al. (1991) found linkage to markers on chromosome 17 and
identified a point mutation in the KRT14 gene (L384P; 148066.0001).

In affected members of a large Irish family with generalized EBS,
Humphries et al. (1993) identified a heterozygous mutation in the KRT14
gene (M272R; 148066.0007).

In affected members of a large Finnish family with the generalized
Koebner type of EBS in which Ryynanen et al. (1991) found linkage to
12q, Dong et al. (1993) identified a heterozygous mutation in the KRT5
gene (L463P; 148040.0002).

In affected members of a family with autosomal dominant epidermolysis
bullosa simplex, Stephens et al. (1995) identified a heterozygous
mutation in the KRT5 gene (K173N; 148040.0006). One family member was
homozygous for the K173N allele, having inherited it from each of her
affected first-cousin parents. However, this patient showed no
significant differences in either the clinical severity or the
ultrastructural organization of the homozygous keratin intermediate
filament cytoskeleton. These data demonstrated that the K173N mutation
behaves as a fully dominant allele.

Among 18 families with various forms of EBS, Pfendner et al. (2005)
identified KRT5 mutations in 7 probands and KRT14 mutations in 11
probands, indicating that mutations in either gene can result in EBS at
approximately equal frequencies. A large number (15 of 18) were de novo
mutations. The clinical spectrum was highly variable.

GENOTYPE/PHENOTYPE CORRELATIONS

Livingston et al. (2001) reported a patient who presented at 3 to 4 days
of age with widespread generalized blistering. Painful hyperkeratosis of
the palms and soles developed in his teen years, whereas blistering
improved somewhat with age. As an adult, he continued to get occasional
blisters in the mouth and cutaneous blisters with increased heat and/or
activity. His skin examination was striking for severe palmoplantar
keratosis, underlying erythema in a 'glove and moccasin' distribution,
and limited range of motion in the fingers. There was no scarring and no
significant nail changes. Clinical, histologic, and ultrastructural
features were consistent with a diagnosis of generalized EBS (Koebner
subtype). Genetic analysis identified a heterozygous nonsense mutation
in the KRT5 gene (K472X; 148040.0016), predicting the synthesis of a
truncated keratin-5, missing the entire tail domain and a highly
conserved motif in the central rod. Ultrastructural analysis of the
patient's nonhyperkeratotic skin was remarkable for basal keratinocytes
with dense and irregular keratin filaments proximal to the basement
membrane. The occurrence of severe palmoplantar hyperkeratosis suggested
that the keratin-5 tail domain may have important functions in
palmoplantar tissues.

HISTORY

In skin fibroblast cultures of 3 patients from 3 kindreds with
generalized EBS, Sanchez et al. (1983) found a 7-fold decrease in
gelatin-specific neutral metalloprotease. Cultures from several other
forms of epidermolysis bullosa showed no deficiency of this enzyme.
Study of gelatinase activity from 13 cases of localized EBS found that 6
had low levels of the enzyme and 7 had normal levels. However, Winberg
and Gedde-Dahl (1986) found that reduced production of gelatinase from
dermal fibroblasts was not a uniform finding in the Koebner form of EBS.
None of 6 patients tested showed this trait.

Mulley et al. (1984) found that both the Koebner and the Weber-Cockayne
types of EBS had suggestive linkage to Duffy blood group (Fy) on
chromosome 1 (maximum lod score 1.5 at theta = 0.2). In 3 generations of
an Irish kindred with the Koebner variety of epidermolysis bullosa,
Humphries et al. (1990) and Ryynanen et al. (1991) found positive lod
scores for 5 markers on 1q. In multilocus analysis, a lod score of 3 was
obtained, with a maximum in the region of AT3 (107300) on 1q23. In 3
generations of a Finnish family with EBS, Ryynanen et al. (1991) found
only low positive lod scores for 1q markers. EBS2 was the designation
for the putative locus on chromosome 1 (Ryynanen et al., 1991).

Hoyheim et al. (1991) excluded EBS from chromosome 1 by demonstration of
negative scores in a region up to 0.10 on each side of F13B (134580),
which is located at 1q31-q32.1. Humphries et al. (1990) excluded EBS
from a region of more than 10 cM on each side of the nidogen gene (NID;
131390), located at 1q43. Epstein (1991) suggested that the linkage to
chromosome 1 markers may have been in error.

In reviewing the molecular genetics of epidermolysis bullosa, Epstein
(1992) suggested that a defect in keratin intermediate filament proteins
should have been suspected in EBS. Anton-Lamprecht and Schnyder (1982)
described clumping of keratin intermediate filaments as the
characteristic abnormality demonstrable by electron microscopy in the
more severe Dowling-Meara subtype of EBS (131760). They also pointed to
the family reported by Sutherland and Hinton (1981) in which a fragile
site at 12q13 was associated with EBS.

*FIELD* SA
Bonifas et al. (1991); Bonifas et al. (1991); Humphries et al. (1990)
*FIELD* RF
1. Anton-Lamprecht, I.; Schnyder, U. W.: Epidermolysis bullosa herpetiformis
Dowling Meara: report of a case and pathomorphogenesis. Dermatologica 164:
221-235, 1982.

2. Bonifas, J. M.; Rothman, A. L.; Epstein, E., Jr.: Linkage of epidermolysis
bullosa simplex to probes in the region of keratin gene clusters on
chromosomes 12q and 17q. (Abstract) Clin. Res. 39: 503A only, 1991.

3. Bonifas, J. M.; Rothman, A. L.; Epstein, E. H., Jr.: Epidermolysis
bullosa simplex: evidence in two families for keratin gene abnormalities. Science 254:
1202-1205, 1991.

4. Bonifas, J. M.; Rothman, A. L.; Epstein, E. H., Jr.: Identification
of a keratin 14 mutation in a family with epidermolysis bullosa simplex.
(Abstract) Am. J. Hum. Genet. 49 (suppl.): 399 only, 1991.

5. Davison, B. C. C.: Epidermolysis bullosa. J. Med. Genet. 2:
233-242, 1965.

6. Dong, W.; Ryynanen, M.; Uitto, J.: Identification of a leucine-to-proline
mutation in the keratin 5 gene in a family with the generalized Koebner
type of epidermolysis bullosa simplex. Hum. Mutat. 2: 94-102, 1993.

7. Epstein, E. H., Jr.: Molecular genetics of epidermolysis bullosa. Science 256:
799-804, 1992.

8. Epstein, E. H., Jr.: Personal Communication. San Francisco, Calif.
5/5/1991.

9. Fine, J.-D.; Bauer, E. A.; Briggaman, R. A.; Carter, D.-M.; Eady,
R. A. J.; Esterly, N. B.; Holbrook, K. A.; Hurwitz, S.; Johnson, L.;
Lin, A.; Pearson, R.; Sybert, V. P.: Revised clinical and laboratory
criteria for subtypes of inherited epidermolysis bullosa: a consensus
report by the subcommittee on diagnosis and classification of the
National Epidermolysis Bullosa Registry. J. Am. Acad. Derm. 24:
119-135, 1991.

10. Fine, J.-D.; Eady, R. A. J.; Bauer, E. A.; Bauer, J. W.; Bruckner-Tuderman,
L.; Heagerty, A.; Hintner, H.; Hovnanian, A.; Jonkman, M. F.; Leigh,
I.; McGrath, J. A.; Mellerio, J. E.; Murrell, D. F.; Shimizu, H.;
Uitto, J.; Vahlquist, A.; Woodley, D.; Zambruno, G.: The classification
of inherited epidermolysis bullosa (EB): report of the Third International
Consensus Meeting on diagnosis and classification of EB. J. Am. Acad.
Derm. 58: 931-950, 2008.

11. Gedde-Dahl, T.: Sixteen types of epidermolysis bullosa. Acta
Derm. Venerol. 95 (suppl.): 74-87, 1981.

12. Gedde-Dahl, T., Jr.: Epidermolysis Bullosa: A Clinical, Genetic
and Epidemiological Study. Baltimore: Johns Hopkins Press (pub.)
1971.

13. Hacham-Zadeh, S.; Rappersberger, K.; Livshin, R.; Konrad, K.:
Epidermolysis bullosa herpetiformis Dowling-Meara in a large family. J.
Am. Acad. Derm. 18: 702-706, 1988.

14. Hoyheim, B.; Gedde-Dahl, T.; Olaisen, B.: An exclusion map of
EBS2 (epidermolysis bullosa simplex), including exclusion from chromosome
1. (Abstract) Cytogenet. Cell Genet. 58: 1854 only, 1991.

