RBCC Red Blood Cell Collection

KRT5 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Keratin, type II cytoskeletal 5 (58 kDa cytokeratin; Cytokeratin-5; CK-5; Keratin-5; K5; Type-II keratin Kb5)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P13647
ID K2C5_HUMAN Reviewed; 590 AA.
AC P13647; Q6PI71; Q6UBJ0; Q8TA91;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 03-APR-2007, sequence version 3.
DT 22-JAN-2014, entry version 165.
DE RecName: Full=Keratin, type II cytoskeletal 5;
DE AltName: Full=58 kDa cytokeratin;
DE AltName: Full=Cytokeratin-5;
DE Short=CK-5;
DE AltName: Full=Keratin-5;
DE Short=K5;
DE AltName: Full=Type-II keratin Kb5;
GN Name=KRT5;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS ARG-79 AND THR-387.
RX PubMed=2456903;
RA Eckert R.L., Rorke E.A.;
RT "The sequence of the human epidermal 58-kD (#5) type II keratin
RT reveals an absence of 5' upstream sequence conservation between
RT coexpressed epidermal keratins.";
RL DNA 7:337-345(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLU-197.
RX PubMed=2476664;
RA Lersch R., Stellmach V., Stocks X., Giudice G., Fuchs E.;
RT "Isolation, sequence, and expression of a human keratin K5 gene:
RT transcriptional regulation of keratins and insights into pairwise
RT control.";
RL Mol. Cell. Biol. 9:3685-3697(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-79 AND THR-387.
RX PubMed=10903910; DOI=10.1006/bbrc.2000.3110;
RA Whittock N.V., Eady R.A.J., McGrath J.A.;
RT "Genomic organization and amplification of the human epidermal type II
RT keratin genes K1 and K5.";
RL Biochem. Biophys. Res. Commun. 274:149-152(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS GLY-528 AND
RP SER-543.
RC TISSUE=Brain, and Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 83-590, AND VARIANT GLU-197.
RX PubMed=2447486;
RA Lersch R., Fuchs E.;
RT "Sequence and expression of a type II keratin, K5, in human epidermal
RT cells.";
RL Mol. Cell. Biol. 8:486-493(1988).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 186-256, AND VARIANT WC-EBS THR-199.
RX PubMed=14723728; DOI=10.1111/j.1365-2230.2004.01434.x;
RA Xu Z., Dong H., Sun X., Zhu X., Yang Y.;
RT "A new keratin 5 mutation (K199T) in a family with Weber-Cockayne
RT epidermolysis bullosa simplex.";
RL Clin. Exp. Dermatol. 29:74-76(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 348-590, AND VARIANT SER-543.
RX PubMed=2455002; DOI=10.1111/1523-1747.ep12463286;
RA Galup C., Darmon M.Y.;
RT "Isolation and characterization of a cDNA clone coding for human
RT epidermal keratin K5. Sequence of the carboxyterminal half of this
RT keratin.";
RL J. Invest. Dermatol. 91:39-42(1988).
RN [8]
RP INTERACTION WITH TCHP.
RX PubMed=15731013; DOI=10.1242/jcs.01667;
RA Nishizawa M., Izawa I., Inoko A., Hayashi Y., Nagata K., Yokoyama T.,
RA Usukura J., Inagaki M.;
RT "Identification of trichoplein, a novel keratin filament-binding
RT protein.";
RL J. Cell Sci. 118:1081-1090(2005).
RN [9]
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 [10]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 350-477 IN COMPLEX WITH
RP KRT14.
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 [11]
RP VARIANT DM-EBS GLY-475.
RX PubMed=1372711; DOI=10.1038/356244a0;
RA Lane E.B., Rugg E.L., Navsaria H.A., Leigh I.M., Heagerty A.H.M.,
RA Ishida-Yamamoto A., Eady R.A.J.;
RT "A mutation in the conserved helix termination peptide of keratin 5 in
RT hereditary skin blistering.";
RL Nature 356:244-246(1992).
RN [12]
RP VARIANT K-EBS PRO-463.
RX PubMed=7686424; DOI=10.1002/humu.1380020206;
RA Dong W., Ryynaenen M., Uitto J.;
RT "Identification of a leucine-to-proline mutation in the keratin 5 gene
RT in a family with the generalized Kobner type of epidermolysis bullosa
RT simplex.";
RL Hum. Mutat. 2:94-102(1993).
RN [13]
RP VARIANT GLU-138.
RX PubMed=7684424; DOI=10.1111/1523-1747.ep12475671;
RA Wanner R., Foerster H.-H., Tilmans I., Mischke D.;
RT "Allelic variations of human keratins K4 and K5 provide polymorphic
RT markers within the type II keratin gene cluster on chromosome 12.";
RL J. Invest. Dermatol. 100:735-741(1993).
RN [14]
RP VARIANT DM-EBS LYS-193.
RA Smith F.J.D., Morley S.M., Rugg E.L., Navsaria H.A., Leigh I.M.,
RA Eady R.A.J., Tidman M.J., Lane E.B.;
RT "Clustering of epidermolysis bullosa simplex mutations in relation to
RT disease phenotype: data from Weber-Cockayne EBS.";
RL J. Invest. Dermatol. 101:481A-481A(1993).
RN [15]
RP VARIANT WC-EBS CYS-331.
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 [16]
RP VARIANT WC-EBS SER-161.
RX PubMed=7688477; DOI=10.1073/pnas.90.15.7414;
RA Chan Y.-M., Yu Q.-C., Fine J.-D., Fuchs E.;
RT "The genetic basis of Weber-Cockayne epidermolysis bullosa simplex.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:7414-7418(1993).
RN [17]
RP VARIANTS WC-EBS THR-327 AND LYS-329.
RX PubMed=7520042;
RA Chan Y.-M., Yu Q.-C., LeBlanc-Straceski J., Christiano A.,
RA Pulkkinen L., Kucherlapati R.S., Uitto J., Fuchs E.;
RT "Mutations in the non-helical linker segment L1-2 of keratin 5 in
RT patients with Weber-Cockayne epidermolysis bullosa simplex.";
RL J. Cell Sci. 107:765-774(1994).
RN [18]
RP VARIANT K-EBS ASN-173.
RX PubMed=7534039;
RA Stephens K., Zlotogorski A., Smith L., Ehrlich P., Wijsman E.M.,
RA Livingston R.J., Sybert V.P.;
RT "Epidermolysis bullosa simplex: a keratin 5 mutation is a fully
RT dominant allele in epidermal cytoskeleton function.";
RL Am. J. Hum. Genet. 56:577-585(1995).
RN [19]
RP VARIANT WC-EBS VAL-328.
RX PubMed=8595431; DOI=10.1093/hmg/4.10.1999;
RA Matsuki M., Hashimoto K., Yoshikawa K., Yasuno H., Yamanishi K.;
RT "Epidermolysis bullosa simplex (Weber-Cockayne) associated with a
RT novel missense mutation of Asp328 to Val in linker 12 domain of
RT keratin 5.";
RL Hum. Mol. Genet. 4:1999-2000(1995).
RN [20]
RP VARIANTS WC-EBS LYS-193 AND THR-327.
RX PubMed=8807337;
RX DOI=10.1002/(SICI)1098-1004(1996)8:1<57::AID-HUMU8>3.3.CO;2-Q;
RA Humphries M.M., Mansergh F.C., Kiang A.-S., Jordan S.A., Sheils D.M.,
RA Martin M.J., Farrar G.J., Kenna P.F., Young M.M., Humphries P.;
RT "Three keratin gene mutations account for the majority of dominant
RT simplex epidermolysis bullosa cases within the population of
RT Ireland.";
RL Hum. Mutat. 8:57-63(1996).
RN [21]
RP VARIANT DM-EBS PHE-175.
RX PubMed=8757772; DOI=10.1111/1523-1747.ep12329741;
RA Nomura K., Shimizu H., Meng X., Umeki K., Tamai K., Sawamura D.,
RA Nagao K., Kawakami T., Nishikawa T., Hashimoto I.;
RT "A novel keratin K5 gene mutation in Dowling-Meara epidermolysis
RT bullosa simplex.";
RL J. Invest. Dermatol. 107:253-254(1996).
RN [22]
RP VARIANT MP-EBS LEU-25.
RX PubMed=8799157; DOI=10.1073/pnas.93.17.9079;
RA Uttam J., Hutton M.E., Coulombe P.A., Anton-Lamprecht I., Yu Q.-C.,
RA Gedde-Dahl T. Jr., Fine J.-D., Fuchs E.;
RT "The genetic basis of epidermolysis bullosa simplex with mottled
RT pigmentation.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:9079-9084(1996).
RN [23]
RP VARIANTS DM-EBS SER-176; SER-179 AND LYS-477.
RX PubMed=9036937; DOI=10.1111/1523-1747.ep12286486;
RA Stephens K., Ehrlich P., Weaver M., Le R., Spencer A., Sybert V.P.;
RT "Primers for exon-specific amplification of the KRT5 gene:
RT identification of novel and recurrent mutations in epidermolysis
RT bullosa simplex patients.";
RL J. Invest. Dermatol. 108:349-353(1997).
RN [24]
RP VARIANT DM-EBS THR-467.
RX PubMed=9406827; DOI=10.1111/1523-1747.ep12341024;
RA Irvine A.D., McKenna K.E., Bingham A., Nevin N.C., Hughes A.E.;
RT "A novel mutation in the helix termination peptide of keratin 5
RT causing epidermolysis bullosa simplex Dowling-Meara.";
RL J. Invest. Dermatol. 109:815-816(1997).
RN [25]
RP VARIANT K-EBS ALA-323.
RX PubMed=9740251; DOI=10.1046/j.1523-1747.1998.00308.x;
RA Galligan P., Listwan P., Siller G.M., Rothnagel J.A.;
RT "A novel mutation in the L12 domain of keratin 5 in the Koebner
RT variant of epidermolysis bullosa simplex.";
RL J. Invest. Dermatol. 111:524-527(1998).
RN [26]
RP VARIANTS WC-EBS LEU-152; LYS-327 AND HIS-328.
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 MP-EBS LEU-25.
RX PubMed=10494094;
RX DOI=10.1002/(SICI)1096-8628(19991008)86:4<376::AID-AJMG12>3.0.CO;2-W;
RA Moog U., de Die-Smulders C.E.M., Scheffer H., van der Vlies P.,
RA Henquet C.J.M., Jonkman M.F.;
RT "Epidermolysis bullosa simplex with mottled pigmentation: clinical
RT aspects and confirmation of the P24L mutation in the KRT5 gene in
RT further patients.";
RL Am. J. Med. Genet. 86:376-379(1999).
RN [28]
RP VARIANT DM-EBS SER-176, AND VARIANT K-EBS PRO-325.
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 [29]
RP VARIANT DM-EBS PRO-181.
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 [30]
RP VARIANT WC-EBS GLU-328.
RX PubMed=10782015; DOI=10.1159/000022921;
RA Liovic M., Podrumac B., Dragos V., Vouk K., Komel R.;
RT "K5 D328E: a novel missense mutation in the linker 12 domain of
RT keratin 5 associated with epidermolysis bullosa simplex (Weber-
RT Cockayne).";
RL Hum. Hered. 50:234-236(2000).
RN [31]
RP VARIANT K-EBS LEU-186.
RX PubMed=11407988; DOI=10.1046/j.1523-1747.2001.01334.x;
RA Liovic M., Stojan J., Bowden P.E., Gibbs D., Vahlquist A., Lane E.B.,
RA Komel R.;
RT "A novel keratin 5 mutation (K5V186L) in a family with EBS-K: a
RT conservative substitution can lead to development of different disease
RT phenotypes.";
RL J. Invest. Dermatol. 116:964-969(2001).
RN [32]
RP VARIANTS K-EBS LYS-170 AND LYS-418.
RX PubMed=11973334; DOI=10.1074/jbc.M200974200;
RA Yasukawa K., Sawamura D., McMillan J.R., Nakamura H., Shimizu H.;
RT "Dominant and recessive compound heterozygous mutations in
RT epidermolysis bullosa simplex demonstrate the role of the stutter
RT region in keratin intermediate filament assembly.";
RL J. Biol. Chem. 277:23670-23674(2002).
RN [33]
RP VARIANTS WC-EBS LYS-167; PRO-311 AND ASP-324.
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 [34]
RP VARIANTS WC-EBS GLU-404 AND ASP-438, AND VARIANTS DM-EBS LYS-475 AND
RP LYS-477.
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 [35]
RP INVOLVEMENT IN EBS WITH MIGRATORY CIRCINATE ERYTHEMA.
RX PubMed=12925204; DOI=10.1046/j.1523-1747.2003.12424.x;
RA Gu L.-H., Kim S.-C., Ichiki Y., Park J., Nagai M., Kitajima Y.;
RT "A usual frameshift and delayed termination codon mutation in keratin
RT 5 causes a novel type of epidermolysis bullosa simplex with migratory
RT circinate erythema.";
RL J. Invest. Dermatol. 121:482-485(2003).
RN [36]
RP VARIANT WC-EBS GLY-328.
RX PubMed=15347343; DOI=10.1111/j.1365-2230.2004.01565.x;
RA Li J.-G., Feng J., Xiao S.-X., Ai Y.-L., Wang J.-M., Peng Z.-H.;
RT "A new mutation in the linker 12 domain of keratin 5 in a Chinese
RT family with Weber-Cockayne epidermolysis bullosa simplex.";
RL Clin. Exp. Dermatol. 29:539-541(2004).
RN [37]
RP VARIANT WC-EBS SER-177.
RX PubMed=15140024; DOI=10.1111/j.0906-6705.2004.00171.x;
