RBCC Red Blood Cell Collection

KRT16 (KRT16A) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Keratin, type I cytoskeletal 16 (Cytokeratin-16; CK-16; Keratin-16; K16)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P08779
ID K1C16_HUMAN Reviewed; 473 AA.
AC P08779; A8K488; P30654; Q16402; Q9UBG8;
DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 146.
DE RecName: Full=Keratin, type I cytoskeletal 16;
DE AltName: Full=Cytokeratin-16;
DE Short=CK-16;
DE AltName: Full=Keratin-16;
DE Short=K16;
GN Name=KRT16; Synonyms=KRT16A;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2431270;
RA Raychaudhury A., Marchuk D., Lindhurst M., Fuchs E.;
RT "Three tightly linked genes encoding human type I keratins:
RT conservation of sequence in the 5'-untranslated leader and 5'-upstream
RT regions of coexpressed keratin genes.";
RL Mol. Cell. Biol. 6:539-548(1986).
RN [2]
RP SEQUENCE REVISION.
RX PubMed=2451124;
RA Rosenberg M., Raychaudhury A., Shows T.B., le Beau M.M., Fuchs E.;
RT "A group of type I keratin genes on human chromosome 17:
RT characterization and expression.";
RL Mol. Cell. Biol. 8:722-736(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Keratinocyte;
RX PubMed=7487986; DOI=10.1006/bbrc.1995.2495;
RA Paladini R.D., Takahashi K., Gant T.M., Coulombe P.A.;
RT "cDNA cloning and bacterial expression of the human type I keratin
RT 16.";
RL Biochem. Biophys. Res. Commun. 215:517-523(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RA Smith F.J.D., Fisher M.P., Healy E., Rees J.L., McKusick V.A.,
RA Bonifas J.M., Epstein E.H. Jr., Tan E., Uitto J., McLean W.H.I.;
RT "Cloning of multiple keratin 16 genes: genotype-phenotype correlation
RT and protein expression studies in pachyonychia congenita type 1 and
RT focal palmoplantar keratoderma.";
RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Mammary gland;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 118-134, AND VARIANT PC1 PRO-132.
RX PubMed=7539673; DOI=10.1038/ng0395-273;
RA McLean W.H.I., Rugg E.L., Lunny D.P., Morley S.M., Lane E.B.,
RA Swensson O., Dopping-Hepenstal P.J.C., Griffiths W.A.D., Eady R.A.J.,
RA Higgins C., Navsaria H.A., Leigh I.M., Strachan T., Kunkeler L.,
RA Munro C.S.;
RT "Keratin 16 and keratin 17 mutations cause pachyonychia congenita.";
RL Nat. Genet. 9:273-278(1995).
RN [9]
RP PROTEIN SEQUENCE OF 137-148; 178-195 AND 264-283.
RC TISSUE=Keratinocyte;
RX PubMed=1286667; DOI=10.1002/elps.11501301199;
RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E.,
RA Vandekerckhove J.;
RT "Microsequences of 145 proteins recorded in the two-dimensional gel
RT protein database of normal human epidermal keratinocytes.";
RL Electrophoresis 13:960-969(1992).
RN [10]
RP MASS SPECTROMETRY.
RC TISSUE=Mammary cancer;
RX PubMed=11840567;
RX DOI=10.1002/1615-9861(200202)2:2<212::AID-PROT212>3.0.CO;2-H;
RA Harris R.A., Yang A., Stein R.C., Lucy K., Brusten L., Herath A.,
RA Parekh R., Waterfield M.D., O'Hare M.J., Neville M.A., Page M.J.,
RA Zvelebil M.J.;
RT "Cluster analysis of an extensive human breast cancer cell line
RT protein expression map database.";
RL Proteomics 2:212-223(2002).
RN [11]
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 [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP VARIANTS FNEPPK SER-125 AND CYS-127.