15. Humphries, M.; Nagayoshi, T.; Shiels, D.; Humphries, P.; Uitto,
J.: Human nidogen gene: identification of multiple RFLP and exclusion
as candidate gene in a family with epidermolysis bullosa (EBS2) with
evidence for linkage to chromosome 1. J. Invest. Derm. 95: 568-570,
1990.

16. Humphries, M. M.; Sheils, D.; Lawler, M.; Farrar, G. J.; McWilliam,
P.; Kenna, P.; Bradley, D. G.; Sharp, E. M.; Gaffney, E. F.; Young,
M.; Uitto, J.; Humphries, P.: Epidermolysis bullosa: evidence for
linkage to genetic markers on chromosome 1 in a family with the autosomal
dominant simplex form. Genomics 7: 377-381, 1990.

17. Humphries, M. M.; Shiels, D. M.; Farrar, G. J.; Kumar-Singh, R.;
Kenna, P. F.; Mansergh, F. C.; Jordan, S. A.; Young, M.; Humphries,
P.: A mutation (met-to-arg) in the type I keratin (K14) gene responsible
for autosomal dominant epidermolysis bullosa simplex. Hum. Mutat. 2:
37-42, 1993.

18. Livingston, R. J.; Sybert, V. P.; Smith, L. T.; Dale, B. A.; Presland,
R. B.; Stephens, K.: Expression of a truncated keratin 5 may contribute
to severe palmar-plantar hyperkeratosis in epidermolysis bullosa simplex
patients. J. Invest. Derm. 116: 970-974, 2001.

19. Mulley, J. C.; Nicholls, C. M.; Propert, D. N.; Turner, T.; Sutherland,
G. R.: Genetic linkage analysis of epidermolysis bullosa simplex,
Koebner type. Am. J. Med. Genet. 19: 573-577, 1984.

20. Passarge, E.: Epidermolysis bullosa hereditaria simplex: a kindred
affected in four generations. J. Pediat. 67: 819-825, 1965.

21. Pfendner, E. G.; Sadowski, S. G.; Uitto, J.: Epidermolysis bullosa
simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes,
phenotype/genotype correlations, and implications for genetic counseling
and prenatal diagnosis. J. Invest. Derm. 125: 2390243, 2005.

22. Ryynanen, M.; Humphries, M.; Sheils, D.; Knowlton, R.; Humphries,
P.; Uitto, J.: Epidermolysis bullosa: evidence for possible linkage
to genetic markers on chromosome 1 in two families with the autosomal
dominant simplex form. Miami Short Reports. Advances in Gene Technology:
The Molecular Biology of Human Genetic Disease. Vol. 1 New York:
IRL Press (pub.) 1991. P. 37.

23. Ryynanen, M.; Knowlton, R. G.; Uitto, J.: An epidermolysis bullosa
simplex mutation maps to chromosome 12. (Abstract) Am. J. Hum. Genet. 49
(suppl.): 358 only, 1991.

24. Ryynanen, M.; Knowlton, R. G.; Uitto, J.: Mapping of epidermolysis
bullosa simplex mutation to chromosome 12. Am. J. Hum. Genet. 49:
978-984, 1991.

25. Sanchez, G.; Seltzer, J. L.; Eisen, A. Z.; Stapler, P.; Bauer,
E. A.: Generalized dominant epidermolysis bullosa simplex: decreased
activity of a gelatinolytic protease in cultured fibroblasts as a
phenotypic marker. J. Invest. Derm. 81: 576-579, 1983.

26. Stephens, K.; Zlotogorski, A.; Smith, L.; Ehrlich, P.; Wijsman,
E.; Livingston, R. J.; Sybert, V. P.: Epidermolysis bullosa simplex:
a keratin 5 mutation is a fully dominant allele in epidermal cytoskeleton
function. Am. J. Hum. Genet. 56: 577-585, 1995.

27. Sutherland, G. R.; Hinton, L.: Heritable fragile sites on human
chromosomes. VI. Characterization of the fragile site at 12q13. Hum.
Genet. 57: 217-219, 1981.

28. Winberg, J.-O.; Gedde-Dahl, T.: Gelatinase expression in generalized
epidermolysis bullosa simplex fibroblasts. J. Invest. Derm. 87:
326-329, 1986.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Mouth];
Oral blistering

SKIN, NAILS, HAIR:
[Skin];
Blistering, generalized, recurrent (occurs after mild physical trauma);
Hyperkeratosis of the palms and soles;
Milia (less common);
Lack of scarring;
ELECTRON MICROSCOPY:;
Cleavage within basal keratinocytes;
No clumping of keratin filaments in basal epidermal cells;
[Nails];
Dystrophic nails (less common)

MISCELLANEOUS:
Onset at birth or in early infancy;
Disease exacerbation during summer due to heat;
Improvement with age;
Blistering becomes confined to the palms and soles with age

MOLECULAR BASIS:
Caused by mutation in the keratin 5 gene (KRT5, 148040.0002);
Caused by mutation in the keratin 14 gene (KRT14, 148066.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 8/25/2009

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

*FIELD* ED
joanna: 01/07/2010
ckniffin: 8/25/2009

*FIELD* CN
Cassandra L. Kniffin - updated: 11/3/2009
Cassandra L. Kniffin - reorganized: 9/14/2009
Cassandra L. Kniffin - updated: 8/25/2009

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

*FIELD* ED
ckniffin: 11/19/2010
wwang: 11/19/2009
ckniffin: 11/3/2009
carol: 9/14/2009
ckniffin: 8/25/2009
mimadm: 9/24/1994
davew: 8/17/1994
warfield: 4/8/1994
pfoster: 3/31/1994
carol: 12/10/1993
carol: 10/26/1993

MIM 148066
*RECORD*
*FIELD* NO
148066
*FIELD* TI
*148066 KERATIN 14; KRT14
;;K14
*FIELD* TX

DESCRIPTION

KRT14 belongs to a large group of acidic type I keratins that interact
read morewith basic type II keratins to form the 8-nm cytoskeletal filaments of
epithelial cells. Both type I and type II keratins have a central
alpha-helical domain of over 300 amino acids that mediates keratin
interaction. KRT14 is expressed in the basal layer of stratified
squamous epithelia, including epidermis (summary by Albers and Fuchs
(1987) and Rosenberg et al. (1988)).

CLONING

Albers and Fuchs (1987) constructed a complete human K14 cDNA using a
partial cDNA isolated by Hanukoglu and Fuchs (1982) and a genomic clone
described by Marchuk et al. (1984, 1985). The deduced 472-amino acid
protein has an N-terminal domain, 4 helical domains, and a short
C-terminal tail. Helical domain-4 has a highly conserved sequence
(TYRRLLEGE) found in nearly all intermediate filament proteins.

MAPPING

Rosenberg et al. (1988) mapped the keratin-14 gene to chromosome 17.
Rosenberg et al. (1991) stated that the KRT14 and KRT16 (148067) genes,
as well as a yet-unidentified keratin gene, had been localized to
chromosome 17q12-q21. Another cluster of genes located at chromosome
17p12-p11 contained a nonfunctional gene for KRT16 and 2 genes for
KRT14, at least 1 of which was found to be a pseudogene.

Milisavljevic et al. (1996) analyzed P1 clones containing multiple
acidic keratin genes using restriction analysis and Southern blot
hybridization with PCR-amplified probes specific for functional human
keratin genes 15 (148030), 17 (148069), and 19 (148020). Their results
showed that there are 2 clusters of acidic keratin loci on chromosome
17q12-q21, very closely linked to each other within a 55-kb region. The
genes were organized 5-prime to 3-prime in the following order:
K19--K15--K17--K16--K14. Between K15 and K17 at least 1 additional,
unidentified keratin gene was present.

GENE FUNCTION

PtK2 potoroo kidney epithelial cells express only the type I keratin K18
(148070) and the type II keratin K8 (148060). Albers and Fuchs (1987)
showed that epitope-tagged human K14 was incorporated into endogenous
keratin filaments along with K18 and K8 in PtK2 cells. Truncation of K14
after helical domain-4 had no effect on incorporation of K14 into
filaments. However, progressive truncation of K14 within helix-4
resulted in a correspondingly progressive disruption of filament
structure and accumulation of the truncated protein into cytoplasmic
aggregates. The integrity of all other cytoskeletal structures remained
intact. Albers and Fuchs (1987) concluded that the mutant protein both
interfered with the formation of new keratin filaments and disrupted the
existing keratin cytoskeleton.

Langbein et al. (2005) examined the expression of several keratins in
eccrine sweat gland and in plantar epidermis. In the sweat gland, KRT14
was expressed in lower portions of the duct and in the deeper secretory
region of the gland, but not in the superficial region. In plantar
epidermis, KRT14 was expressed only in the basal layer and in part of
the lower suprabasal layer.