RA Liovic M., Bowden P.E., Marks R., Komel R.;
RT "A mutation (N177S) in the structurally conserved helix initiation
RT peptide motif of keratin 5 causes a mild EBS phenotype.";
RL Exp. Dermatol. 13:332-334(2004).
RN [38]
RP INVOLVEMENT IN DDD1.
RX PubMed=16465624; DOI=10.1086/500850;
RA Betz R.C., Planko L., Eigelshoven S., Hanneken S., Pasternack S.M.,
RA Buessow H., Bogaert K.V., Wenzel J., Braun-Falco M., Ruetten A.,
RA Rogers M.A., Ruzicka T., Noethen M.M., Magin T.M., Kruse R.;
RT "Loss-of-function mutations in the keratin 5 gene lead to Dowling-
RT Degos disease.";
RL Am. J. Hum. Genet. 78:510-519(2006).
RN [39]
RP VARIANTS WC-EBS LEU-25; VAL-158 AND SER-352, VARIANTS K-EBS ASP-143;
RP MET-186; LEU-186; PRO-191 AND ASP-517, VARIANTS DM-EBS SER-176;
RP LYS-475 AND LYS-477, AND VARIANT MP-EBS LEU-25.
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 [40]
RP VARIANTS DM-EBS LYS-168; PRO-169 AND PRO-469, AND VARIANTS WC-EBS
RP LYS-190 AND HIS-331.
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 -!- SUBUNIT: Heterotetramer of two type I and two type II keratins.
CC Keratin-5 associates with keratin-14. Interacts with TCHP.
CC -!- INTERACTION:
CC P18054:ALOX12; NbExp=7; IntAct=EBI-702187, EBI-1633210;
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, with migratory circinate
CC erythema (EBSMCE) [MIM:609352]: A form of intraepidermal
CC epidermolysis bullosa characterized by unusual migratory circinate
CC erythema. Skin lesions appear from birth primarily on the hands,
CC feet, and legs but spare nails, ocular epithelia and mucosae.
CC Lesions heal with brown pigmentation but no scarring. Electron
CC microscopy findings are distinct from those seen in the DM-EBS,
CC with no evidence of tonofilament clumping. Note=The disease is
CC caused by mutations affecting the gene 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, with mottled pigmentation
CC (MP-EBS) [MIM:131960]: A form of intraepidermal epidermolysis
CC bullosa characterized by blistering at acral sites and 'mottled'
CC pigmentation of the trunk and proximal extremities with hyper- and
CC hypopigmentation macules. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Dowling-Degos disease 1 (DDD1) [MIM:179850]: An autosomal
CC dominant genodermatosis. Affected individuals develop a
CC postpubertal reticulate hyperpigmentation that is progressive and
CC disfiguring, and small hyperkeratotic dark brown papules that
CC affect mainly the flexures and great skin folds. Patients usually
CC show no abnormalities of the hair or nails. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: There are two types of cytoskeletal and
CC microfibrillar keratin: I (acidic; 40-55 kDa) and II (neutral to
CC basic; 56-70 kDa).
CC -!- SIMILARITY: Belongs to the intermediate filament family.
CC -!- WEB RESOURCE: Name=Human Intermediate Filament Mutation Database;
CC URL="http://www.interfil.org";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/KRT5";
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DR EMBL; M21389; AAA36143.1; -; mRNA.
DR EMBL; M28496; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF274874; AAF97931.1; -; Genomic_DNA.
DR EMBL; BC024292; AAH24292.1; -; mRNA.
DR EMBL; BC042132; AAH42132.1; -; mRNA.
DR EMBL; BC071906; AAH71906.1; -; mRNA.
DR EMBL; M19723; AAA36145.1; -; mRNA.
DR EMBL; AY373434; AAQ81588.1; -; mRNA.
DR PIR; A29904; A29904.
DR RefSeq; NP_000415.2; NM_000424.3.
DR RefSeq; XP_005268919.1; XM_005268862.1.
DR UniGene; Hs.433845; -.
DR PDB; 3TNU; X-ray; 3.00 A; B=350-477.
DR PDBsum; 3TNU; -.
DR ProteinModelPortal; P13647; -.
DR SMR; P13647; 165-304, 334-476.
DR DIP; DIP-39N; -.
DR IntAct; P13647; 14.
DR STRING; 9606.ENSP00000252242; -.
DR Allergome; 415; Hom s 5.
DR PhosphoSite; P13647; -.
DR DMDM; 143811411; -.
DR PaxDb; P13647; -.
DR PRIDE; P13647; -.
DR ProMEX; P13647; -.
DR DNASU; 3852; -.
DR Ensembl; ENST00000252242; ENSP00000252242; ENSG00000186081.
DR GeneID; 3852; -.
DR KEGG; hsa:3852; -.
DR UCSC; uc001san.3; human.
DR CTD; 3852; -.
DR GeneCards; GC12M052908; -.
DR H-InvDB; HIX0010655; -.
DR HGNC; HGNC:6442; KRT5.
DR HPA; CAB000027; -.
DR HPA; CAB000129; -.
DR MIM; 131760; phenotype.
DR MIM; 131800; phenotype.
DR MIM; 131900; phenotype.
DR MIM; 131960; phenotype.
DR MIM; 148040; gene.
DR MIM; 179850; phenotype.
DR MIM; 609352; phenotype.
DR neXtProt; NX_P13647; -.
DR Orphanet; 79145; Dowling-Degos disease.
DR Orphanet; 158681; Epidermolysis bullosa simplex with circinate migratory erythema.
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 PharmGKB; PA30230; -.
DR eggNOG; NOG146769; -.
DR HOGENOM; HOG000230976; -.
DR HOVERGEN; HBG013015; -.
DR InParanoid; P13647; -.
DR KO; K07605; -.
DR OMA; CGVGGYG; -.
DR OrthoDB; EOG7FV3Q8; -.
DR PhylomeDB; P13647; -.
DR Reactome; REACT_111155; Cell-Cell communication.
DR ChiTaRS; KRT5; human.
DR GeneWiki; Keratin_5; -.
DR GenomeRNAi; 3852; -.
DR NextBio; 15157; -.
DR PRO; PR:P13647; -.
DR ArrayExpress; P13647; -.
DR Bgee; P13647; -.
DR CleanEx; HS_KRT5; -.
DR Genevestigator; P13647; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0045095; C:keratin filament; IDA:MGI.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:ProtInc.
DR GO; GO:0008544; P:epidermis development; TAS:ProtInc.
DR GO; GO:0031581; P:hemidesmosome assembly; TAS:Reactome.
DR InterPro; IPR001664; IF.
DR InterPro; IPR018039; Intermediate_filament_CS.
DR InterPro; IPR003054; Keratin_II.
DR PANTHER; PTHR23239; PTHR23239; 1.
DR Pfam; PF00038; Filament; 1.
DR PRINTS; PR01276; TYPE2KERATIN.
DR PROSITE; PS00226; IF; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Coiled coil; Complete proteome; Disease mutation;
KW Epidermolysis bullosa; Intermediate filament; Keratin; Polymorphism;
KW Reference proteome.
FT CHAIN 1 590 Keratin, type II cytoskeletal 5.
FT /FTId=PRO_0000063727.
FT REGION 1 167 Head.
FT REGION 168 477 Rod.
FT REGION 168 203 Coil 1A.
FT REGION 204 222 Linker 1.
FT REGION 223 315 Coil 1B.
FT REGION 316 338 Linker 12.
FT REGION 339 477 Coil 2.
FT REGION 478 590 Tail.
FT COMPBIAS 39 139 Gly-rich.
FT COMPBIAS 528 590 Ser-rich.
FT SITE 419 419 Stutter.
FT VARIANT 25 25 P -> L (in MP-EBS; dbSNP:rs57499817).
FT /FTId=VAR_010453.
FT VARIANT 79 79 S -> R (in dbSNP:rs1065115).
FT /FTId=VAR_028763.
FT VARIANT 138 138 G -> E (in dbSNP:rs11170164).
FT /FTId=VAR_003871.
FT VARIANT 143 143 V -> D (in K-EBS; dbSNP:rs59851104).
FT /FTId=VAR_031640.
FT VARIANT 152 152 P -> L (in WC-EBS; dbSNP:rs60617604).
FT /FTId=VAR_010454.
FT VARIANT 158 158 D -> V (in WC-EBS; dbSNP:rs61222761).
FT /FTId=VAR_031641.
FT VARIANT 161 161 I -> S (in WC-EBS; dbSNP:rs58058996).
FT /FTId=VAR_003872.
FT VARIANT 167 167 E -> K (in WC-EBS; dbSNP:rs57378129).
FT /FTId=VAR_026536.
FT VARIANT 168 168 E -> K (in DM-EBS; dbSNP:rs58619430).
FT /FTId=VAR_027722.
FT VARIANT 169 169 R -> P (in DM-EBS; dbSNP:rs60720877).
FT /FTId=VAR_027723.
FT VARIANT 170 170 E -> K (in K-EBS; dbSNP:rs59115483).
FT /FTId=VAR_026537.
FT VARIANT 173 173 K -> N (in K-EBS; dbSNP:rs58163069).
FT /FTId=VAR_010455.
FT VARIANT 175 175 L -> F (in DM-EBS; dbSNP:rs57890479).
FT /FTId=VAR_010456.
FT VARIANT 176 176 N -> S (in DM-EBS; dbSNP:rs59092197).
FT /FTId=VAR_010457.
FT VARIANT 177 177 N -> S (in WC-EBS; dbSNP:rs61495052).
FT /FTId=VAR_026538.
FT VARIANT 179 179 F -> S (in DM-EBS; dbSNP:rs57781042).
FT /FTId=VAR_010458.
FT VARIANT 181 181 S -> P (in DM-EBS; with laryngeal
FT involvement; dbSNP:rs60715293).
FT /FTId=VAR_010459.
FT VARIANT 186 186 V -> L (in K-EBS; dbSNP:rs61305583).
FT /FTId=VAR_013829.
FT VARIANT 186 186 V -> M (in K-EBS).
FT /FTId=VAR_031642.
FT VARIANT 190 190 E -> K (in WC-EBS; requires 2 nucleotide
FT substitutions; dbSNP:rs58976397).
FT /FTId=VAR_027724.
FT VARIANT 191 191 Q -> P (in K-EBS; dbSNP:rs57751134).
FT /FTId=VAR_031643.
FT VARIANT 193 193 N -> K (in DM-EBS and WC-EBS;
FT dbSNP:rs60586163).
FT /FTId=VAR_003873.
FT VARIANT 197 197 D -> E (in dbSNP:rs641615).
FT /FTId=VAR_028764.
FT VARIANT 199 199 K -> T (in WC-EBS; dbSNP:rs58766676).
FT /FTId=VAR_026539.
FT VARIANT 232 232 S -> N (in dbSNP:rs3194286).
FT /FTId=VAR_028765.
FT VARIANT 311 311 L -> P (in WC-EBS).
FT /FTId=VAR_026540.
FT VARIANT 323 323 V -> A (in K-EBS; dbSNP:rs59840738).
FT /FTId=VAR_010460.
FT VARIANT 324 324 V -> D (in WC-EBS; dbSNP:rs59335325).
FT /FTId=VAR_026541.
FT VARIANT 325 325 L -> P (in K-EBS; dbSNP:rs58107458).
FT /FTId=VAR_010461.
FT VARIANT 327 327 M -> K (in WC-EBS).
FT /FTId=VAR_010462.
FT VARIANT 327 327 M -> T (in WC-EBS; dbSNP:rs58072617).
FT /FTId=VAR_003874.
FT VARIANT 328 328 D -> E (in WC-EBS; dbSNP:rs59464425).
FT /FTId=VAR_026542.
FT VARIANT 328 328 D -> G (in WC-EBS).
FT /FTId=VAR_026543.
FT VARIANT 328 328 D -> H (in WC-EBS; dbSNP:rs56790237).
FT /FTId=VAR_010463.
FT VARIANT 328 328 D -> V (in WC-EBS; dbSNP:rs57142010).
FT /FTId=VAR_010464.
FT VARIANT 329 329 N -> K (in WC-EBS; dbSNP:rs59730172).
FT /FTId=VAR_010465.
FT VARIANT 331 331 R -> C (in WC-EBS).
FT /FTId=VAR_003875.
FT VARIANT 331 331 R -> H (in WC-EBS).
FT /FTId=VAR_027725.
FT VARIANT 352 352 R -> S (in WC-EBS).
FT /FTId=VAR_031644.
FT VARIANT 387 387 S -> T (in dbSNP:rs2669875).
FT /FTId=VAR_028766.
FT VARIANT 404 404 K -> E (in WC-EBS).
FT /FTId=VAR_023726.
FT VARIANT 418 418 E -> K (in K-EBS).
FT /FTId=VAR_026544.
FT VARIANT 438 438 A -> D (in WC-EBS).
FT /FTId=VAR_023727.
FT VARIANT 463 463 L -> P (in K-EBS).
FT /FTId=VAR_003876.
FT VARIANT 467 467 I -> T (in DM-EBS).
FT /FTId=VAR_010466.
FT VARIANT 469 469 T -> P (in DM-EBS).
FT /FTId=VAR_027726.
FT VARIANT 475 475 E -> G (in DM-EBS).
FT /FTId=VAR_003877.
FT VARIANT 475 475 E -> K (in DM-EBS).
FT /FTId=VAR_023728.
FT VARIANT 477 477 E -> K (in DM-EBS).
FT /FTId=VAR_010467.
FT VARIANT 517 517 G -> D (in K-EBS).
FT /FTId=VAR_031645.
FT VARIANT 528 528 S -> G (in dbSNP:rs11549950).
FT /FTId=VAR_028767.
FT VARIANT 543 543 G -> S (in dbSNP:rs11549949).
FT /FTId=VAR_028768.
FT CONFLICT 9 11 FRS -> SGA (in Ref. 2).
FT CONFLICT 261 261 E -> Q (in Ref. 5; AAA36145).
FT CONFLICT 271 271 E -> H (in Ref. 5; AAA36145).
FT CONFLICT 375 375 H -> E (in Ref. 7).
FT CONFLICT 558 558 G -> S (in Ref. 2 and 5; AAA36145).
FT HELIX 383 472
SQ SEQUENCE 590 AA; 62378 MW; E9D5318E01F55145 CRC64;
MSRQSSVSFR SGGSRSFSTA SAITPSVSRT SFTSVSRSGG GGGGGFGRVS LAGACGVGGY
GSRSLYNLGG SKRISISTSG GSFRNRFGAG AGGGYGFGGG AGSGFGFGGG AGGGFGLGGG
AGFGGGFGGP GFPVCPPGGI QEVTVNQSLL TPLNLQIDPS IQRVRTEERE QIKTLNNKFA
SFIDKVRFLE QQNKVLDTKW TLLQEQGTKT VRQNLEPLFE QYINNLRRQL DSIVGERGRL
DSELRNMQDL VEDFKNKYED EINKRTTAEN EFVMLKKDVD AAYMNKVELE AKVDALMDEI
NFMKMFFDAE LSQMQTHVSD TSVVLSMDNN RNLDLDSIIA EVKAQYEEIA NRSRTEAESW
YQTKYEELQQ TAGRHGDDLR NTKHEISEMN RMIQRLRAEI DNVKKQCANL QNAIADAEQR
GELALKDARN KLAELEEALQ KAKQDMARLL REYQELMNTK LALDVEIATY RKLLEGEECR
LSGEGVGPVN ISVVTSSVSS GYGSGSGYGG GLGGGLGGGL GGGLAGGSSG SYYSSSSGGV
GLGGGLSVGG SGFSASSGRG LGVGFGSGGG SSSSVKFVST TSSSRKSFKS
//