RX PubMed=8595410; DOI=10.1093/hmg/4.10.1875;
RA Shamsheer M.K., Navsaria H.A., Stevens H.P., Ratnavel R.C.,
RA Purkis P.E., McLean W.H.I., Cook L.J., Griffiths W.A.D.,
RA Geschmeissner S., Spurr N., Leigh I.M.;
RT "Novel mutations in keratin 16 gene underly focal nonepidermolytic
RT palmoplantar keratoderma (NEPPK) in two families.";
RL Hum. Mol. Genet. 4:1875-1881(1995).
RN [14]
RP VARIANTS PC1 PRO-122 AND PRO-127.
RX PubMed=10606845; DOI=10.1046/j.1365-2133.1999.03198.x;
RA Smith F.J.D., Del Monaco M., Steijlen P.M., Munro C.S., Morvay M.,
RA Coleman C.M., Rietveld F.J.R., Uitto J., McLean W.H.I.;
RT "Novel proline substitution mutations in keratin 16 in two cases of
RT pachyonychia congenita type 1.";
RL Br. J. Dermatol. 141:1010-1016(1999).
RN [15]
RP VARIANT PC1 SER-130 DEL.
RX PubMed=10521820;
RX DOI=10.1002/(SICI)1097-0223(199910)19:10<941::AID-PD663>3.3.CO;2-N;
RA Smith F.J., McKusick V.A., Nielsen K., Pfendner E., Uitto J.,
RA McLean W.H.I.;
RT "Cloning of multiple keratin 16 genes facilitates prenatal diagnosis
RT of pachyonychia congenita type 1.";
RL Prenat. Diagn. 19:941-946(1999).
RN [16]
RP VARIANT PC1 ARG-124.
RX PubMed=10839714; DOI=10.1034/j.1600-0625.2000.009003170.x;
RA Smith F.J., Fisher M.P., Healy E., Rees J.L., Bonifas J.M.,
RA Epstein E.H. Jr., Tan E.M., Uitto J., McLean W.H.I.;
RT "Novel keratin 16 mutations and protein expression studies in
RT pachyonychia congenita type 1 and focal palmoplantar keratoderma.";
RL Exp. Dermatol. 9:170-177(2000).
RN [17]
RP VARIANT UPVN 104-GLY--ALA-107 DEL.
RX PubMed=10844556; DOI=10.1046/j.1523-1747.2000.00983.x;
RA Terrinoni A., Puddu P., Didona B., De Laurenzi V., Candi E.,
RA Smith F.J., McLean W.H.I., Melino G.;
RT "A mutation in the V1 domain of K16 is responsible for unilateral
RT palmoplantar verrucous nevus.";
RL J. Invest. Dermatol. 114:1136-1140(2000).
RN [18]
RP VARIANT PC1 ASN-354.
RX PubMed=11359398; DOI=10.1046/j.1365-2133.2001.04199.x;
RA Connors J.B., Rahil A.K., Smith F.J.D., McLean W.H.I., Milstone L.M.;
RT "Delayed-onset pachyonychia congenita associated with a novel mutation
RT in the central 2B domain of keratin 16.";
RL Br. J. Dermatol. 144:1058-1062(2001).
RN [19]
RP VARIANTS PC1 THR-121 AND PC1 GLN-128.
RX PubMed=11886499; DOI=10.1046/j.0022-202x.2001.01565.x;
RA Terrinoni A., Smith F.J.D., Didona B., Canzona F., Paradisi M.,
RA Huber M., Hohl D., David A., Verloes A., Leigh I.M., Munro C.S.,
RA Melino G., McLean W.H.I.;
RT "Novel and recurrent mutations in the genes encoding keratins K6a, K16
RT and K17 in 13 cases of pachyonychia congenita.";
RL J. Invest. Dermatol. 117:1391-1396(2001).
CC -!- SUBUNIT: Heterodimer of a type I and a type II keratin. KRT16
CC associates with KRT6 isomers. Interacts with TCHP. Interacts with
CC TRADD (By similarity).
CC -!- TISSUE SPECIFICITY: Expressed in the hair follicle, nail bed and
CC in mucosal stratified squamous epithelia and, suprabasally, in
CC oral epithelium and palmoplantar epidermis. Also found in luminal
CC cells of sweat and mammary gland ducts.
CC -!- MASS SPECTROMETRY: Mass=50924.66; Method=MALDI; Range=2-473;
CC Source=PubMed:11840567;
CC -!- DISEASE: Pachyonychia congenita 1 (PC1) [MIM:167200]: An autosomal
CC dominant ectodermal dysplasia characterized by hypertrophic nail