In mice, Takeo et al. (2013) showed that nail stem cells (NSCs) reside
in the proximal nail matrix and are defined by high expression of
keratin-14, keratin-17, and KI67 (MKI67; 176741). The mechanisms
governing NSC differentiation are coupled directly to their ability to
orchestrate digit regeneration. Early nail progenitors undergo Wnt (see
164820)-dependent differentiation into the nail. After amputation, this
Wnt activation is required for nail regeneration and also for attracting
nerves that promote mesenchymal blastema growth, leading to the
regeneration of the digit. Amputations proximal to the Wnt-active nail
progenitors result in failure to regenerate the nail or digit.
Nevertheless, beta-catenin (116806) stabilization in the NSC region
induced their regeneration. Takeo et al. (2013) concluded that their
results established a link between nail stem cell differentiation and
digit regeneration, and suggested that NSCs may have the potential to
contribute to the development of novel treatments for amputees.

MOLECULAR GENETICS

Missense mutations in the KRT14 gene act in a dominant-negative fashion
because the mutant protein combines with the wildtype proteins in the
keratin heterodimers to perturb intermediate filament (IF) assembly
(Fuchs and Coulombe, 1992).

- Epidermolysis Bullosa Simplex

In a family with at least 16 affected individuals in 5 generations with
localized epidermolysis bullosa simplex (131800), Chen et al. (1993)
identified a heterozygous mutation in the KRT14 gene (148066.0005).

Although all previous mutations identified in the KRT14 and KRT5 genes
behaved as dominant negatives with an autosomal dominant pattern of the
clinical disorder, Hovnanian et al. (1993) described a French family in
which 2 children with unaffected first-cousin parents had EB simplex and
homozygosity for a glu144-to-ala mutation (148066.0004) which was
present in heterozygous state in both parents.

Chan et al. (1994) analyzed a very rare case of severe recessive
epidermolysis bullosa simplex (EBSB1; 601001) in which the patient
lacked a discernible keratin filament network in basal epidermal cells.
Genetic analyses demonstrated homozygosity for a point mutation in the
KRT14 gene (Y204X; 148066.0006) that yielded a premature termination
codon in the major basal type I keratin gene and caused complete
ablation of KRT14. The consanguineous parents were clinically normal,
each harboring 1 copy of the null KRT14 mutation. Analysis of cultured
keratinocytes revealed that the loss of KRT14 was not compensated for by
the upregulation of other type I keratins. Thus, the cell fragility
resulted from lack of an extensive basal keratin network.

Chen et al. (1995) systematically screened genomic sequences of KRT14
for mutations in patients of 49 apparently independent EBS kindreds
using SSCP analysis. Most affected individuals were identified through
assistance of the National EB Registry or through DEBRA of America, a
genetic support group. KRT14 mutations were found in 10 of the families.
The 10 mutations were clustered at 3 sites--the ends of the helices and
the L12 linker region, where previous, more limited studies had
identified mutations. Early onset of blistering in these 10 families was
correlated with more widespread distribution of cutaneous mutations.
Those with early onset of blisters (e.g., by age 1 week) had generalized
disease; those with the later onset (e.g., after several months to 2
years) had blisters predominantly at acral sites. As in other families,
patients with substitution of arg125 (148066.0002, 148066.0003) all had
generalized blistering (131760). Chen et al. (1995) reported a family
with an arg125-to-ser mutation in which the proband had onset at 2 days
of age. Generalized blistering was also present in a kindred with a
gln120-to-arg mutation, giving onset in the first week of life. Chen et
al. (1995) stated that they were aware of formal publication of
mutations in either KRT5 or KRT14 in 22 apparently independent kindreds
(7 in KRT5 and 15 in KRT14). They discussed the reason that mutation was
identified in only 10 of the 49 kindreds.

Humphries et al. (1996) concluded that the M272R mutation (148066.0007)
in KRT14 accounts for many cases of generalized dominant epidermolysis
bullosa simplex (131900) in Ireland.

- Other Disorders

Naegeli-Franceschetti-Jadassohn syndrome (NFJS; 161000) and
dermatopathia pigmentosa reticularis (DPR; 125595) are 2 closely related
autosomal dominant ectodermal dysplasia syndromes that clinically share
complete absence of dermatoglyphics (fingerprint lines), a reticulate
pattern of skin hyperpigmentation, thickening of the palms and soles
(palmoplantar keratoderma), abnormal sweating, and other subtle
developmental anomalies of the teeth, hair, and skin. Lugassy et al.
(2006) studied one family with DPR and 4 families with NFJS. Both
disorders map to 17q11.2-q21 (Whittock et al., 2000; Sprecher et al.,
2002), which supported the suggestion that the disorders are allelic.
Lugassy et al. (2006) refined the mapping of NFJS/DPR, finding a maximum
lod score of 8.3 at marker D17S800 at a recombination fraction of 0.0.
The disease interval was found to harbor 230 genes, including a large
cluster of keratin genes. Heterozygous nonsense or frameshift mutations
in KRT14 were found to segregate with the disease traits in all 5
families.

GENOTYPE/PHENOTYPE CORRELATIONS

In contrast with mutations affecting the central alpha-helical rod
domain of keratin-14, which are found in association with epidermolysis
bullosa simplex in its various clinical forms, NFJS/DPR-associated
mutations were found in a region of the gene encoding the nonhelical
head (E1/V1) domain and were found to result in very early termination
of translation (Lugassy et al., 2006). The data suggested that KRT14
plays an important role during ontogenesis of dermatoglyphics and sweat
glands. Among other functions, the N-terminal part of keratin molecules
confers protection against proapoptotic signals. Ultrastructural
examination of patient skin biopsy specimens provided evidence for
increased apoptotic activity in the basal cell layer where KRT14 is
expressed, suggesting that apoptosis is an important mechanism in the
pathogenesis of NFJS/DPR.

HISTORY

In mapping studies, McAlpine (1990) used the symbols KRT14L1, KRT14L2,
and KRT14L3 because of the uncertainty as to which of the hybridizing
bands represent active gene(s).

ANIMAL MODEL

In transgenic mice, Vassar et al. (1991) showed that a mutant KRT14
gene, which was driven by the normal human KRT14 enhancer/promoter at
the 5-prime end and encoded a truncated keratin molecule lacking 135
amino acids from its carboxyl terminus, resulted in abnormalities
resembling the group of genetic disorders known as epidermolysis bullosa
simplex (e.g., 131950, 131900).

*FIELD* AV
.0001
EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED
KRT14, LEU384PRO

In a family with generalized epidermolysis bullosa simplex of the
Koebner type (131900), Bonifas et al. (1991) demonstrated linkage of the
disorder to the gene encoding keratin 14. Further studies demonstrated a
T-to-C substitution at bp 3542 in exon 6 resulting in a change of amino
acid 384 from leucine to proline. The mutation created a new MspI site.
It is notable that finding the particular mutation was a 'stroke of
luck.' No polymorphism of the KRT14 gene was known and linkage of EBS to
DNA markers in the family in question were inconclusive. Bonifas et al.
(1991), however, hybridized a 3-prime untranslated KRT14 probe to DNA
from members of the family digested with 9 restriction endonucleases.
This revealed the unique MspI restriction site change which was tightly
linked to EBS in this family with a lod score of 3.0. It was found in
all affected members and in no unaffected members. Vassar et al. (1991)
produced basal keratinocyte fragility causing neonatal death in mice
carrying a transgene encoding a shortened KRT14. The phenotype of the
human disease caused by the leu384-to-pro mutation is much less severe
than that caused by deletion of 135 amino acids from the KRT14 carboxyl
terminus in the transgenic mice.

.0002
EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
KRT14, ARG125CYS

The Dowling-Meara type of EBS (131760) is distinguished from other
subtypes not only by its severity but also by the presence of large
cytoplasmic clumps of tonofilaments that can be labeled with antibodies
against the basal epidermal keratins. In 2 patients with the
Dowling-Meara form, Coulombe et al. (1991) demonstrated critical
mutations in the KRT14 gene. One patient had a C-to-T transition
corresponding to nucleotide 433 of the gene, converting an arginine
residue (CGC) to a cysteine residue (TGC) at amino acid 125, located
near the amino end of the KRT14 rod segment. To demonstrate the effect
on function, Coulombe et al. (1991) engineered the arg125-to-cys
mutation in a KRT14 cDNA and showed that this cDNA disrupted keratin
network formation in transfected keratinocytes and disturbed filament
assembly in vitro. Also see 148066.0003.

Sasaki et al. (1999) reported that the arg125-to-cys mutation had been
identified in 4 of 6 Japanese families with the Dowling-Meara type of
EBS. They stated that 8 of 19 families with mutations in the KRT14 gene
carried the arg125-to-cys mutation.