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 131960
*RECORD*
*FIELD* NO
131960
*FIELD* TI
#131960 EPIDERMOLYSIS BULLOSA SIMPLEX WITH MOTTLED PIGMENTATION; EBS-MP
;;SPECKLED HYPERPIGMENTATION WITH PUNCTATE PALMOPLANTAR KERATOSES AND
read moreCHILDHOOD BLISTERING
*FIELD* TX
A number sign (#) is used with this entry because of evidence that EBS
with mottled pigmentation is caused by heterozygous mutation in the
keratin-5 gene (KRT5; 148040) on chromosome 12q13.

Mutation in the same gene causes several other forms of epidermolysis
bullosa simplex, including EBS Dowling-Meara type (131760), EBS Koebner
type (131900), and EBS Weber-Cockayne type (131800). Similar disorders
may also be caused by mutation in the keratin-14 gene (148066).

CLINICAL FEATURES

Fischer and Gedde-Dahl (1979) reported a Swedish family in which 11
members presented with epidermolysis bullosa simplex with some unusual
features, 10 of whom (1 male and 9 females) had a congenital mottled
appearance of the skin. Both anomalies were inherited together in an
autosomal dominant pattern. Recurrent blistering from birth resembled
that of EBS Koebner, but in addition the patients showed 2- to 5-mm
hyper- and hypopigmented spots giving the skin, especially of the limbs,
a mottled 'dirty' appearance. 'Premature aging of the skin,' mild
bruisability of the legs, and longitudinally curved nails were other
features. The pigmentary anomaly was delayed in some individuals.
Linkage with GPT (138200) on chromosome 8q was excluded. The
epidermolysis without dyspigmentation in the eleventh individual
suggested to the authors that the syndrome in the other 10 members may
be due to genetic linkage of 2 independent genes and not to pleiotropism
of a single mutant gene. Matthews and Peachey (1977) reported a father
and daughter with EBS with pigmentation and palmar and plantar
keratosis; pigmentation was delayed. Reports of other families (Sparrow
et al., 1976; Verbov, 1980; Boss et al., 1981) suggested pleiotropism.

Histologically and ultrastructurally, the blistering in EBS with mottled
pigmentation closely resembles that found in other EBS subtypes. This is
consistent with a disorder of the basal keratinocyte cytoskeleton in
which disease-causing mutations have been found within the central rod
domains of keratins 5 and 14 (KRT14; 148066) (Irvine et al., 1997).

Glasz-Bona et al. (2010) reported a large 4-generation Hungarian
pedigree with EBS-MP. There were 10 affected members, 5 of whom were
deceased. All had localized blistering and skin fragility in childhood,
followed by the development of brownish, lentigo-like mottled
pigmentation and hypopigmentation on the trunk and/or extremities during
adolescence and adulthood. Two patients also had nail dystrophy.

MOLECULAR GENETICS

In 2 unrelated families with EBS-MP, Uttam et al. (1996) identified a
mutation in the KRT5 gene (P25L; 148040.0009). The same mutation was
found in a sporadic case (Irvine et al., 1997) and in 2 additional
families (Irvine et al., 2001), increasing the total number of EBS-MP
kindreds with this mutation to 7.

In affected members of a Hungarian family with EBD-MP, Glasz-Bona et al.
(2010) identified a heterozygous P25L mutation in the KRT5 gene.

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. Boss, J. M.; Matthews, C. N. A.; Peachey, R. D. G.; Summerly, R.
: Speckled hyperpigmentation, palmo-plantar punctate keratoses and
childhood blistering: a clinical triad, with variable associations
(a report of two families). Brit. J. Derm. 105: 579-585, 1981.