CC dystrophy resulting in onchyogryposis (thickening and increase in
CC curvature of the nail), palmoplantar keratoderma, follicular
CC hyperkeratosis, and oral leukokeratosis. Hyperhidrosis of the
CC hands and feet is usually present. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Keratoderma, palmoplantar, non-epidermolytic, focal
CC (FNEPPK) [MIM:613000]: A dermatological disorder characterized by
CC non-epidermolytic palmoplantar keratoderma limited to the pressure
CC points on the balls of the feet, with later mild involvement on
CC the palms. Oral, genital and follicular keratotic lesions are
CC often present. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: Unilateral palmoplantar verrucous nevus (UPVN)
CC [MIM:144200]: UPVN is characterized by a localized epidermolytic
CC hyperkeratosis in parts of the right palm and the right sole,
CC following the lines of Blaschko. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Note=KRT16 and KRT17 are coexpressed only in pathological
CC situations such as metaplasias and carcinomas of the uterine
CC cervix and in psoriasis vulgaris.
CC -!- MISCELLANEOUS: There are two types of cytoskeletal and
CC microfibrillar keratin, I (acidic) and II (neutral to basic) (40-
CC 55 and 56-70 kDa, respectively).
CC -!- SIMILARITY: Belongs to the intermediate filament family.
CC -!- 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/KRT16";
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DR EMBL; M28439; AAA59460.1; -; Genomic_DNA.
DR EMBL; M28432; AAA59460.1; JOINED; Genomic_DNA.
DR EMBL; M28433; AAA59460.1; JOINED; Genomic_DNA.
DR EMBL; M28434; AAA59460.1; JOINED; Genomic_DNA.
DR EMBL; M28435; AAA59460.1; JOINED; Genomic_DNA.
DR EMBL; M28436; AAA59460.1; JOINED; Genomic_DNA.
DR EMBL; M28437; AAA59460.1; JOINED; Genomic_DNA.
DR EMBL; M28438; AAA59460.1; JOINED; Genomic_DNA.
DR EMBL; S79867; AAB35421.1; -; mRNA.
DR EMBL; AF061809; AAD15829.1; -; Genomic_DNA.
DR EMBL; AF061812; AAC99326.1; -; mRNA.
DR EMBL; AK290853; BAF83542.1; -; mRNA.
DR EMBL; CH471152; EAW60749.1; -; Genomic_DNA.
DR EMBL; BC039169; AAH39169.1; -; mRNA.
DR EMBL; S78514; AAB34564.1; -; Genomic_DNA.
DR PIR; A33652; A33652.
DR PIR; JC4313; JC4313.
DR RefSeq; NP_005548.2; NM_005557.3.
DR UniGene; Hs.655160; -.
DR ProteinModelPortal; P08779; -.
DR SMR; P08779; 167-265, 281-423.
DR IntAct; P08779; 10.
DR MINT; MINT-1145021; -.
DR STRING; 9606.ENSP00000301653; -.
DR PhosphoSite; P08779; -.
DR DMDM; 23503075; -.
DR PaxDb; P08779; -.
DR PeptideAtlas; P08779; -.
DR PRIDE; P08779; -.
DR DNASU; 3868; -.
DR Ensembl; ENST00000301653; ENSP00000301653; ENSG00000186832.
DR GeneID; 3868; -.
DR KEGG; hsa:3868; -.
DR UCSC; uc002hxg.4; human.
DR CTD; 3868; -.
DR GeneCards; GC17M039766; -.
DR H-InvDB; HIX0059709; -.
DR H-InvDB; HIX0136649; -.
DR H-InvDB; HIX0173645; -.
DR HGNC; HGNC:6423; KRT16.
DR HPA; CAB000136; -.
DR MIM; 144200; phenotype.
DR MIM; 148067; gene.
DR MIM; 167200; phenotype.
DR MIM; 613000; phenotype.
DR neXtProt; NX_P08779; -.
DR Orphanet; 2199; Epidermolytic palmoplantar keratoderma.
DR Orphanet; 2309; Pachyonychia congenita.
DR PharmGKB; PA30210; -.
DR eggNOG; NOG148784; -.
DR HOGENOM; HOG000230975; -.
DR HOVERGEN; HBG013015; -.
DR InParanoid; P08779; -.
DR KO; K07604; -.