Ma et al. (2001) used differential interference contrast microscopy to
show that the arg125-to-cys mutation in the KRT14 gene greatly reduced
the ability of reconstituted mutant filaments to bundle under
crosslinking conditions, possibly causing the fragility of epithelial
cells seen in some keratin-based disorders.

.0003
EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
KRT14, ARG125HIS

In a second patient with epidermolysis bullosa simplex of the
Dowling-Meara type (131760), Coulombe et al. (1991) demonstrated a
G-to-A transition converting an arginine residue (CGC) to a histidine
residue (CAC) at amino acid 125. Also see 148066.0002.

Although laryngeal involvement is generally associated with junctional
forms of EB, Shemanko et al. (2000) reported 2 unrelated infants with no
family history of skin disease who presented within hours of birth with
extensive blistering of the skin and oral mucosa and subsequently
developed hoarse cries. One had a heterozygous type 5 keratin mutation
(ser181 to pro; 148040.0012), and the other had a heterozygous type 14
keratin mutation (arg125 to his), consistent with a diagnosis of
Dowling-Meara EBS.

.0004
EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE 1
KRT14, GLU144ALA

In 2 French sibs, born of consanguineous parents, with localised
recessive EBS (EBSB1; 601001), Hovnanian et al. (1993) identified a
homozygous 491A-C transversion in the KRT14 gene, resulting in a
glu144-to-ala (E144A) substitution in the first helical segment of the
rod domain. The loss of an ionic interaction with keratin 5 was thought
to affect KRT14-KRT5 heterodimer formation. Genetic linkage with keratin
5 was excluded. The parents were unaffected.

.0005
EPIDERMOLYSIS BULLOSA SIMPLEX, LOCALIZED
KRT14, 3-BP DEL, GLU375DEL

In a family with at least 16 affected individuals in 5 generations with
localized epidermolysis bullosa simplex of the Weber-Cockayne type
(131800), in which nonscarring blisters are limited to the hands and
feet, Chen et al. (1993) found deletion of 3 nucleotides in the KRT14
gene, resulting in deletion of a glutamic acid residue from the helix 2B
region of the gene product.

.0006
EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE 1
KRT14, TYR204TER

In a patient with severe recessive epidermolysis bullosa simplex
(601001), Chan et al. (1994) identified a homozygous 612T-A transversion
in the KRT14 gene, resulting in a tyr204-to-ter (Y204X) substitution.
Each of the unaffected parents, who were related, were heterozygous for
the mutation. Skin biopsy of the patient showed lack of a discernible
keratin filament network in basal epidermal cells.

.0007
EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED
KRT14, MET272ARG

Humphries et al. (1993) identified a met272-to-arg mutation in the K14
gene as the cause of the generalized simplex (Koebner) form of
epidermolysis bullosa (131900) in an Irish family.

.0008
EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE 1
KRT14, IVS1AS, A-C, -2

Jonkman et al. (1996) studied a kindred with recessive epidermolysis
bullosa simplex (601001) in which affected members lacked expression of
keratin 14 and showed homozygosity for a acceptor splice site mutation
that resulted in skipping of exon 2 in 24% of the KRT14 transcripts and
to the use of a cryptic splice site in 76% of the transcripts.
Clinically the patients had severe generalized skin blistering that
improved slightly with age. The basal cells of the patient did not
express keratin 14 and contained no keratin intermediate filaments. The
expression of keratin 5, the obligate copolymer of keratin 14, was
slightly reduced. The expression of keratin 15, the alternative basal
cell keratin, was increased, suggesting upregulation or stabilization to
compensate for the lack of keratin 14. The expression of keratin 16,
keratin 17, and keratin 19 was not different from controls. The
homozygous mutation identified by Jonkman et al. (1996) was located at
the 3-prime acceptor splice site of intron 1 where nucleotide 1840
showed an A-to-C transversion in the affected individuals. Premature
termination codons were generated in all transcripts at either codon
175+1 or codon 175+29, leading to a keratin-14 protein truncated within
the helical 1B rod domain. The disorder was associated with
circumscribed hyperkeratotic lesions with the histology of epidermolytic
hyperkeratosis.

.0009
EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
KRT14, MET119THR

Shemanko et al. (1998) described a heterozygous T-to-C transition in the
KRT14 gene, resulting in a met119-to-thr (M119T) substitution, in a
patient with an EBS Dowling-Meara phenotype (131760) with severe
palmoplantar hyperkeratosis. The patient was a 41-year-old man whose
case had been included previously in 2 brief reports. He had widespread
skin fragility and blistering from birth. From early childhood he
developed gross palmoplantar hyperkeratosis resulting in flexion
contractures of the hands and considerable functional and cosmetic
difficulties. The patient's sibs and parents were clinically normal. See
also M119I (148066.0010) for another mutation affecting the same codon.

.0010
EPIDERMOLYSIS BULLOSA SIMPLEX, LOCALIZED
EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE 1, INCLUDED
KRT14, MET119ILE

In a patient with localized EBS of the Weber-Cockayne type (131800).
Chen et al. (1995) found a 417G-A transition in the KRT14 gene,
resulting in a met119-to-ile (M119I) substitution.

Hu et al. (1997) reported a French-Portuguese family with localized EBS
due to a heterozygous M119I mutation. Blistering began around 1 year of
age and was limited to the hands and feet. There was disease
exacerbation in the summer, and the disorder tended to decrease with
age. One family member, born of a consanguineous union, was homozygous
for the mutation, consistent with autosomal recessive inheritance
(601001). This patient had a more severe phenotype, with earlier onset,
more generalized blistering, and involvement of the oral, vaginal, and
anal mucosa. Since age 14, blistering has been limited to the hands and
feet. The distal skin was scarred, all 10 toenails were missing, and
small areas of palmar hyperkeratosis were present. Hu et al. (1997)
concluded that this mutation acts as a 'partial dominant' in that
heterozygotes have milder localized disease and homozygotes have a more
severe disease.

See also M119T (148066.0009) for another mutation affecting the same
codon.

.0011
EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
KRT14, TYR415HIS

In a patient with Dowling-Meara epidermolysis bullosa simplex (131760),
Hut et al. (2000) identified a tyr415-to-his (Y415H) mutation in the
helix termination motif of the keratin 14 rod domain 2B using a
restriction enzyme strategy to eliminate a KRT14 pseudogene that
complicates KRT14 mutation detection in genomic DNA.

.0012
EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
KRT14, LEU419GLN

In a patient with Dowling-Meara epidermolysis bullosa simplex (131760),
Hut et al. (2000) identified a leu419-to-gln (L419Q) mutation in the
helix termination motif of the keratin 14 rod domain 2B using a
restriction enzyme strategy to eliminate a KRT14 pseudogene that
complicates KRT14 mutation detection in genomic DNA.

.0013
EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
KRT14, GLU422LYS

In a patient with Dowling-Meara epidermolysis bullosa simplex (131760),
Hut et al. (2000) identified a glu422-to-lys (E422K) mutation in the
helix termination motif of the keratin 14 rod domain 2B using a
restriction enzyme strategy to eliminate a KRT14 pseudogene that
complicates KRT14 mutation detection in genomic DNA.

.0014
EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE 1
KRT14, 1-BP DEL, 92T

In a child, born of consanguineous Pakistani parents, with a mild form
of recessive EBS (601001), Batta et al. (2000) reported a homozygous
mutation (92delT) in codon 31 of the KRT14 gene. This mutation causes a
frameshift that results in a premature termination codon further
downstream in exon 1 and was predicted to encode a protein of 116 amino
acids, of which the first 30 are identical to the normal KRT14 sequence
and the remaining 86 residues are missense sequence. There was complete
absence of KRT14 in the epidermis and the child exhibited only mild to
moderate disease. The unaffected mother was heterozygous for the
mutation. The K14-negative basal epidermal cells from the patient
stained positively for K15 (148030), suggesting that upregulation of
expression of K15 may have compensated for the loss of K14.

.0015
NAEGELI-FRANCESCHETTI-JADASSOHN SYNDROME
KRT14, 1-BP DEL, 17G

In the historic multigenerational Swiss family in which
Naegeli-Franceschetti-Jadassohn syndrome (NFJS; 161000) was first
reported by Naegeli (1927), with follow-up by Franceschetti and
Jadassohn (1954) and Itin et al. (1993), Lugassy et al. (2006) found a
heterozygous frameshift mutation in the KRT14 gene: a heterozygous
guanosine deletion at position 17 (17delG) of the KRT14 cDNA sequence
(numbering starting from the initiation codon). This mutation was
predicted to result in a frameshift and to generate a stop codon 8 amino
acids downstream of the mutation site.