2. Fischer, T.; Gedde-Dahl, T., Jr.: Epidermolysis bullosa simplex
with mottled pigmentation: a new dominant syndrome. I. Clinical and
histological features. Clin. Genet. 15: 228-238, 1979.

3. Glasz-Bona, A.; Medvecz, M.; Viragh, Z.; Hatvani, Z.; Blazsek,
A.; Karpati, S.: Epidermolysis bullosa simplex with mottled pigmentation--mutation
analysis proved the diagnosis in a four-generation pedigree. Europ.
J. Derm. 20: 698-700, 2010.

4. Irvine, A. D.; McKenna, K. E.; Jenkinson, H.; Hughes, A. E.: A
mutation in the V1 domain of keratin 5 causes epidermolysis bullosa
simplex with mottled pigmentation. J. Invest. Derm. 108: 809-810,
1997.

5. Irvine, A. D.; Rugg, E. L.; Lane, E. B.; Hoare, S.; Peret, C.;
Hughes, A. E.; Heagerty, A. H.: Molecular confirmation of the unique
phenotype of epidermolysis bullosa simplex with mottled pigmentation. Brit.
J. Derm. 144: 40-45, 2001.

6. Matthews, C. N. A.; Peachey, R. D.: Epidermolysis bullosa with
pigmentation and palmar and plantar keratoses. Brit. J. Derm. 97
(suppl. 5): 44-45, 1977.

7. 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.

8. 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.

9. Uttam, J.; Hutton, E.; Coulombe, P. A.; Anton-Lamprecht, I.; Yu,
Q.-C.; Gedde-Dahl, T., Jr.; Fine, J.-D.; Fuchs, E.: The genetic basis
of epidermolysis bullosa simplex with mottled pigmentation. Proc.
Nat. Acad. Sci. 93: 9079-9084, 1996.

10. Verbov, J.: Hereditary diffuse hyperpigmentation. Clin. Exp.
Derm. 5: 227-234, 1980.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKIN, NAILS, HAIR:
[Skin];
Epidermolysis bullosa simplex;
Blistering at acral sites;
'Mottled' pigmentation of the trunk and proximal extremities;
Discrete 2 to 5-mm hyper- and hypopigmented macules;
Punctate palmoplantar hyperkeratosis (later onset);
Degeneration of basal epidermal cells;
Basal cell layer contains clumped keratin filaments;
[Nails];
Dystrophic nails;
Thickened nails

MISCELLANEOUS:
Onset in childhood of blistering and pigmentary changes;
May have seasonal variance in severity;
Allelic disorder to EBS Dowling-Meara (131760), EBS Koebner (131900),
and EBS Weber-Cockayne (131800);
Disorders with overlapping phenotypes can be caused by mutation in
the keratin-14 gene (148066)

MOLECULAR BASIS:
Caused by mutation in the keratin-5 gene (KRT5, 148040.0009)

*FIELD* CN
Cassandra L. Kniffin - revised: 10/07/2003

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

*FIELD* ED
ckniffin: 10/07/2003
alopez: 4/9/2001

*FIELD* CN
Cassandra L. Kniffin - updated: 3/26/2012
Cassandra L. Kniffin - updated: 8/25/2009
Cassandra L. Kniffin - reorganized: 10/13/2003
Gary A. Bellus - updated: 4/9/2001
Victor A. McKusick - updated: 6/21/1997

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
alopez: 03/29/2012
terry: 3/28/2012
ckniffin: 3/26/2012
carol: 9/4/2009
ckniffin: 8/25/2009
wwang: 5/4/2009
carol: 10/13/2003
ckniffin: 10/7/2003
carol: 7/16/2003
alopez: 4/9/2001
carol: 11/4/1999
terry: 6/24/1997
alopez: 6/23/1997
terry: 6/21/1997
joanna: 12/5/1996
mimadm: 9/24/1994
warfield: 4/8/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

MIM 148040
*RECORD*
*FIELD* NO
148040
*FIELD* TI
*148040 KERATIN 5; KRT5
;;K5
*FIELD* TX
For background information on keratins, see KRT15 (148030).
read more
CLONING

Lersch and Fuchs (1988) reported the cDNA and amino acid sequences of a
human 58-kD type II keratin, K5, which is coexpressed with a 50-kD type
I keratin, K14 (148040), in stratified squamous epithelia.

Eckert and Rorke (1988) cloned full-length KRT5 from a cultured
keratinocyte cDNA library. The deduced 590-amino acid protein contains a
central alpha-helical core region of about 310 amino acids with a
7-amino acid repeat found in coiled-coil structures. The N and C termini
are serine rich and contain gly-gly-gly-x motifs.

Mischke et al. (1990) showed that 2 electrophoretic variants for each of
the human keratins K4 and K5 that are expressed in squamous
nonkeratinizing epithelia lining the upper digestive tract could be
distinguished by SDS-PAGE. K5 appears to have 2 codominant alleles, a
and b. On the basis of a population sample, they concluded that the
alleles are in Hardy-Weinberg equilibrium.

BIOCHEMICAL FEATURES

Trask et al. (1990) showed that normal mammary epithelial cells in
culture produce keratins K5, K6 (see 148041), K7 (148059), K14, and K17
(148069), whereas tumor cells produced mainly keratins K8 (148060), K18
(148070), and K19 (148020).

GENE STRUCTURE

Eckert and Rorke (1988) determined that the 5-prime region of the KRT5
gene contains a TATA box and a potential CAAT box. The 3-prime region
contains a single polyadenylation signal.

GENE FUNCTION

Knox et al. (2010) hypothesized that parasympathetic innervation is
required for epithelial progenitor cell function during organogenesis.
Removal of the parasympathetic ganglion in mouse explant organ culture
decreased the number and morphogenesis of keratin 5-positive epithelial
progenitor cells. These effects were rescued with an acetylcholine
analog. Knox et al. (2010) demonstrated that acetylcholine signaling,
via the muscarinic M1 receptor (118510) and epidermal growth factor
receptor (131550), increased epithelial morphogenesis and proliferation
of the keratin 5-positive progenitor cells. Parasympathetic innervation
maintained the epithelial progenitor cell population in an
undifferentiated state, which was required for organogenesis.

MAPPING

Rosenberg et al. (1991) assigned the type II epidermal keratin gene KRT5
to chromosome 12 by use of Southern blot analysis of somatic cell
hybrids. Bonifas et al. (1991) reported that a K5-specific human cosmid
was localized to a position on chromosome 12 (12q11-q13) nearly
indistinguishable from the location of D12S14 and D12S17 by 2-color
fluorescence in situ hybridization. Inasmuch as epidermolysis bullosa
simplex was found to be linked to D12S14 in 1 family, the very close
localization of the KRT5 gene to D12S14 by multicolor fluorescence in
situ hybridization supported KRT5 as a candidate gene (Bonifas et al.,
1992).

MOLECULAR GENETICS

- Epidermolysis Bullosa Simplex

In affected members of a large family with Dowling-Meara epidermolysis
bullosa simplex (EBS) (131760), Lane et al. (1992) identified a
heterozygous mutation in the KRT5 gene (E475G; 148040.0001).

In the large Finnish family with the generalized (Koebner) type of EBS
(131900), Dong et al. (1993) identified a heterozygous mutation in the
KRT5 gene (L462P; 148040.0002).

In affected members of 2 unrelated families with localized epidermolysis
bullosa simplex (131800), Chan et al. (1993) identified a heterozygous
mutation in the KRT5 gene (I161S; 148040.0003). Ehrlich et al. (1995)
identified the I161S mutation in 6 of 13 cases of the localized type of
EB simplex. The high frequency of this mutation suggested either a
hotspot or founder effect.

Humphries et al. (1996) concluded that the M327T (148040.0004) and N193K
(148040.0007) mutations in KRT5 account for most cases of dominant
localized epidermolysis bullosa simplex in Ireland.

In affected members of 2 unrelated families with epidermolysis bullosa
simplex with mottled pigmentation (EBS-MP; 131960), Uttam et al. (1996)
identified a heterozygous mutation in the KRT5 gene (P24L; 148040.0009).
Irvine et al. (1997) identified the P24L mutation in the sporadic case
of a 6-year-old boy who showed acral blistering, mottled pigmentation of
the limbs, and punctate hyperkeratoses primarily affecting the soles.
The authors speculated that recurrence of this mutation may be related
to the fact that it occurred in a CpG site. Although the mutation might
explain the epidermolysis, the cause of the mottled pigmentation
remained obscure.

In a Japanese girl with epidermolysis bullosa simplex with migratory
circinate erythema (609352) and affected members of an unrelated Korean
family, Gu et al. (2003) identified heterozygosity for a 1-bp deletion
(148040.0017) in the KRT5 gene. The patients had a phenotype that was
less severe than that of EBS Dowling-Meara, with an unusual migratory
circinate erythema and multiple vesicles on the erythematous area.

Yasukawa et al. (2002) reported an unusual Japanese family with both
autosomal recessive and dominant inheritance of EBS resulting in
phenotypic variability. The proband was a man with classic generalized
autosomal recessive EBS (EBSB1; 601001) who was compound heterozygous
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 (131800), 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.

- Dowling-Degos Disease 1

Dowling-Degos disease-1 (DDD1; 179850) is an autosomal dominant
genodermatosis characterized by progressive and disfiguring reticulate
hyperpigmentation of the flexures. Betz et al. (2006) performed a
genomewide linkage analysis of 2 German families and mapped DDD1 to
chromosome 12q, with a total lod score of 4.42 (theta = 0.0) for marker
D12S368. This region included the keratin gene cluster, which they
screened for mutations. They identified loss-of-function mutations in
the KRT5 gene (see, e.g., 148040.0018; 148040.0019) in all affected
family members and in 6 unrelated patients with DDD1. This represented
the first identified mutations that led to haploinsufficiency in a
keratin gene. The identification of loss-of-function mutations, along
with the results from additional functional studies, suggested a crucial
role for keratin in the organization of cell adhesion, melanosome
uptake, organelle transport, and nuclear anchorage.

- Susceptibility to Basal Cell Carcinoma

For a discussion of a possible association between the KRT5 gene and
susceptibility to basal cell carcinoma, see BCC4 (613061).

ANIMAL MODEL

Peters et al. (2001) found that Krt5-null mice died shortly after birth,
lacked keratin filaments in the basal epidermis, and were more severely
affected than Krt14 (148066)-null mice. In contrast to the Krt14-null
mice, Krt5-null mice showed a strong induction of the wound-healing
Krt6a (148041) in the suprabasal epidermis of cytolyzed areas. Krt5-null
and Krt14-null mice also differed with respect to tongue lesions. In the
absence of Krt5, residual Krt14 and Krt15 (148030) aggregated along
hemidesmosomes, demonstrating that individual keratins without a partner
can be stable in vivo. The data also indicated that Krt5 may be the
natural partner of Krt15 and Krt17 (148069). The findings suggested that
KRT5 null mutations may be lethal in human epidermolysis bullosa simplex
patients.