DR OMA; HASGQSY; -.
DR OrthoDB; EOG7FV3Q8; -.
DR PhylomeDB; P08779; -.
DR GeneWiki; Keratin_16; -.
DR GenomeRNAi; 3868; -.
DR NextBio; 15205; -.
DR PRO; PR:P08779; -.
DR ArrayExpress; P08779; -.
DR Bgee; P08779; -.
DR CleanEx; HS_KRT16; -.
DR Genevestigator; P08779; -.
DR GO; GO:0005882; C:intermediate filament; NAS:UniProtKB.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; NAS:UniProtKB.
DR GO; GO:0008283; P:cell proliferation; TAS:ProtInc.
DR GO; GO:0007010; P:cytoskeleton organization; NAS:UniProtKB.
DR GO; GO:0008544; P:epidermis development; TAS:ProtInc.
DR GO; GO:0045104; P:intermediate filament cytoskeleton organization; IEA:Ensembl.
DR InterPro; IPR001664; IF.
DR InterPro; IPR018039; Intermediate_filament_CS.
DR InterPro; IPR002957; Keratin_I.
DR PANTHER; PTHR23239; PTHR23239; 1.
DR Pfam; PF00038; Filament; 1.
DR PRINTS; PR01248; TYPE1KERATIN.
DR PROSITE; PS00226; IF; 1.
PE 1: Evidence at protein level;
KW Coiled coil; Complete proteome; Direct protein sequencing;
KW Disease mutation; Ectodermal dysplasia; Intermediate filament;
KW Keratin; Palmoplantar keratoderma; Reference proteome.
FT CHAIN 1 473 Keratin, type I cytoskeletal 16.
FT /FTId=PRO_0000063662.
FT REGION 1 116 Head.
FT REGION 117 424 Rod.
FT REGION 117 152 Coil 1A.
FT REGION 153 170 Linker 1.
FT REGION 171 262 Coil 1B.
FT REGION 263 285 Linker 12.
FT REGION 286 424 Coil 2.
FT REGION 425 473 Tail.
FT VARIANT 104 107 Missing (in UPVN; somatic mutation).
FT /FTId=VAR_012854.
FT VARIANT 121 121 M -> T (in PC1; dbSNP:rs28928894).
FT /FTId=VAR_017065.
FT VARIANT 122 122 Q -> P (in PC1; dbSNP:rs59349773).
FT /FTId=VAR_012855.
FT VARIANT 124 124 L -> R (in PC1; dbSNP:rs58293603).
FT /FTId=VAR_013837.
FT VARIANT 125 125 N -> S (in FNEPPK; dbSNP:rs60723330).
FT /FTId=VAR_009183.
FT VARIANT 127 127 R -> C (in FNEPPK; dbSNP:rs59856285).
FT /FTId=VAR_009184.
FT VARIANT 127 127 R -> P (in PC1; dbSNP:rs57424749).
FT /FTId=VAR_012856.
FT VARIANT 128 128 L -> Q (in PC1; dbSNP:rs28928895).
FT /FTId=VAR_017066.
FT VARIANT 130 130 Missing (in PC1).
FT /FTId=VAR_035440.
FT VARIANT 132 132 L -> P (in PC1; dbSNP:rs60944949).
FT /FTId=VAR_003846.
FT VARIANT 354 354 K -> N (in PC1; late onset;
FT dbSNP:rs59328451).
FT /FTId=VAR_017067.
FT CONFLICT 2 2 T -> A (in Ref. 3; AAB35421).
FT CONFLICT 26 26 G -> A (in Ref. 1; AAA59460).
FT CONFLICT 38 38 G -> A (in Ref. 1; AAA59460).
FT CONFLICT 41 43 RAP -> PA (in Ref. 1; AAA59460).
FT CONFLICT 49 50 GL -> A (in Ref. 1; AAA59460).
FT CONFLICT 187 189 QPI -> HAL (in Ref. 1; AAA59460).
FT CONFLICT 208 211 HELA -> ARTG (in Ref. 1; AAA59460).
FT CONFLICT 352 352 S -> R (in Ref. 1; AAA59460).
FT CONFLICT 452 460 SRQTRPILK -> AVRPGPSS (in Ref. 1;
FT AAA59460).
SQ SEQUENCE 473 AA; 51268 MW; BA8CE9F4716A88A4 CRC64;
MTTCSRQFTS SSSMKGSCGI GGGIGGGSSR ISSVLAGGSC RAPSTYGGGL SVSSRFSSGG
ACGLGGGYGG GFSSSSSFGS GFGGGYGGGL GAGFGGGLGA GFGGGFAGGD GLLVGSEKVT
MQNLNDRLAS YLDKVRALEE ANADLEVKIR DWYQRQRPSE IKDYSPYFKT IEDLRNKIIA
ATIENAQPIL QIDNARLAAD DFRTKYEHEL ALRQTVEADV NGLRRVLDEL TLARTDLEMQ
IEGLKEELAY LRKNHEEEML ALRGQTGGDV NVEMDAAPGV DLSRILNEMR DQYEQMAEKN
RRDAETWFLS KTEELNKEVA SNSELVQSSR SEVTELRRVL QGLEIELQSQ LSMKASLENS
LEETKGRYCM QLSQIQGLIG SVEEQLAQLR CEMEQQSQEY QILLDVKTRL EQEIATYRRL
LEGEDAHLSS QQASGQSYSS REVFTSSSSS SSRQTRPILK EQSSSSFSQG QSS
//