.0016
DERMATOPATHIA PIGMENTOSA RETICULARIS
KRT14, CYS18TER

Studying a family from the United States with the diagnosis of
dermatopathia pigmentosa reticularis (DPR; 125595), first reported by
Heimer et al. (1992), Lugassy et al. (2006) demonstrated a heterozygous
C-to-A transversion at cDNA position 54 of KRT14, resulting in the
nonsense mutation cys 18 to ter (C18X).

.0017
EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE 1
KRT14, 2-BP DEL, NT313

In a patient, born of consanguineous parents, with a severe form of
generalized EBS (601001), Rugg et al. (1994) identified a homozygous
2-bp deletion (313_314del) in the KRT14 gene, resulting in premature
termination. The was no KRT14 expression in the skin and no intermediate
filaments were seen in the basal cells of the epidermis. Each unaffected
parent was heterozygous for the mutation.

.0018
EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
KRT14, ASN123SER

In 4 unrelated probands with Dowling-Meara EBS (131760), Pfendner et al.
(2005) identified a heterozygous mutation in the KRT14 gene, resulting
in an asn123-to-ser (N123S) substitution. All of the patients had a de
novo mutation and severe generalized blistering with oral mucous
membrane involvement. The affected residue is within the 1A domain of
the molecule and was predicted to severely perturb the intermediate
filament network.

*FIELD* SA
Bonifas et al. (1991)
*FIELD* RF
1. Albers, K.; Fuchs, E.: The expression of mutant epidermal keratin
cDNAs transfected in simple epithelial and squamous cell carcinoma
lines. J. Cell Biol. 105: 791-806, 1987.

2. Batta, K.; Rugg, E. L.; Wilson, N. J.; West, N.; Goodyear, H.;
Lane, E. B.; Gratian, M.; Dopping-Hepenstal, P.; Moss, C.; Eady, R.
A. J.: A keratin 14 'knockout' mutation in recessive epidermolysis
bullosa simplex resulting in less severe disease. Brit. J. Derm. 143:
621-627, 2000.

3. Bonifas, J. M.; Rothman, A. L.; Epstein, E. H., Jr.: Epidermolysis
bullosa simplex: evidence in two families for keratin gene abnormalities. Science 254:
1202-1205, 1991.

4. Bonifas, J. M.; Rothman, A. L.; Epstein, E. H., Jr.: Identification
of a keratin 14 mutation in a family with epidermolysis bullosa simplex.
(Abstract) Am. J. Hum. Genet. 49 (suppl.): 399, 1991.

5. Chan, Y.; Anton-Lamprecht, I.; Yu, Q.-C.; Jackel, A.; Zabel, B.;
Ernst, J.-P.; Fuchs, E.: A human keratin 14 'knockout': the absence
of K14 leads to severe epidermolysis bullosa simplex and a function
for an intermediate filament protein. Genes Dev. 8: 2574-2587, 1994.

6. Chen, H.; Bonifas, J. M.; Mstsumura, K.; Ikeda, S.; Leyden, W.
A.; Epstein, E. H.: Keratin 14 gene mutations in patients with epidermolysis
bullosa simplex. J. Invest. Derm. 105: 629-632, 1995.

7. Chen, M. A.; Bonifas, J. M.; Matsumura, K.; Blumenfeld, A.; Epstein,
E. H., Jr.: A novel three-nucleotide deletion in the helix 2B region
of keratin 14 in epidermolysis bullosa simplex: delE375. Hum. Molec.
Genet. 2: 1971-1972, 1993.

8. Coulombe, P. A.; Hutton, M. E.; Letai, A.; Hebert, A.; Paller,
A. S.; Fuchs, E.: Point mutations in human keratin 14 genes of epidermolysis
bullosa simplex patients: genetic and functional analyses. Cell 66:
1301-1311, 1991.

9. Franceschetti, A.; Jadassohn, W.: A propos de l'incontinentia
pigmenti, delimitation de deux syndromes differents figurant sous
le meme terme. Dermatologica 108: 1-28, 1954.

10. Fuchs, E.; Coulombe, P. A.: Of mice and men: genetic skin diseases
of keratin. Cell 69: 899-902, 1992.

11. Hanukoglu, I.; Fuchs, E.: The cDNA sequence of a human epidermal
keratin: divergence of sequence but conservation of structure among
intermediate filament proteins. Cell 31: 243-252, 1982.

12. Heimer, W. L., II; Brauner, G.; James, W. D.: Dermatopathia pigmentosa
reticularis: a report of a family demonstrating autosomal dominant
inheritance. J. Am. Acad. Derm. 26: 298-301, 1992.

13. Hovnanian, A.; Pollack, E.; Hilal, L.; Rochat, A.; Prost, C.;
Barrandon, Y.; Goossens, M.: A missense mutation in the rod domain
of keratin 14 associated with recessive epidermolysis bullosa simplex. Nature
Genet. 3: 327-331, 1993.

14. Hu, Z. L.; Smith, L.; Martins, S.; Bonifas, J. M.; Chen, H.; Epstein,
E. H., Jr.: Partial dominance of a keratin 14 mutation in epidermolysis
bullosa simplex: increased severity of disease in a homozygote. J.
Invest. Derm. 109: 360-364, 1997.

15. Humphries, M. M.; Mansergh, F. C.; Kiang, A.-S.; Jordan, S. A.;
Sheils, D. M.; Martin, M. J.; Farrar, G. J.; Kenna, P. F.; Young,
M. M.; Humphries, P.: Three keratin gene mutations account for the
majority of dominant simplex epidermolysis bullosa cases within the
population of Ireland. Hum. Mutat. 8: 57-63, 1996.

16. Humphries, M. M.; Shiels, D. M.; Farrar, G. J.; Kumar-Singh, R.;
Kenna, P. F.; Mansergh, F. C.; Jordan, S. A.; Young, M.; Humphries,
P.: A mutation (met-to-arg) in the type I keratin (K14) gene responsible
for autosomal dominant epidermolysis bullosa simplex. Hum. Mutat. 2:
37-42, 1993.

17. Hut, P. H. L.; Vlies, P. V. D.; Jonkman, M. F.; Verlind, E.; Shimizu,
H.; Buys, C. H. C. M.; Scheffer, H.: Exempting homologous pseudogene
sequences from polymerase chain reaction amplification allows genomic
keratin 14 hotspot analysis. J. Invest. Derm. 114: 616-619, 2000.

18. Itin, P. H.; Lautenschlager, S.; Meyer, R.; Mevorah, B.; Rufli,
T.: Natural history of the Naegeli-Franceschetti-Jadassohn syndrome
and further delineation of its clinical manifestations. J. Am. Acad.
Derm. 28: 942-950, 1993.

19. Jonkman, M. F.; Heeres, K.; Pas, H. H.; van Luyn, M. J. A.; Elema,
J. D.; Corden, L. D.; Smith, F. J. D.; McLean, W. H. I.; Ramaekers,
F. C. S.; Burton, M.; Scheffer, H.: Effects of keratin 14 ablation
on the clinical and cellular phenotype in a kindred with recessive
epidermolysis bullosa simplex. J. Invest. Derm. 107: 764-769, 1996.

20. Langbein, L.; Rogers, M. A.; Praetzel, S.; Cribier, B.; Peltre,
B.; Gassler, N.; Schweizer, J.: Characterization of a novel human
type II epithelial keratin K1b, specifically expressed in eccrine
sweat glands. J. Invest. Derm. 125: 428-444, 2005.

21. Lugassy, J.; Itin, P.; Ishida-Yamamoto, A.; Holland, K.; Huson,
S.; Geiger, D.; Hennies, H. C.; Indelman, M.; Bercovich, D.; Uitto,
J.; Bergman, R.; McGrath, J. A.; Richard, G.; Sprecher, E.: Naegeli-Franceschetti-Jadassohn
syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal
dysplasias caused by dominant mutations in KRT14. Am. J. Hum. Genet. 79:
724-730, 2006.

22. Ma, L.; Yamada, S.; Wirtz, D.; Coulombe, P. A.: A 'hot-spot'
mutation alters the mechanical properties of keratin filament networks. Nature
Cell Biol. 3: 503-506, 2001.

23. Marchuk, D.; McCrohon, S.; Fuchs, E.: Complete sequence of a
gene encoding a human type I keratin: sequences homologous to enhancer
elements in the regulatory region of the gene. Proc. Nat. Acad. Sci. 82:
1609-1613, 1985.

24. Marchuk, D.; McCrohon, S.; Fuchs, E.: Remarkable conservation
of structure among intermediate filament genes. Cell 39: 491-498,
1984.