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
(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 human patients with various forms of EBS due to
KRT5 mutations, but not in EBS patients with KRT14 gene mutations. These
data provided an first explanation for distinct, keratin-type-specific
genotype-phenotype correlations in EBS, and suggested that the
pathophysiology of EBS involves more than mutant keratins.

*FIELD* AV
.0001
EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
KRT5, GLU475GLY

In affected members of a large family with Dowling-Meara EBS (131760),
Lane et al. (1992) identified a heterozygous A-to-G transition in the
KRT5 gene, resulting in a glu475-to-gly (E475G) substitution in a highly
conserved position 3 residues before the end of the rod domain, in a
sequence known as the helix termination peptide.

.0002
EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED
KRT5, LEU462PRO

In the large Finnish family with the generalized (Koebner) type of EBS
(131900) in which Ryynanen et al. (1991) found linkage to the type II
keratin cluster on 12q, Dong et al. (1993) found a heterozygous mutation
in KRT5. The disorder was associated with a T-to-C transition (CTG to
CCG) within exon 7, resulting in substitution of leucine by proline at
codon 462 (L462P). The substituted leucine is one that is invariant
among 8 different human keratins in a highly conserved segment at the
carboxy-terminal region of the keratin 5 polypeptide.

.0003
EPIDERMOLYSIS BULLOSA SIMPLEX, LOCALIZED
KRT5, ILE161SER

In affected members of 2 unrelated families with localized EBS (131800),
Chan et al. (1993) found a heterozygous T-to-G transversion in the
second base position of codon 161 of 1 of the 2 K5 alleles, leading to a
substitution of serine for isoleucine (I161S). Linkage analysis mapped
the defect to 12q11-q13. Ehrlich et al. (1995) identified the same
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.

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

.0004
EPIDERMOLYSIS BULLOSA SIMPLEX, LOCALIZED
KRT5, MET327THR

localized EBS (131800), Chan et al. (1994) identified a heterozygous
met327-to-thr (M327T) mutation in KRT5. The mutation cosegregated with
the disease, was located in the nonhelical linker segment L1-2, and
perturbed the ability of keratin 5 to assemble with its partner into
10-nm filaments.

Humphries et al. (1996) identified a heterozygous M327T mutation in
affected members of a large Irish family with localized EBS.

.0005
EPIDERMOLYSIS BULLOSA SIMPLEX, LOCALIZED
KRT5, ASN329LYS

Chan et al. (1994) found a heterozygous N329K mutation in the KRT5 gene
as the cause of localized EBS (131800) in a family with affected members
in 2 generations. Like the M327T mutation (148040.0004), it was located
in the nonhelical linker segment L1-2 of keratin 5 and perturbed the
ability of keratin 5 to assemble with its partner into 10-nm filaments.

.0006
EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED
KRT5, LYS173ASN

In a family with autosomal dominant generalized EBS (131900), Stephens
et al. (1995) demonstrated a mutation predicted to result in the
substitution of an evolutionarily conserved lysine by an asparagine
residue (K173N). Unlike previous heterozygous mutations located within
the initial segment of domain 1A of keratins, K173N heterozygosity did
not result in severe disease or clumping of keratin filaments. One
family member was homozygous for the K173N allele, having inherited it
from each of her affected first-cousin parents. Despite a lack of normal
keratin-5 molecules and an effective doubling of abnormal molecules
available for heterodimerization with keratin-14 during formation of
intermediate filaments (IFs), there were no significant differences in
either the clinical severity or the ultrastructural organization of the
homozygous individual's keratin IF cytoskeleton. These data demonstrated
that the K173N mutation behaves as a fully dominant allele. The findings
indicated also that a limited number of abnormal keratin molecules are
sufficient to impair cytoskeletal function and elicit epidermal
fragility and blistering.

.0007
EPIDERMOLYSIS BULLOSA SIMPLEX, LOCALIZED
KRT5, ASN193LYS

In affected members of a large Irish family with localized EBS (131800),
Humphries et al. (1996) identified a heterozygous mutation in the KRT5
gene, resulting in an asn193-to-lys (N193K) substitution.

.0008
EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
KRT5, LEU174PHE

In a Japanese patient with epidermolysis bullosa simplex Dowling-Meara
type (131760), Nomura et al. (1996) identified a heterozygous C-to-T
transition in the KRT5 gene, resulting in a leu174-to-phe (L174F)
substitution in the highly conserved 1A region within the helix
initiation peptide.

.0009
EPIDERMOLYSIS BULLOSA SIMPLEX WITH MOTTLED PIGMENTATION
KRT5, PRO25LEU

In 2 unrelated families with epidermolysis bullosa simplex with mottled
pigmentation (EBS-MP; 131960), Uttam et al. (1996) found a heterozygous
C-to-T transition at base position 71 of the KRT5 gene, causing a P24L
substitution. The mutation occurred in the V1 domain of keratin 5;
previous mutations of K5 or K14 (148066) reported in EBS had been
located in the central helical rod domains, with a tendency to aggregate
at the highly conserved helix boundary peptides or at the nonhelical L12
linker domain. Irvine et al. (1997) identified the same mutation in the
sporadic case of a 6-year-old boy who showed acral blistering, mottled
pigmentation of the limbs, and punctate hyperkeratoses primarily
affecting the soles. The authors speculated that recurrence of this
mutation may be related to the fact that it occurred in a CpG site.
Although the mutation might explain the epidermolysis, the cause of the
mottled pigmentation remained obscure.

Until 1999, the P24L mutation of the KRT5 gene was the only mutation
identified in patients with EBS-MP. Moog et al. (1999) described a
sporadic patient and a family with an affected 6-year-old girl, her
mother, and maternal aunt; all of them had the P24L mutation. The
6-year-old girl showed erythema with telangiectasia on the cheeks and
above the upper lip at birth. From 6 months of age, blisters arose daily
after minor trauma, predominantly on the distal extremities. The lesions
healed without scarring. Over time, the tendency to blistering decreased
considerably. However, her skin remained fragile on sites where adhesive
tape was used. Hyperpigmented spots that were not preceded by blistering
developed from infancy. The mother had mild blistering (always confined
to the feet) and mottled pigmentation from infancy.

Irvine et al. (2001) reported a KRT5 pro25-to-leu mutation in 2
additional families, increasing the total number of EBS-MP kindreds with
this mutation to 7. This mutation was previously reported as PRO24LEU
based on the numbering suggested by Lersch et al. (1989), which ignores
the initial methionine. All other KRT5 mutations are numbered according
to GenBank GENBANK M21389, which includes methionine. Irvine et al.
(2001) suggested that the P25L designation be used in future reports.

Glasz-Bona et al. (2010) identified a heterozygous P25L mutation in
affected members of a 4-generation Hungarian pedigree with EBS-MP. There
were 10 affected members, 5 of whom were deceased. All had localized
blistering and skin fragility in childhood, followed by the development
of brownish, lentigo-like mottled pigmentation and hypopigmentation on
the trunk and/or extremities in adolescence and adulthood. Two patients
also had nail dystrophy. In this family, the P25L mutation segregated
with a gly138-to-glu (G138E) polymorphism.

.0010
EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED
KRT5, VAL7ALA

In a family with the autosomal dominant generalized variant of
epidermolysis bullosa simplex (131900), Galligan et al. (1998) found a
heterozygous T-to-C transition in codon 323 of KRT5 in affected
individuals, resulting in a valine to alanine substitution of the
seventh residue within the L12 linker domain. The valine at this
position is absolutely conserved in all type II keratins, and in other
intermediate filament subunits as well, which suggests that this residue
makes an important contribution to filament integrity. Secondary
structure analysis revealed that alanine at this position markedly
reduces both the hydrophobicity and the beta-sheet nature of the L12
domain.

.0011
EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
KRT5, IVS1DS, G-A, +1

In affected members of a large French family with Dowling-Meara EBS
(131760), Rugg et al. (1999) identified a heterozygous G-to-A transition
at the +1 position of the consensus GT donor splice site of intron 1 of
KRT5. This mutation leads to the use of an exonic GT cryptic donor
splice site located 66 nucleotides upstream from the normal donor splice
site. The corresponding peptide deletion includes 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. Owing to the functional
importance of the removed region, the data strongly suggested that
shortened keratin polypeptide can impair keratin filament assembly in a
dominant manner and cause the Dowling-Meara type of EBS.

.0012
EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
KRT5, SER181PRO

In an infant 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, Shemanko et al. (2000) detected a
T-to-C transition at the second nucleotide position of codon 181,
resulting in a ser-to-pro amino acid change (ser181 to pro; S181P). The
serine at position 181 in the helix initiation motif of keratin 5 is a
highly conserved amino acid across keratins and other intermediate
filament proteins. Although hoarseness is not a well documented feature
of Dowling-Meara epidermolysis bullosa simplex (131760), this patient
and another (see 148066.0003) demonstrated that hoarseness does not
necessarily indicate a poor prognosis.

.0013
EPIDERMOLYSIS BULLOSA SIMPLEX, LOCALIZED
KRT5, 1-BP DEL, 1635G

Sprecher et al. (2003) reported a 25-year-old male of Ashkenazi Jewish
origin whose initial clinical presentation, structural abnormalities of
lesional skin, and course of disease were consistent with a very mild
localized form of EBS (131800). DNA sequence analysis of the complete
coding sequence of the K5 gene disclosed in exon 9 a heterozygous
guanine deletion at position 1635 downstream of the ATG start codon of
K5 (1635delG). This mutation introduced a frameshift and delayed stop
codon 80 amino acids downstream of the mutation site. The deletion was
predicted to lead to the translation of an aberrant K5 protein carrying
an elongated tail domain.

.0014
EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED
KRT5, VAL186LEU

In a family with severe generalized EBS (131900), Liovic et al. (2001)
found a novel K5 mutation, val186 to leu (V186L), that produced a
conservative amino acid change at position 18 of the 1A helix. The
phenotype was unexpectedly severe for the location of the mutation,
which lies outside the consensus helix initiation motif mutation
hotspot, and other mutations at this position have been associated with
Weber-Cockayne (mild) epidermolysis bullosa simplex (131800) only. De
novo K5/K14 (148066) (mutant and wildtype) filament assembly in cultured
cells was studied to determine the effect of this mutation on filament
polymerization and stability. To visualize the structural impact of this
mutation and to compare it with an analogous mutation causing mild
disease, Liovic et al. (2001) generated a computer model of the 1A
region of the K5/K14 coiled-coil. The results showed a high level of
concordance between genetic, cell culture, and molecular modeling data,
suggesting that even a conservative substitution can cause severe
dysfunction in a structural protein, depending on the size and structure
of the amino acid involved.

.0015
EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE, WITH SEVERE PALMOPLANTAR
KERATODERMA
KRT5, GLU477TER

In a German patient with epidermolysis bullosa simplex, Dowling-Meara
type (131760) with severe palmoplantar keratoderma, Muller et al. (1999)
found a 1429G-T transversion in the KRT5 gene that predicted a
glu477-to-ter (E477X) substitution at the last glutamate residue of the
KLLEGE motif. As a child, the patient developed severe palmoplantar
hyperkeratoses before she began to walk.