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

DESCRIPTION

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

- Genetic Heterogeneity of Palmoplantar Keratoderma

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

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

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

NOMENCLATURE

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

CLINICAL FEATURES

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

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

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

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

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

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

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

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

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

- Unilateral Palmoplantar Verrucous Nevus

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

- Epidermolytic Palmoplantar Keratoderma Associated With Knuckle
Pads

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

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

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

INHERITANCE

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

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

POPULATION GENETICS

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

MAPPING

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

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

- Heterogeneity

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

MOLECULAR GENETICS

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

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

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

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

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

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

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

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

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

GENOTYPE/PHENOTYPE CORRELATIONS

Both epidermolytic and nonepidermolytic forms of palmoplantar
keratoderma have been observed with various mutations in the KRT1 gene
(139350). Kimonis et al. (1994) suggested that the specific region of
the keratin protein affected by mutation might be a major determining
factor in the different clinical and histologic consequences. Mutations
of the KRT1 and KRT9 genes that are associated with the epidermolytic
form of PPK affect the central regions of the protein that are important
for filament assembly and stability, and for that reason lead to
cellular degeneration or disruption. On the other hand, the mutation of
the KRT1 gene (139350.0004) that Kimonis et al. (1994) found in
association with nonepidermolytic PPK (600962) was located in the
amino-terminal variable end region, which may be involved in
supramolecular interactions of keratin filaments rather than stability.