25. McAlpine, P. J.: Personal Communication. Winnipeg, Manitoba,
Canada 6/1990.

26. Milisavljevic, V.; Freedberg, I. M.; Blumenberg, M.: Close linkage
of the two keratin gene clusters in the human genome. Genomics 34:
134-138, 1996.

27. Naegeli, B.: Familiarer Chromatophorennavus. Schweiz. Med. Wschr. 8:
48 only, 1927.

28. Pfendner, E. G.; Sadowski, S. G.; Uitto, J.: Epidermolysis bullosa
simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes,
phenotype/genotype correlations, and implications for genetic counseling
and prenatal diagnosis. J. Invest. Derm. 125: 239-243, 2005.

29. Rosenberg, M.; Fuchs, E.; Le Beau, M. M.; Eddy, R. L.; Shows,
T. B.: Three epidermal and one simple epithelial type II keratin
genes map to human chromosome 12. Cytogenet. Cell Genet. 57: 33-38,
1991.

30. Rosenberg, M.; RayChaudhury, A.; Shows, T. B.; Le Beau, M. M.;
Fuchs, E.: A group of type I keratin genes on human chromosome 17:
characterization and expression. Molec. Cell. Biol. 8: 722-736,
1988.

31. Rugg, E. L.; McLean, W. H. I.; Lane, E. B.; Pitera, R.; McMillan,
J. R.; Dopping-Hepenstal, P. J. C.; Navsaria, H. A.; Leigh, I. M.;
Eady, R. A. J.: A functional 'knockout' of human keratin 14. Genes
Dev. 8: 2563-2573, 1994.

32. Sasaki, Y.; Shimizu, H.; Akiyama, M.; Hiraoka, Y.; Takizawa, Y.;
Yamada, S.; Morishima, Y.; Yamanishi, K.; Aiso, S.; Nishikawa, T.
: A recurrent keratin 14 mutation in Dowling-Meara epidermolysis bullosa
simplex. (Letter) Brit. J. Derm. 141: 747-776, 1999.

33. Shemanko, C. S.; Horn, H. M.; Keohane, S. G.; Hepburn, N.; Kerr,
A. I. G.; Atherton, D. J.; Tidman, M. J.; Lane, E. B.: Laryngeal
involvement in the Dowling-Meara variant of epidermolysis bullosa
simplex with keratin mutations of severely disruptive potential. Brit.
J. Derm. 142: 315-320, 2000.

34. Shemanko, C. S.; Mellerio, J. E.; Tidman, M. J.; Lane, E. B.;
Eady, R. A. J.: Severe palmo-plantar hyperkeratosis in Dowling-Meara
epidermolysis bullosa simplex caused by a mutation in the keratin
14 gene (KRT14). J. Invest. Derm. 111: 893-895, 1998.

35. Sprecher, E.; Itin, P.; Whittock, N. V.; McGrath, J. A.; Meyer,
R.; DiGiovanna, J. J.; Bale, S. J.; Uitto, J.; Richard, G.: Refined
mapping of Naegeli-Franceschetti-Jadassohn syndrome to a 6 cM interval
on chromosome 17q11.2-q21 and investigation of candidate genes. J.
Invest. Derm. 119: 692-698, 2002.

36. Takeo, M.; Chou, W. C.; Sun, Q.; Lee, W.; Rabbani, P.; Loomis,
C.; Taketo, M. M.; Ito, M.: Wnt activation in nail epithelium couples
nail growth to digit regeneration. Nature 499: 228-232, 2013.

37. Vassar, R.; Coulombe, P. A.; Degenstein, L.; Albers, K.; Fuchs,
E.: Mutant keratin expression in transgenic mice causes marked abnormalities
resembling a human genetic skin disease. Cell 64: 365-380, 1991.

38. Whittock, N. V.; Coleman, C. M.; McLean, W. H. I.; Ashton, G.
H. S.; Acland, K. M.; Eady, R. A. J.; McGrath, J. A.: The gene for
Naegeli-Franceschetti-Jadassohn syndrome maps to 17q21. J. Invest.
Derm. 115: 694-698, 2000.

*FIELD* CN
Ada Hamosh - updated: 8/29/2013
Patricia A. Hartz - updated: 11/19/2009
Cassandra L. Kniffin - reorganized: 9/14/2009
Cassandra L. Kniffin - updated: 8/25/2009
Patricia A. Hartz - updated: 6/22/2007
Victor A. McKusick - updated: 9/22/2006
Paul J. Converse - updated: 2/22/2002
Gary A. Bellus - updated: 4/5/2001
Gary A. Bellus - updated: 6/13/2000
Gary A. Bellus - updated: 6/12/2000
Victor A. McKusick - updated: 1/31/2000
Victor A. McKusick - updated: 2/3/1999
Moyra Smith - updated: 8/29/1996

*FIELD* CD
Victor A. McKusick: 6/6/1990

*FIELD* ED
ckniffin: 09/24/2013
carol: 9/5/2013
alopez: 8/29/2013
carol: 9/9/2011
alopez: 4/6/2010
terry: 1/21/2010
mgross: 12/2/2009
terry: 11/19/2009
ckniffin: 9/14/2009
carol: 9/14/2009
ckniffin: 8/25/2009
ckniffin: 2/12/2009
wwang: 7/2/2007
terry: 6/22/2007
alopez: 9/27/2006
terry: 9/22/2006
mgross: 2/22/2002
cwells: 4/11/2001
cwells: 4/5/2001
alopez: 6/13/2000
alopez: 6/12/2000
carol: 1/31/2000
terry: 1/31/2000
mgross: 3/16/1999
carol: 2/12/1999
terry: 2/3/1999
mark: 2/12/1997
terry: 2/5/1997
terry: 1/17/1997
mark: 8/29/1996
terry: 8/28/1996
terry: 8/22/1996
terry: 6/5/1996
terry: 6/3/1996
mark: 1/23/1996
mark: 1/20/1996
carol: 1/24/1995
mimadm: 4/29/1994
warfield: 4/12/1994
carol: 12/10/1993
carol: 4/29/1993
carol: 7/14/1992

MIM 161000
*RECORD*
*FIELD* NO
161000
*FIELD* TI
#161000 NAEGELI SYNDROME
;;NAEGELI-FRANCESCHETTI-JADASSOHN SYNDROME;;
NFJ SYNDROME; NFJS
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
Naegeli-Franceschetti-Jadassohn syndrome (NFJS) is caused by
heterozygous mutation in the keratin-14 gene (KRT14; 148066) on
chromosome 17q21.

CLINICAL FEATURES

Naegeli (1927) described the syndrome in a father and 2 daughters. In a
restudy of the original family, Franceschetti and Jadassohn (1954)
documented autosomal dominant inheritance. The disorder was earlier
confused with incontinentia pigmenti (IP; see 308300). Differences from
IP include (1) equal frequency in males and females; (2) plantar and
palmar hypohidrosis and hyperkeratosis; and (3) uncommon blistering and
inflammatory phenomena. The cardinal features are reticular cutaneous
pigmentation (starting at about the age of 2 years without a preceding
inflammatory stage), discomfort provoked by heat with diminished sweat
gland function, poor teeth, and moderate hyperkeratosis of the palms and
soles. Males and females are equally affected.

Sparrow et al. (1976) described 7 affected persons in 1 family, with
male-to-male transmission. Hypoplasia of the dermatoglyphics was
present.

Itin et al. (1993) reexamined the original family with NFJS 65 years
after the first description (Naegeli, 1927). The pedigree included 62
members with 14 affected patients; Itin et al. (1993) examined the 10
living patients. They found that the reticulate pigmentation faded after
puberty and sometimes disappeared completely in old age. Hypohidrosis,
the main problem for the patients, remained constant. Teeth were always
severely affected, leading to early total loss. All patients lacked
dermatoglyphics. (Adermatoglyphia is a feature of several ectodermal
dysplasias (Freire-Maia and Pinheiro, 1984).) Diffuse palmoplantar
keratoderma may coexist with punctate keratoses that are sometimes
accentuated in the creases or exhibit a linear pattern. Four patients
had congenital malalignment of the great toenails, a feature not
previously described.

See 246500 for a similar condition possibly inherited as a recessive.

NFJS and dermatopathia pigmentosa reticularis (DPR; 125595) are closely
related autosomal dominant ectodermal dysplasia syndromes that
clinically share complete absence of dermatoglyphics (fingerprint
lines), a reticulate pattern of skin hyperpigmentation, thickening of
the palms and soles (palmoplantar keratoderma), abnormal sweating, and
other subtle developmental anomalies of the teeth, hair, and skin.