.0016
EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED, WITH SEVERE PALMOPLANTAR
KERATOSIS
KRT5, LYS472TER

Livingston et al. (2001) reported an epidermolysis bullosa simplex
patient with severe palmoplantar keratosis, underlying erythema in a
'glove and moccasin' distribution, and limited range of motion in the
fingers. Clinical, histologic, and ultrastructural features were
consistent with a diagnosis of generalized EBS (Koebner subtype;
131900). The patient had a novel single-base substitution, 1414A-T, in
the KRT5 gene that changed the lysine residue at amino acid 472 to a
nonsense codon (K472X). This change predicted the synthesis of a
truncated keratin-5, missing 119 amino acids, including the entire tail
domain and the highly conserved KLLEGE motif at the carboxy terminus of
the 2B domain of the central rod. Expression of an altered keratin-5, of
predicted mass and pI for the product of the K472X allele, was
documented by 1- and 2-dimensional Western blots of protein extracts
from patient skin. Ultrastructural analysis of the patient's
nonhyperkeratotic skin was remarkable for basal keratinocytes with dense
and irregular keratin filaments proximal to the basement membrane.
Keratinocytes, transfected with a cDNA carrying the K472X nonsense
mutation, overexpressed a truncated keratin-5, and showed a disorganized
and collapsed keratin filament cytoskeleton. This was the second
epidermolysis bullosa simplex patient reported with a premature
termination mutation in the KLLEGE motif (see 148040.0015). The
occurrence of severe palmoplantar hyperkeratosis in both patients
suggested that the keratin-5 tail domain may have important functions in
palmoplantar tissues.

.0017
EPIDERMOLYSIS BULLOSA SIMPLEX WITH MIGRATORY CIRCINATE ERYTHEMA
KRT5, 1-BP DEL, 1649G

In a Japanese girl with epidermolysis bullosa simplex with migratory
circinate erythema (609352) and affected members of an unrelated Korean
family, Gu et al. (2003) identified heterozygosity for a deletion
mutation (1649delG) in exon 9 of the KRT5 gene, involving the V2 domain
and predicted to cause a frameshift that would delay the termination
codon and result in a protein 35 amino acids longer than the wildtype.
The patients had a phenotype that was less severe than that of EBS
Dowling-Meara, with an unusual migratory circinate erythema and multiple
vesicles on the erythematous area. The mutation was assumed to have
arisen de novo in the Japanese girl, as there were no other affected
family members, and the mutation was not found in the DNA of blood
samples from her parents.

When a younger sister with EBS was born into the Japanese family
previously reported by Gu et al. (2003) and was found to have the same
1649delG mutation as her older sib, Nagao-Watanabe et al. (2004)
reinvestigated the familial segregation of the mutation and identified
heterozygosity for the deletion in the mother's DNA from hair bulb and
buccal cell samples. Closer scrutiny of the mother's history revealed
that she had migratory circinate pigmentation of the skin in childhood,
and Nagao-Watanabe et al. (2004) concluded that this represented
maternal somatic and germline mosaicism.

.0018
DOWLING-DEGOS DISEASE 1
KRT5, 1-BP DUP, 418A

In 2 German pedigrees with Dowling-Degos disease (DDD1; 179850)
described by Biltz and Kiessling (1988) and Milde et al. (1994), Betz et
al. (2006) demonstrated a single adenine base insertion in the KRT5 gene
(418dupA). The mutation was predicted to lead to frameshift and
premature termination of translation at codon 178 (Ile140AsnfsTer39).
Haplotype and SNP analyses revealed that the mutation arose on the same
genetic background in the 2 families, suggesting a common ancestor. Betz
et al. (2006) also performed mutation analysis on the KRT5 gene in 8
patients not belonging to the original pedigrees. In 5 of the 8 screened
patients, the frameshift mutation was also identified. Genotyping of
additional markers around the mutation showed a result compatible with
the existence of a common ancestor for all affected individuals. Milde
et al. (1994) described the disorder in the family they reported as
Dowling-Degos-Kitamura disease.

In 5 unrelated patients with Dowling-Degos disease who also exhibited
acantholysis on histopathology, Hanneken et al. (2010) identified
heterozygosity for the 418dupA mutation; the duplication was also
present in 4 clinically affected family members of 1 of the probands.
Review of histopathologic findings in 3 DDD1 patients previously found
to carry the 418dupA mutation in KRT5 by Betz et al. (2006) revealed
acantholytic changes in biopsy specimens from all 3 patients.

.0019
DOWLING-DEGOS DISEASE 1
KRT5, SER5TER

In a patient with Dowling-Degos disease (179850) reported by Braun-Falco
and Ring (2003), Betz et al. (2006) found a heterozygous nonsense
mutation resulting in a premature stop codon (14C-A; S5X).

.0020
EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE 1
EPIDERMOLYSIS BULLOSA SIMPLEX, LOCALIZED, INCLUDED
KRT5, GLU170LYS

In an unusual Japanese patient with autosomal recessive inheritance of
generalized EBS (EBSB1; 601001), Yasukawa et al. (2002) identified
compound heterozygosity for 2 mutations in the KRT5 gene: a G-to-A
transition in exon 1, resulting in a glu170-to-lys (E170K) substitution
in the highly conserved helix initiation peptide sequence of the 1A rod
domain, and a G-to-A transition in exon 7, resulting in a glu418-to-lys
(E418K; 148040.0021) substitution in the 2B domain, which is the
so-called 'stutter' region, an interruption in the heptad repeat
substructure. He had the classic phenotype, with blistering of the trunk
and extremities, improvement with age, and cytolysis within basal
keratinocytes on biopsy. His paternal uncle, who had blisters restricted
to the palms and soles consistent with localized EBS (131800), 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.
Neither mutation was identified in 100 control alleles. 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.

.0021
EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE 1
KRT5, GLU418LYS

See 148040.0020 and Yasukawa et al. (2002).

*FIELD* RF
1. Betz, R. C.; Planko, L.; Eigelshoven, S.; Hanneken, S.; Pasternack,
S. M.; Bussow, H.; Van Den Bogaert, K.; Wenzel, J.; Braun-Falco, M.;
Rutten, A.; Rogers, M. A.; Ruzicka, T.; Nothen, M. M.; Magin, T. M.;
Kruse, R.: Loss-of-function mutations in the keratin 5 gene lead
to Dowling-Degos disease. Am. J. Hum. Genet. 78: 510-519, 2006.

2. Biltz, H.; Kiessling, M.: Dowling-Degos disease--an autosomally
dominant genodermatosis. Zeitsch. Hautk. 63: 642-644, 1988.

3. Bonifas, J. M.; Bare, J. W.; Lynch, E. D.; Lebo, R. V.; Epstein,
E. H., Jr.: Regional assignment of the human keratin 5 (KRT5) gene
to chromosome 12q near D12S14 by PCR analysis of somatic cell hybrids
and multicolor in situ hybridization. Genomics 13: 452-454, 1992.

4. 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.

5. Braun-Falco, M.; Ring, J.: Enhanced cytoplasmic expression of
desmocollin 3 in epidermal rete ridges of Dowling-Degos syndrome. Brit.
J. Derm. 149: 1293-1296, 2003.

6. 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.

7. 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.

8. 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.

9. Eckert, R. L.; Rorke, E. A.: The sequence of the human epidermal
58-kD (#5) type II keratin reveals an absence of 5-prime upstream
sequence conservation between coexpressed epidermal keratins. DNA 7:
337-345, 1988.

10. 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.

11. Galligan, P.; Listwan, P.; Siller, G. M.; Rothnagel, J. A.: A
novel mutation in the L12 domain of keratin 5 in the Koebner variant
of epidermolysis bullosa simplex. J. Invest. Derm. 111: 524-527,
1998.

12. Glasz-Bona, A.; Medvecz, M.; Viragh, Z.; Hatvani, Z.; Blazsek,
A.; Karpati, S.: Epidermolysis bullosa simplex with mottled pigmentation--mutation
analysis proved the diagnosis in a four-generation pedigree. Europ.
J. Derm. 20: 698-700, 2010.

13. Gu, L.-H.; Kim, S.-C.; Ichiki, Y.; Park, J.; Nagai, M.; Kitajima,
Y.: A usual frameshift and delayed termination codon mutation in
keratin 5 causes a novel type of epidermolysis bullosa simplex with
migratory circinate erythema. J. Invest. Derm. 121: 482-485, 2003.

14. Hanneken, S.; Rutten, A.; Pasternack, S. M.; Eigelshoven, S.;
El Shabrawi-Caelen, L.; Wenzel, J.; Braun-Falco, M.; Ruzicka, T.;
Nothen, M. M.; Kruse, R.; Betz, R. C.: Systematic mutation screening
of KRT5 supports the hypothesis that Galli-Galli disease is a variant
of Dowling-Degos disease. Brit. J. Derm. 163: 197-200, 2010.

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. Irvine, A. D.; McKenna, K. E.; Jenkinson, H.; Hughes, A. E.:
A mutation in the V1 domain of keratin 5 causes epidermolysis bullosa
simplex with mottled pigmentation. J. Invest. Derm. 108: 809-810,
1997.

17. Irvine, A. D.; Rugg, E. L.; Lane, E. B.; Hoare, S.; Peret, C.;
Hughes, A. E.; Heagerty, A. H.: Molecular confirmation of the unique
phenotype of epidermolysis bullosa simplex with mottled pigmentation. Brit.
J. Derm. 144: 40-45, 2001.

18. Knox, S. M.; Lombaert, I. M. A.; Reed, X.; Vitale-Cross, L.; Gutkind,
J. S.; Hoffman, M. P.: Parasympathetic innervation maintains epithelial
progenitor cells during salivary organogenesis. Science 329: 1645-1647,
2010.

19. 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.

20. Lersch, R.; Fuchs, E.: Sequence and expression of a type II keratin,
K5, in human epidermal cells. Molec. Cell. Biol. 8: 486-493, 1988.

21. Lersch, R.; Stellmach, V.; Stocks, C.; Giudice, G.; Fuchs, E.
: Isolation, sequence, and expression of a human keratin K5 gene:
transcriptional regulation of keratins and insights into pairwise
control. Molec. Cell. Biol. 9: 3685-3697, 1989.

22. Liovic, M.; Stojan, J.; Bowden, P. E.; Gibbs, D.; Vahlquist, A.;
Lane, E. B.; Komel, R.: A novel keratin 5 mutation (K5V186L) in a
family with EBS-K: a conservative substitution can lead to development
of different disease phenotypes. J. Inves. Derm. 116: 964-969, 2001.

23. 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.

24. Milde, P.; Suss, R.; Megahed, M.; Goerz, G.: Morbus Dowling-Degos-Kitamura. Z.
Hautkr. 69: 282-283, 1994.

25. Mischke, D.; Wille, G.; Wild, A. G.: Allele frequencies and segregation
of human polymorphic keratins K4 and K5. Am. J. Hum. Genet. 46:
548-552, 1990.