*FIELD* SA
Chung (1937); Klintworth and Anderson (1961); Torchard et al. (1994)
*FIELD* RF
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10. Covello, S. P.; Irvine, A. D.; McKenna, K. E.; Munro, C. S.; Nevin,
N. C.; Smith, F. J. D.; Uitto, J.; McLean, W. H. I.: Mutations in
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13. Goette, D. K.: Familial congenital epidermolytic hyperkeratosis
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15. Hatsell, S. J.; Eady, R. A.; Wennerstrand, L.; Dopping-Hepenstal,
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16. Hennies, H.-C.; Kuster, W.; Mischke, D.; Reis, A.: Localization
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*FIELD* CS
INHERITANCE:
Autosomal dominant

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

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

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

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

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

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

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

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

MIM 148067
*RECORD*
*FIELD* NO
148067
*FIELD* TI
*148067 KERATIN 16; KRT16
;;K16
*FIELD* TX

DESCRIPTION

KRT16 belongs to a large group of acidic type I keratins that interact
read morewith basic type II keratins to form the 8-nm cytoskeletal filaments of
epithelial cells. Both type I and type II keratins have a central
alpha-helical domain of over 300 amino acids that mediates keratin
interaction. KRT16 is constitutively expressed in most stratified
squamous epithelia, but it is only transiently expressed in epidermis
during hyperproliferation (summary by Albers and Fuchs (1987) and
Rosenberg et al. (1988)).

CLONING

Rosenberg et al. (1988) obtained a genomic clone containing the human
K16 gene. The predicted 472-amino acid K16 protein contains a large
alpha-helical domain. Northern blot analysis detected a 1.6-kb K16
transcript in cultured human epidermal cells and in a squamous cell
carcinoma cell line. K16 had an apparent molecular mass of 48 kD by
SDS-PAGE.

Paladini et al. (1995) cloned keratin-16 by applying RT-PCR on total RNA
extracted from cultured primary human epidermal keratinocytes. The KRT16
cDNA encodes a deduced 473-amino acid protein with a calculated
molecular mass of 48 kD. The protein shares strong sequence homology
with the type I keratins KRT14 (148066) and KRT17 (148069).

Langbein et al. (2005) examined the expression of several keratins in
eccrine sweat gland and in plantar epidermis. In the sweat gland, KRT16
was expressed throughout the duct region and also in the deeper
secretory portion of the gland. In plantar epidermis, KRT16 was
expressed only in the basal layer and in the lower suprabasal layer.

GENE STRUCTURE

Rosenberg et al. (1988) determined that the KRT16 gene contains 8 exons.

MAPPING

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

MOLECULAR GENETICS

In a sporadic case of the Jadassohn-Lewandowsky type of pachyonychia
congenita (167200), McLean et al. (1995) identified heterozygosity for a
leu132-to-pro mutation (148067.0001) in the helix initiation peptide of
keratin-16.

Shamsher et al. (1995) identified mutations in the helix initiation
domain of the KRT16 gene (148067.0002-148067.0003) in 2 unrelated
families with focal nonepidermolytic palmoplantar keratoderma (FNEPPK;
613000). These mutations did not appear to cause epidermolysis on light
or electron microscopy, which may reflect differences in function,
assembly, or interaction of the 'hyperproliferative' or
'mucoregenerative' keratins from other major types of keratins.

The helix initiation motif (HIM) of KRT16 is a short sequence of about
20 amino acids at the start of the central alpha-helical rod domain
whose sequence is conserved in all type I or acidic keratins. Most
strongly dominant-negative mutations in keratins have been found to be
missense (or occasionally in-frame deletion) mutations in this sequence
or the equivalent sequence at the end of the rod domain, the helix
termination motif (McLean, 1997). The helix initiation motif of KRT16 is
KVTMQNLNDRLASYLDKA. It is the practice of keratin researchers to refer
to mutations by the number of the amino acid affected in the helix 1A
domain. Thus, the first mutation to be identified (148067.0001) can
alternatively be designated leu132-to-pro or leu15-to-pro.

McLean (1997) pointed out that 2 families studied by Shamsher et al.
(1995) had mild nail changes similar to those that occur in a much more
severe form in pachyonychia congenita. McLean (1997) concluded that
expression of the nail dystrophy in addition to the palmoplantar
keratoderma is not dependent on the specific mutation, as this has been
found to vary greatly within large families. Phenotype seems to vary
greatly in all keratin diseases, even among persons with the same
mutation, so there are probably modifier genes and/or environmental
influences yet to be defined.