MAPPING

Whittock et al. (2000) studied a multigeneration NFJS family of
Anglo-Saxon British descent using microsatellite markers. Significant
genetic linkage to chromosome 17q was observed using marker D17S1787,
with a maximum 2-point lod score of 4.166 at a recombination fraction of
theta = 0. Recombination events in the family place the gene in a
26.97-cM interval between markers D17S798 and D17S957, a region known to
contain the type I keratin (601077) gene cluster and other genes
expressed in epithelia. Keratins K15 (148030), K19 (148020), and K20
(173325), plakoglobin, and MEOX1 (600147) were excluded as candidates by
direct sequencing of genomic PCR products.

Sprecher et al. (2002) studied the large Swiss family with NFJS
originally described by Naegeli (1927) and assessed linkage to
chromosome 17q, which was proposed to harbor the NFJ syndrome gene.
Their results narrowed the NFJS locus region to 6 cM flanked by D17S933
and D17S934 with a maximum multipoint lod score of 2.7 at marker locus
D17S800. The critical interval spanned approximately 5.4 Mb and
contained a minimum of 45 distinct genes. Sprecher et al. (2002)
scrutinized 13 new candidate genes in addition to 5 genes previously
examined, established the genomic organization of 10 of these genes, and
excluded all of them by mutation analysis. They identified a novel
keratin protein (KRT24; 607742) that bears high similarity to the type I
keratins and displays a unique expression profile.

MOLECULAR GENETICS

To determine the molecular basis of NJFS and the closely related
disorder dermatopathia pigmentosa reticularis (DPR; 125595), Lugassy et
al. (2006) studied 1 family with DPR and 4 families with NFJS. They
first confirmed the previously demonstration of linkage of LFJS/DPR to
17q11.2-q21. Combined multipoint analysis generated a maximal lod score
of 8.3 at marker D17S800 at a recombination fraction of 0.0. The disease
interval was found to harbor 230 genes, including a large cluster of
keratin genes. Heterozygous nonsense or frameshift mutations in KRT14
were found to segregate with the disease trait in all 5 families. In
contrast with KRT14 mutations affecting the central alpha-helical rod
domain of keratin-14, which cause epidermolysis bullosa simplex of
several clinical types, NFJS/DPR-associated mutations were found in a
region of the gene encoding the nonhelical head (E1/V1) domain and were
predicted to result in very early termination of translation. The data
suggested that KRT14 plays an important role during ontogenesis of
dermatoglyphics and sweat glands. Among other functions, the N-terminal
part of keratin molecules confers protection against proapoptotic
signals. Ultrastructural examination of patient skin biopsy specimens
provided evidence for increased apoptotic activity in the basal cell
layer where KRT14 is expressed, suggesting that apoptosis is an
important mechanism in the pathogenesis of NFJS/DPR.

HISTORY

Family 1 in the study of NFJS by Lugassy et al. (2006) was the large
multigenerational Swiss family in which the disorder was originally
described by Naegeli in 1927 and had been followed since that time in a
number of reports over a period of 80 years (Franceschetti and
Jadassohn, 1954; Itin et al., 1993).

*FIELD* SA
Kitamura and Hirako (1955); Vilanova and Aguade (1959)
*FIELD* RF
1. Franceschetti, A.; Jadassohn, W.: A propos de l'incontinentia
pigmenti, delimitation de deux syndromes differents figurant sous
le meme terme. Dermatologica 108: 1-28, 1954.

2. Freire-Maia, N.; Pinheiro, M.: Ectodermal Dysplasias: A Clinical
and Genetic Study. New York: Alan R. Liss (pub.) 1984.

3. Itin, P. H.; Lautenschlager, S.; Meyer, R.; Mevorah, B.; Rufli,
T.: Natural history of the Naegeli-Franceschetti-Jadassohn syndrome
and further delineation of its clinical manifestations. J. Am. Acad.
Derm. 28: 942-950, 1993.

4. Kitamura, K.; Hirako, T.: Ueber zwei japanische Faelle einer eigenartigen
retikulaeren Pigmentierung: zur Frage der Dermatose pigmentaire reticulee
(Franceschetti-Jadassohn). Dermatologica 110: 97-107, 1955.

5. Lugassy, J.; Itin, P.; Ishida-Yamamoto, A.; Holland, K.; Huson,
S.; Geiger, D.; Hennies, H. C.; Indelman, M.; Bercovich, D.; Uitto,
J.; Bergman, R.; McGrath, J. A.; Richard, G.; Sprecher, E.: Naegeli-Franceschetti-Jadassohn
syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal
dysplasias caused by dominant mutations in KRT14. Am. J. Hum. Genet. 79:
724-730, 2006.

6. Naegeli, B.: Familiarer Chromatophorennavus. Schweiz. Med. Wschr. 8:
48 only, 1927.

7. Sparrow, G. P.; Samman, P. D.; Wells, R. S.: Hyperpigmentation
and hypohidrosis (the Naegeli-Franceschetti-Jadassohn syndrome): report
of a family and review of the literature. Clin. Exp. Derm. 1: 127-140,
1976.

8. Sprecher, E.; Itin, P.; Whittock, N. V.; McGrath, J. A.; Meyer,
R.; DiGiovanna, J. J.; Bale, S. J.; Uitto, J.; Richard, G.: Refined
mapping of Naegeli-Franceschetti-Jadassohn syndrome to a 6 cM interval
on chromosome 17q11.2-q21 and investigation of candidate genes. J.
Invest. Derm. 119: 692-698, 2002.

9. Vilanova, X.; Aguade, J. P.: Incontinentia pigmenti: troubles
sudoripares fonctionnels dysplastiques et pigmentaires chez les ascendants. Ann.
Derm. Syph. 86: 247-258, 1959.

10. Whittock, N. V.; Coleman, C. M.; McLean, W. H. I.; Ashton, G.
H. S.; Acland, K. M.; Eady, R. A. J.; McGrath, J. A.: The gene for
Naegeli-Franceschetti-Jadassohn syndrome maps to 17q21. J. Invest.
Derm. 115: 694-698, 2000.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Teeth];
Premature tooth loss;
Carious teeth;
Yellow discoloration

SKIN, NAILS, HAIR:
[Skin];
Reticulate hyperpigmentation (periocular, perioral, chest, neck, abdomen);
Hypohidrosis;
Absent fingerprints;
Palmoplantar keratoderma;
Multiple, small punctate keratoses (palms and soles);
[Nails];
Brittle nails;
Congenital malalignment of great toenails

MISCELLANEOUS:
Heat intolerance;
Onset of hyperpigmentation in early childhood (3 months-6 years) that
fades after puberty

MOLECULAR BASIS:
Caused by mutation in the keratin-14 gene (KRT14, 148066.0015)

*FIELD* CN
Kelly A. Przylepa - revised: 11/8/2005

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

*FIELD* ED
carol: 06/11/2012
alopez: 9/27/2006
joanna: 11/8/2005

*FIELD* CN
Victor A. McKusick - updated: 9/22/2006
Gary A. Bellus - updated: 5/1/2003
Gary A. Bellus - updated: 3/28/2001

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

*FIELD* ED
carol: 10/09/2012
alopez: 9/27/2006
terry: 9/22/2006
mgross: 3/17/2004
alopez: 5/1/2003
cwells: 4/4/2001
cwells: 3/28/2001
mimadm: 12/2/1994
jason: 7/14/1994
davew: 7/12/1994
warfield: 3/2/1994
carol: 8/12/1993
carol: 7/6/1993

MIM 601001
*RECORD*
*FIELD* NO
601001
*FIELD* TI
#601001 EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE 1; EBSB1
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreautosomal recessive epidermolysis bullosa simplex-1 (EBSB1) is caused by
homozygous or compound heterozygous mutation in eitgher the KRT14
(148066) or the KRT5 (148066) gene.

DESCRIPTION

Epidermolysis bullosa simplex (EBS) is a clinically and genetically
heterogeneous group of disorders characterized by recurrent blistering
and cleavage within basal keratinocytes. Most forms show autosomal
dominant inheritance (see, e.g., 131800, 131760, and 131900), but
autosomal recessive inheritance has been described (Fine et al., 2008).

CLINICAL FEATURES

Fine et al. (1989) reported a kindred in which 4 individuals had
localized EBS (see 131800), previously known as the Weber-Cockayne type,
inherited in an autosomal recessive pattern. Except for scattered oral
erosions in 1 patient, there was no evidence of associated
extracutaneous disease. The authors noted the implications for genetic
counseling.