26. Moog, U.; de Die-Smulders, C. E. M.; Scheffer, H.; van der Vlies,
P.; Henquet, C. J. M.; Jonkman, M. F.: Epidermolysis bullosa simplex
with mottled pigmentation: clinical aspects and confirmation of the
P24L mutation in the KRT5 gene in further patients. Am. J. Med. Genet. 86:
376-379, 1999.

27. Muller, F. B.; Anton-Lamprecht, I.; Kuster, W.; Korge, B. P.:
A premature stop codon mutation in the 2B helix termination peptide
of keratin 5 in a German epidermolysis bullosa simplex Dowling-Meara
case. J. Invest. Derm. 112: 988-990, 1999.

28. Nagao-Watanabe, M.; Fukao, T.; Matsui, E.; Kaneko, H.; Inoue,
R.; Kawamoto, N.; Kasahara, K.; Nagai, M.; Ichiki, Y.; Kitajima, Y.;
Kondo, N.: Identification of somatic and germline mosaicism for a
keratin 5 mutation in epidermolysis bullosa simplex in a family of
which the proband was previously regarded as a sporadic case. Clin.
Genet. 66: 236-238, 2004.

29. Nomura, K.; Shimizu, H.; Meng, X.; Umeki, K.; Tamai, K.; Sawamura,
D.; Nagao, K.; Kawakami, T.; Nishikawa, T.; Hashimoto, I.: A novel
keratin K5 mutation in Dowling-Meara epidermolysis bullosa simplex. J.
Invest. Derm. 107: 253-254, 1996.

30. Peters, B.; Kirfel, J.; Bussow, H.; Vidal, M.; Magin, T. M.:
Complete cytolysis and neonatal lethality in keratin 5 knockout mice
reveal its fundamental role in skin integrity and in epidermolysis
bullosa simplex. Molec. Biol. Cell 12: 1775-1789, 2001.

31. 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.

32. 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.

33. 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.

34. 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.

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

36. 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.

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

38. 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.

39. Trask, D. K.; Band, V.; Zajchowski, D. A.; Yaswen, P.; Suh, T.;
Sager, R.: Keratins as markers that distinguish normal and tumor-derived
mammary epithelial cells. Proc. Nat. Acad. Sci. 87: 2319-2323, 1990.

40. Uttam, J.; Hutton, E.; Coulombe, P. A.; Anton-Lamprecht, I.; Yu,
Q.-C.; Gedde-Dahl, T., Jr.; Fine, J.-D.; Fuchs, E.: The genetic basis
of epidermolysis bullosa simplex with mottled pigmentation. Proc.
Nat. Acad. Sci. 93: 9079-9084, 1996.

41. 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* CN
Marla J. F. O'Neill - updated: 11/26/2013
Marla J. F. O'Neill - updated: 7/23/2013
Cassandra L. Kniffin - updated: 3/26/2012
Ada Hamosh - updated: 11/10/2010
Cassandra L. Kniffin - updated: 11/3/2009
Cassandra L. Kniffin - updated: 8/25/2009
Victor A. McKusick - updated: 2/27/2006
Marla J. F. O'Neill - updated: 4/29/2005
Patricia A. Hartz - updated: 11/12/2004
Gary A. Bellus - updated: 4/28/2003
Gary A. Bellus - updated: 4/25/2003
Gary A. Bellus - updated: 4/10/2003
Gary A. Bellus - updated: 4/9/2001
Gary A. Bellus - updated: 6/13/2000
Victor A. McKusick - updated: 10/28/1999
Wilson H. Y. Lo - updated: 9/9/1999
Victor A. McKusick - updated: 2/3/1999
Victor A. McKusick - updated: 6/21/1997
Cynthia K. Ewing - updated: 11/22/1996
Moyra Smith - updated: 8/29/1996

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

*FIELD* ED
carol: 11/26/2013
mcolton: 11/26/2013
carol: 11/4/2013
carol: 9/30/2013
ckniffin: 9/24/2013
carol: 7/23/2013
alopez: 3/29/2012
terry: 3/28/2012
ckniffin: 3/26/2012
ckniffin: 11/19/2010
alopez: 11/15/2010
terry: 11/10/2010
wwang: 11/19/2009
ckniffin: 11/3/2009
alopez: 10/2/2009
carol: 9/14/2009
ckniffin: 8/25/2009
wwang: 9/21/2006
alopez: 3/1/2006
alopez: 2/28/2006
terry: 2/27/2006
wwang: 5/5/2005
wwang: 5/2/2005
terry: 4/29/2005
mgross: 11/12/2004
alopez: 4/28/2003
alopez: 4/25/2003
alopez: 4/10/2003
mgross: 2/22/2002
alopez: 4/9/2001
alopez: 6/13/2000
carol: 11/3/1999
terry: 10/28/1999
carol: 9/9/1999
carol: 2/7/1999
terry: 2/3/1999
alopez: 5/14/1998
terry: 6/24/1997
alopez: 6/23/1997
terry: 6/21/1997
alopez: 6/2/1997
mark: 11/22/1996
mark: 8/29/1996
terry: 8/28/1996
terry: 8/22/1996
mark: 8/18/1995
jason: 7/1/1994
carol: 10/4/1993
carol: 6/30/1993
carol: 4/6/1993
carol: 7/6/1992

MIM 179850
*RECORD*
*FIELD* NO
179850
*FIELD* TI
#179850 DOWLING-DEGOS DISEASE 1; DDD1
;;DDD;;
RETICULAR PIGMENT ANOMALY OF FLEXURES
read more*FIELD* TX
A number sign (#) is used in this entry because of evidence that
Dowling-Degos disease-1 (DDD1) is caused by heterozygous mutation in the
KRT5 gene (148040) on chromosome 12q13.

DESCRIPTION

Dowling-Degos disease (DDD) is an autosomal dominant genodermatosis
characterized by reticular pigmentation, usually in a flexural
distribution. However, generalized DDD can also occur, with numerous
hypopigmented or erythematous macules and papules on the neck, chest,
and abdomen. The histopathology of DDD shows characteristic thin
branch-like patterns of epidermal downgrowth (summary by Li et al.,
2013).

- Review of Reticulate Pigment Disorders

Muller et al. (2012) reviewed the spectrum of reticulate pigment
disorders of the skin, tabulating all reported cases of patients with
Dowling-Degos disease, reticulate acropigmentation of Kitamura (RAK;
615537), reticulate acropigmentation of Dohi (RAD; 127400), Galli-Galli
disease (GGD), and Haber syndrome (HS). Of 82 cases, 26 (31.7%) were
clinically diagnosed as DDD, 13 (15.9%) as RAD, 11 (13.4%) as GGD, 8
(9.8%) as RAK, and 8 (9.8%) as HS; in addition, 16 (19.5%) of the cases
showed overlap between DDD and RAK. Muller et al. (2012) also published
photographs of an affected individual exhibiting an overlap of clinical
features of DDD, GGD, RAD, and RAK. The authors noted that in reticulate
disorders of the skin, the main disease entity is DDD, with a subset of
cases exhibiting acantholysis (GGD), facial erythema (HS), or an acral
distribution (RAD; RAK). Muller et al. (2012) concluded that all
reticulate pigment diseases of the skin are varying manifestations of a
single entity.

- Genetic Heterogeneity of Reticulate Pigment Disorders

Dowling-Degos disease-2 (DDD2; 615327) is caused by mutation in the
POFUT1 gene (607491) on chromosome 20q11. Dyschromatosis symmetrica
hereditaria (DSH; 127400), also known as reticulate acropigmentation of
Dohi (RAD), is caused by mutation in the ADAR gene (146920) on
chromosome 1q21. Reticulate acropigmentation of Kitamura (RAK; 615537)
is caused by mutation in the ADAM10 gene (602192) on chromosome 15q21.

CLINICAL FEATURES

Dowling-Degos disease is an autosomal dominant form of reticulate
pigmentary disorder. It was first described by Dowling and Freudenthal
(1938) and was termed 'dermatose reticulee des plis' (reticulate
dermatosis of flexures) by Degos and Ossipowski (1954).

Individuals with Dowling-Degos disease develop a postpubertal reticulate
hyperpigmentation that is progressive and disfiguring, and small
hyperkeratotic dark brown papules that affect mainly the flexures and
great skin folds. Pitted perioral acneiform scars and genital and
perianal reticulated pigmented lesions have also been described (Milde
et al., 1992; Jafari et al., 2003). Patients usually show no
abnormalities of the hair or nails. Histology shows filiform epithelial
downgrowth of epidermal rete ridges, with a concentration of melanin at
the tips.

Reticulate acropigmentation of Kitamura and Dowling-Degos disease are
characterized by reticulate patterns of hyperpigmented macules without
hypopigmented macules, affecting acral areas in the former and flexures
in the latter (Al Hawsawi et al., 2002). Several groups considered
Kitamura reticulate acropigmentation and DDD to be the same disorder
with different spectra (e.g., Cox and Long, 1991; Lestringant et al.,
1997). Thami et al. (1998) described a large kindred in which reticulate
acropigmentation of Kitamura and acropigmentation of Dohi were
associated with features of DDD.

Milde et al. (1994) described the disorder in 2 sisters as
Dowling-Degos-Kitamura disease.

Shen et al. (2011) described a 55-year-old woman with reticulate
hyperpigmentation on the neck, axillae, inframammary region, inguinal
areas, extremities, and the dorsa of hands and feet. Scalp hair and
nails were normal, but axillary hair was sparse. The eruptions began in
childhood and became more extensive throughout adulthood, with
pigmentation worsening after sun exposure. Beginning at age 40, a large
number of seborrheic keratosis-like lesions gradually developed,
predominantly in the flexural pigmented areas, and she also had pitted
perioral scars. Some family members had a similar presentation.
Histopathology of inguinal skin showed thin branching and elongation of
rete ridges with basal hyperpigmentation. Biopsy of a seborrheic papule
showed features typical of adenoid or reticulated seborrheic keratoses
including epidermal thickening consisting of basaloid cells and multiple
keratin-filled cysts. Shen et al. (2011) suggested that this patient
might represent an unusual variant of DDD, associated with RAK and
scarce axillary hair.

INHERITANCE

Autosomal dominant inheritance of Dowling-Degos disease was established
by Crovato et al. (1983) and Biltz and Kiessling (1988).

MAPPING

Betz et al. (2006) performed a genomewide linkage analysis of the 2
German families described by Biltz and Kiessling (1988) and Milde et al.
(1994) and mapped a DDD locus to 12q13.11-q15, with a total lod score of
4.42 (theta = 0.0) for marker D12S368.

MOLECULAR GENETICS

The region on 12q to which Betz et al. (2006) mapped a locus for DDD
includes the keratin gene cluster. Betz et al. (2006) screened the
cluster for mutations and identified heterozygosity for loss-of-function
mutations in the keratin-5 gene (418dupA, 148040.0018; S5X, 148040.0019)
in all affected members of the families described by Biltz and Kiessling
(1988) and Milde et al. (1994) and in 6 unrelated patients with DDD.
This was said to be the first identified mutation that led to
haploinsufficiency in a keratin gene. The finding, along with the
results from additional functional studies, suggested a crucial role for
keratins in the organization of cell adhesion, melanosome uptake,
organelle transport, and nuclear anchorage.

The findings of Betz et al. (2006) together with those of Uttam et al.
(1996) demonstrating a missense mutation in the KRT5 gene (P25L;
148040.0009) as the cause of epidermolysis bullosa simplex with mottled
pigmentation (131960) suggested a distinct role for KRT5 in melanosome
transport.

In 7 unrelated patients who had been diagnosed with Galli-Galli disease
(GGD), in which the clinical presentation is identical to DDD but
patients exhibit acantholysis on histopathology, Hanneken et al. (2010)
sequenced the KRT5 gene and identified heterozygosity for the 418dupA
mutation in 5 of them. The duplication was also present in 4 clinically
affected family members of 1 of the probands. In addition, the authors
reviewed the histopathologic findings in 3 DDD patients previously found
to carry the 418dupA mutation in KRT5 by Betz et al. (2006) and in 3 DDD
patients who did not carry a mutation in KRT5, and found characteristic
acantholytic changes in biopsy specimens from all 6 patients. Hanneken
et al. (2010) concluded that GGD is a variant of DDD rather than a
distinct entity.

*FIELD* SA
Crovato et al. (1983); Howell and Freeman (1978); Wilson-Jones and
Grice (1974)
*FIELD* RF
1. Al Hawsawi, K.; Al Aboud, K.; Alfadley, A.; Al Aboud, D.: Reticulate
acropigmentation of Kitamura-Dowling Degos disease overlap: a case
report. Int. J. Derm. 41: 518-520, 2002.

2. Betz, R. C.; Planko, L.; Eigelshoven, S.; Hanneken, S.; Pasternack,
S. M.; Bussow, H.; Van Den Bogaert, K.; Wenzel, J.; Braun-Falco, M.;
Rutten, A.; Rogers, M. A.; Ruzicka, T.; Nothen, M. M.; Magin, T. M.;
Kruse, R.: Loss-of-function mutations in the keratin 5 gene lead
to Dowling-Degos disease. Am. J. Hum. Genet. 78: 510-519, 2006.

3. Biltz, H.; Kiessling, M.: Dowling-Degos disease--an autosomally
dominant genodermatosis. Zeitsch. Hautk. 63: 642-644, 1988.

4. Cox, N. H.; Long, E.: Dowling-Degos disease and Kitamura's reticulate
acropigmentation: support for the concept of a single disease. Brit.
J. Derm. 125: 169-171, 1991.

5. Crovato, F.; Desirello, G.; Rebora, A.: Is Dowling-Degos disease
the same disease as Kitamura's reticulate acropigmentation? Brit.
J. Derm. 109: 105-110, 1983.

6. Crovato, F.; Nazzari, G.; Rebora, A.: Dowling-Degos disease (reticulate
pigmented anomaly of the flexures) is an autosomal dominant condition. Brit.
J. Derm. 108: 473-476, 1983.

7. Degos, R.; Ossipowski, B.: Dermatose pigmentaire reticulee des
plis. Ann. Derm. 81: 147-151, 1954.

8. Dowling, G. B.; Freudenthal, W.: Acanthosis nigricans. Brit.
J. Derm. 50: 467-471, 1938.

9. Hanneken, S.; Rutten, A.; Pasternack, S. M.; Eigelshoven, S.; El
Shabrawi-Caelen, L.; Wenzel, J.; Braun-Falco, M.; Ruzicka, T.; Nothen,
M. M.; Kruse, R.; Betz, R. C.: Systematic mutation screening of KRT5
supports the hypothesis that Galli-Galli disease is a variant of Dowling-Degos
disease. Brit. J. Derm. 163: 197-200, 2010.

10. Howell, J. B.; Freeman, R. G.: Reticular pigmented anomaly of
the flexures. Arch. Derm. 114: 400-403, 1978.

11. Jafari, R.; Tronnier, M.; Vakilzadeh, F.: Morbus Dowling-Degos
in genitoperianal localisation in a mother and daughter. Akt. Derm. 29:
240-242, 2003.

12. Lestringant, G. G.; Masouye, I.; Frossard, P. M.; Adeghate, E.;
Galadari, I. H.: Co-existence of leukoderma with features of Dowling-Degos
disease: reticulate acropigmentation of Kitamura spectrum in five
unrelated patients. Dermatology 195: 337-343, 1997.

13. Li, M.; Cheng, R.; Liang, J.; Yan, H.; Zhang, H.; Yang, L.; Li,
C.; Jiao, Q.; Lu, Z.; He, J.; Ji, J.; Shen, Z.; Li, C.; Hao, F.; Yu,
H.; Yao, Z.: Mutations in POFUT1, encoding protein O-fucosyltransferase
1, cause generalized Dowling-Degos disease. Am. J. Hum. Genet. 92:
895-903, 2013.

14. Milde, P.; Goerz, G.; Plewig, G.: Morbus Dowling-Degos mit ausschliessich
genitaler Manifestation. Hautarzt 43: 369-372, 1992.

15. Milde, P.; Suss, R.; Megahed, M.; Goerz, G.: Morbus Dowling-Degos-Kitamura. Z.
Hautkr. 69: 282-283, 1994.

16. Muller, C. S. L.; Tremezaygues, L.; Pfohler, C.; Vogt, T.: The
spectrum of reticulate pigment disorders of the skin revisited. Europ.
J. Derm. 22: 596-604, 2012.

17. Shen, Z.; Chen, L.; Ye, Q.; Hao, F.; dos Santos, V. M.; Yang,
X.; Zhong, B.: Coexistent Dowling-Degos disease and reticulate acropigmentation
of Kitamura with progressive seborrheic keratosis. (Letter) Cutis 87:
73-75, 2011.

18. Thami, G. P.; Jaswal, R.; Kanwar, A. J.; Radotra, B. D.; Singh,
I. P.: Overlap of reticulate acropigmentation of Kitamura, acropigmentation
of Dohi and Dowling-Degos disease in four generations. Dermatology 196:
350-351, 1998.

19. Uttam, J.; Hutton, E.; Coulombe, P. A.; Anton-Lamprecht, I.; Yu,
Q.-C.; Gedde-Dahl, T., Jr.; Fine, J.-D.; Fuchs, E.: The genetic basis
of epidermolysis bullosa simplex with mottled pigmentation. Proc.
Nat. Acad. Sci. 93: 9079-9084, 1996.

20. Wilson-Jones, E.; Grice, K.: Reticulate pigmented anomaly of
the flexures (Dowling, Degos): a new genodermatosis. (Abstract) Brit.
J. Derm. 91 (suppl.): 36 only, 1974.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKIN, NAILS, HAIR:
[Skin];
Progressive reticulate hyperpigmentation (axillae, groin, perineal,
perianal);
Hyperkeratotic dark-brown papules;
Pitted, perioral acneiform scars;
HISTOLOGY:;
Filiform epithelial downgrowth of epidermal rete ridges;
Acantholytic changes (in some patients)

MISCELLANEOUS:
Onset after puberty;
Reticulate acropigmentation of Kitamura (hyperpigmentation found primarily
in hands and feet)

MOLECULAR BASIS:
Caused by mutation in the keratin 5 gene (KRT5, 148040.0018)

*FIELD* CN
Kelly A. Przylepa - revised: 1/22/2008

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

*FIELD* ED
joanna: 01/14/2014
joanna: 2/19/2008
joanna: 1/22/2008

*FIELD* CN
Marla J. F. O'Neill - updated: 11/26/2013
Marla J. F. O'Neill - updated: 11/20/2013
Marla J. F. O'Neill - updated: 7/23/2013
Victor A. McKusick - updated: 2/27/2006

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
carol: 11/26/2013
mcolton: 11/26/2013
carol: 11/25/2013
mcolton: 11/20/2013
carol: 7/23/2013
alopez: 4/3/2006
alopez: 3/1/2006
alopez: 2/28/2006
terry: 2/27/2006
mimadm: 3/25/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
reenie: 6/23/1986

MIM 609352
*RECORD*
*FIELD* NO
609352
*FIELD* TI
#609352 EPIDERMOLYSIS BULLOSA SIMPLEX WITH MIGRATORY CIRCINATE ERYTHEMA
*FIELD* TX
read moreA number sign (#) is used with this entry because of evidence that
epidermolysis bullosa simplex (EBS) with migratory circinate erythema
can be caused by mutation in the keratin-5 gene (KRT5; 148040).

CLINICAL FEATURES

Gu et al. (2003) described a form of epidermolysis bullosa simplex that
was milder than the Dowling-Meara phenotype (131760) but involved an
unusual migratory circinate erythema with multiple vesicles on the area
affected by the erythema. The lesions, which appeared from birth
primarily on the hands, feet, and legs but spared the nails, ocular
epithelia, and mucosae, healed with brown pigmentation but no scarring.
Electron microscopy findings were distinct from those seen in the
Dowling-Meara type of EBS, with no evidence of tonofilament clumping.

MOLECULAR GENETICS

In an affected Japanese girl and affected members of an unrelated Korean
family, Gu et al. (2003) identified heterozygosity for a 1649delG
mutation in the KRT5 gene (148040.0017). The mutation was assumed to
have arisen de novo in the Japanese girl. When a younger sister with EBS
was born and was found to have the same 1649delG mutation as her older
sib, Nagao-Watanabe et al. (2004) reinvestigated the familial
segregation of the mutation and identified heterozygosity for the
deletion in the mother's DNA from hair bulb and buccal cell samples.
Closer scrutiny of the mother's history revealed that she had migratory
circinate pigmentation of the skin in childhood, and Nagao-Watanabe et
al. (2004) concluded that this represented maternal somatic and germline
mosaicism.

*FIELD* RF
1. Gu, L.-H.; Kim, S.-C.; Ichiki, Y.; Park, J.; Nagai, M.; Kitajima,
Y.: A usual frameshift and delayed termination codon mutation in
keratin 5 causes a novel type of epidermolysis bullosa simplex with
migratory circinate erythema. J. Invest. Derm. 121: 482-485, 2003.

2. Nagao-Watanabe, M.; Fukao, T.; Matsui, E.; Kaneko, H.; Inoue, R.;
Kawamoto, N.; Kasahara, K.; Nagai, M.; Ichiki, Y.; Kitajima, Y.; Kondo,
N.: Identification of somatic and germline mosaicism for a keratin
5 mutation in epidermolysis bullosa simplex in a family of which the
proband was previously regarded as a sporadic case. Clin. Genet. 66:
236-238, 2004.

*FIELD* CD
Marla J. F. O'Neill: 5/2/2005

*FIELD* ED
wwang: 06/15/2005
wwang: 5/5/2005
wwang: 5/2/2005