Hovnanian et al. (1993) reported a consanguineous French family in which
2 sibs had a recessive form of localized EBS. Both had recurrent,
painful blistering affecting the lateral, dorsal, and plantar aspects of
the feet after walking or minor trauma. Blistering occurred occasionally
on the legs and thighs after horseback riding, but the palms and rest of
the body were spared. Onset was in early childhood. Focal erythematous
and slightly atrophic scars were present on the feet. Hair, nails,
teeth, and oral mucosa were normal, and there were no milia. There was
no hyperkeratosis of the palms or soles. The disorder did not appear to
get better with age, and there was disease exacerbation in the summer.
Electron microscopic examination of the skin showed cleavage within
basal keratinocytes and no clumping of tonofilaments. The parents were
unaffected.

Rugg et al. (1994) reported a child with severe generalized epidermal
blistering beginning 3 days after birth. Blistering occurred virtually
anywhere on the body, including arms, legs, trunk, face, scalp, and oral
mucosa. There was no thickening of the palms or soles on examination at
age 5 years. The front teeth were discolored and notched, but not
pitted, and the fingernails were ridged and of uneven thickness. The
tendency to blister had diminished with age. There was no KRT14
expression in the skin, and no intermediate filaments were seen in the
basal cells of the epidermis. Neither of the parents, who were related,
were affected.

Stephens et al. (1995) reported a large family in which generalized EBS
of the Koebner type was caused by a heterozygous mutation in the KRT5
gene (K173N; 148040.0006). Due to consanguinity in 1 branch of the
family, an affected individual was homozygous for the mutation. However,
the phenotype and the ultrastructural findings in this patient were not
more severe than those observed in heterozygotes. Stephens et al. (1995)
suggested that while the presence of some abnormal KRT5 or KRT14
molecules underlies dominant EBS, the lack of all KRT5 or KRT14
molecules, be they normal or abnormal, appears to underlie recessive
EBS. However, homozygous null KRT5 mutations have not been reported in
humans to date.

Hu et al. (1997) reported a French-Portuguese family with localized EBS
(131800) due to a heterozygous mutation in the KRT14 gene (M119I;
148066.0010). Blistering began around 1 year of age and was limited to
the hands and feet. There was disease exacerbation in the summer, and
the disorder tended to decrease with age. One family member, born of a
consanguineous union, was homozygous for the mutation, consistent with
autosomal recessive inheritance. This patient had a more severe
phenotype, with earlier onset, more generalized blistering, and
involvement of the oral, vaginal, and anal mucosa. Since age 14,
blistering has been limited to the hands and feet. The distal skin was
scarred, all 10 toenails were missing, and small areas of palmar
hyperkeratosis were present. Hu et al. (1997) concluded that this
mutation acts as a 'partial dominant' in that heterozygotes have milder
localized disease and homozygotes have a more severe disease.

Yasukawa et al. (2002) reported an unusual Japanese family with both
autosomal recessive and dominant inheritance of KRT5 mutations resulting
in phenotypic variability. The proband was a man with classic
generalized EBS, manifest as blistering of the trunk and extremities,
improvement with age, and cytolysis within basal keratinocytes on
biopsy. Genetic analysis identified compound heterozygosity for the
E170K (148040.0020) and E418K (148040.0021) mutations in the KRT5 gene.
His paternal uncle, who had blisters restricted to the palms and soles
consistent with localized EBS, was heterozygous for the E170K mutation.
The proband's deceased father and paternal grandmother, who were
putatively heterozygous for the E170K mutation, also reportedly had
localized blistering of the hands and feet. In contrast, 2 unaffected
family members were heterozygous for the E418K substitution, implying
that it is not pathogenic in isolation. In vitro functional expression
studies showed that cells transfected with either mutation developed
small ball-like filament aggregates, indicating a disruption of the
keratin network, although the effect was more pronounced for the E170K
mutation. Expression of both mutant proteins exacerbated the clumping
and resulted in significantly more disruption than either alone. These
findings were consistent with the marked phenotypic and genotypic
variability observed in this family.

MOLECULAR GENETICS

In 2 French sibs, born of consanguineous parents, with autosomal
recessive EBS, Hovnanian et al. (1993) identified a homozygous mutation
in the KRT14 gene (E144A; 148066.0004). The authors predicted that this
change in amino acid size, shape, and hydrophobicity would interfere
with K14-K5 heterodimer production essential to keratin formation.

In a patient with severe recessive EBS, Chan et al. (1994) identified a
homozygous mutation in the KRT14 gene (Y204X; 148066.0006). Each of the
unaffected parents, who were related, were heterozygous for the
mutation. Skin biopsy of the patient showed lack of a discernible
keratin filament network in basal epidermal cells.

In a patient with severe recessive EBS, Rugg et al. (1994) identified a
homozygous 2-bp deletion in the KRT14 gene (148066.0017).

*FIELD* RF
1. Chan, Y.; Anton-Lamprecht, I.; Yu, Q.-C.; Jackel, A.; Zabel, B.;
Ernst, J.-P.; Fuchs, E.: A human keratin 14 'knockout': the absence
of K14 leads to severe epidermolysis bullosa simplex and a function
for an intermediate filament protein. Genes Dev. 8: 2574-2587, 1994.

2. Fine, J.-D.; Eady, R. A. J.; Bauer, E. A.; Bauer, J. W.; Bruckner-Tuderman,
L.; Heagerty, A.; Hintner, H.; Hovnanian, A.; Jonkman, M. F.; Leigh,
I.; McGrath, J. A.; Mellerio, J. E.; Murrell, D. F.; Shimizu, H.;
Uitto, J.; Vahlquist, A.; Woodley, D.; Zambruno, G.: The classification
of inherited epidermolysis bullosa (EB): report of the Third International
Consensus Meeting on diagnosis and classification of EB. J. Am. Acad.
Derm. 58: 931-950, 2008.

3. Fine, J. D.; Johnson, L.; Wright, T.; Horiguchi, Y.: Epidermolysis
bullosa simplex: identification of a kindred with autosomal recessive
transmission of the Weber-Cockayne variety. Pediat. Derm. 6: 1-5,
1989.

4. Hovnanian, A.; Pollack, E.; Hilal, L.; Rochat, A.; Prost, C.; Barrandon,
Y.; Goossens, M.: A missense mutation in the rod domain of keratin
14 associated with recessive epidermolysis bullosa simplex. Nature
Genet. 3: 327-331, 1993.

5. Hu, Z. L.; Smith, L.; Martins, S.; Bonifas, J. M.; Chen, H.; Epstein,
E. H., Jr.: Partial dominance of a keratin 14 mutation in epidermolysis
bullosa simplex: increased severity of disease in a homozygote. J.
Invest. Derm. 109: 360-364, 1997.

6. Rugg, E. L.; McLean, W. H. I.; Lane, E. B.; Pitera, R.; McMillan,
J. R.; Dopping-Hepenstal, P. J. C.; Navsaria, H. A.; Leigh, I. M.;
Eady, R. A. J.: A functional 'knockout' of human keratin 14. Genes
Dev. 8: 2563-2573, 1994.

7. Stephens, K.; Zlotogorski, A.; Smith, L.; Ehrlich, P.; Wijsman,
E.; Livingston, R. J.; Sybert, V. P.: Epidermolysis bullosa simplex:
a keratin 5 mutation is a fully dominant allele in epidermal cytoskeleton
function. Am. J. Hum. Genet. 56: 577-585, 1995.

8. Yasukawa, K.; Sawamura, D.; McMillan, J. R.; Nakamura, H.; Shimizu,
H.: Dominant and recessive compound heterozygous mutations in epidermolysis
bullosa simplex demonstrate the role of the stutter region in keratin
intermediate filament assembly. J. Biol. Chem. 277: 23670-23674,
2002.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Mouth];
Oral blistering

SKIN, NAILS, HAIR:
[Skin];
Epidermolysis bullosa simplex;
Blistering, recurrent;
Blistering may be generalized or localized;
Cleavage within basal keratinocytes;
Atrophic scarring (less common);
[Nails];
Ridged nails;
Thickened nails

MISCELLANEOUS:
Onset at birth or early childhood;
Variable severity;
Heterozygotes are not affected;
Blistering tends to improve with age;
Disease exacerbation during summer due to heat

MOLECULAR BASIS:
Caused by mutation in the keratin-14 gene (KRT14, 148066.0004).

*FIELD* CN
Cassandra L. Kniffin - revised: 08/25/2009

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

*FIELD* ED
ckniffin: 08/25/2009
alopez: 3/24/2006

*FIELD* CN
Cassandra L. Kniffin - updated: 8/25/2009

*FIELD* CD
Victor A. McKusick: 1/20/1996

*FIELD* ED
carol: 09/30/2013
ckniffin: 9/24/2013
alopez: 1/22/2013
ckniffin: 11/19/2010
alopez: 4/6/2010
carol: 11/5/2009
carol: 9/14/2009
ckniffin: 8/25/2009
mark: 2/19/1996
terry: 2/15/1996
mark: 1/24/1996