In a father and son with classic PC1 and a 3-generation family with mild
focal NEPPK, Smith et al. (2000) identified a heterozygous mutation
(L124R; 148067.0007) and a complex deletion (148067.0011) in the KRT16
gene, respectively. The authors noted that the deletion, which removes a
K16 helix termination motif, unexpectedly resulted in a relatively mild
phenotype. Studies in cultured epithelial cells demonstrated morphologic
differences in the K16 aggregates produced by the missense and the
deletion mutations; in addition, the L124R mutation appeared to cause
complete collapse of the endogenous filament network, whereas some
residual filamentous keratin was seen in cells expressing the deletion,
implying that the deleted K16 may be less capable of disrupting keratin
filaments by dominant-negative interference compared to the L124R
mutation.

*FIELD* AV
.0001
PACHYONYCHIA CONGENITA, TYPE 1
KRT16, LEU132PRO

In a sporadic case of the Jadassohn-Lewandowsky type of pachyonychia
congenita (167200), McLean et al. (1995) identified heterozygosity for a
leu132-to-pro (L130P) mutation in the helix initiation motif of
keratin-16. An alternative designation for this mutation is L15P.

.0002
PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC, FOCAL
KRT16, ARG127CYS

In a 4-generation family with focal nonepidermolytic palmoplantar
keratoderma (FNEPPK; 613000), previously studied by Stevens et al.
(1994), in which affected individuals also had follicular and orogenital
hyperkeratosis, Shamsher et al. (1995) identified heterozygosity for an
arg127-to-cys (R127C) substitution in the KRT16 gene at a highly
conserved residue in the helix initiation motif of the 1A domain. The
mutation was not found in unaffected family members or 20 controls. An
alternative designation for this mutation is R10C.

.0003
PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC, FOCAL
KRT16, ASN125SER

In a father and daughter with focal nonepidermolytic palmoplantar
keratoderma (FNEPPK; 613000), who also had follicular and orogenital
hyperkeratosis, Shamsher et al. (1995) identified heterozygosity for an
asn125-to-ser (N125S) substitution in the KRT16 gene at a highly
conserved residue in the helix initiation motif of the 1A domain. The
mutation was not found in 20 controls. An alternative designation for
this mutation is N8S.

.0004
PACHYONYCHIA CONGENITA, TYPE 1
KRT16, 3-BP DEL, NT388

In a sporadic case of pachyonychia congenita type 1 (167200), Smith et
al. (1999) identified heterozygosity for a 3-bp deletion (388del3) in
the KRT16 gene, resulting in deletion of ser130. Using a genomic PCR
system, they carried out the first prenatal diagnosis of this disorder
using CVS material and correctly predicted a normal fetus.

.0005
PACHYONYCHIA CONGENITA, TYPE 1
KRT16, ARG127PRO

In a family of Dutch origin with pachyonychia congenita type 1 (167200),
Smith et al. (1999) identified a heterozygous G-to-C transversion at
nucleotide 380 of the KRT16 gene, resulting in an arg127-to-pro (R127P)
amino acid change, using a novel long-range PCR strategy that eliminated
amplification of KRT16 pseudogenes. This mutation affected the helix 1A
domain of the KRT16 polypeptide.

.0006
PACHYONYCHIA CONGENITA, TYPE 1
KRT16, GLN122PRO

In a family of Hungarian origin with pachyonychia congenita type 1
(167200), Smith et al. (1999) identified a heterozygous A-to-C
transversion at nucleotide 365 of the KRT16 gene, resulting in a
gln122-to-pro (Q122P) amino acid change, using a novel long-range PCR
strategy that eliminated amplification of KRT16 pseudogenes. This
mutation affected the helix 1A domain of the KRT16 polypeptide.

.0007
PACHYONYCHIA CONGENITA, TYPE 1
KRT16, LEU124ARG

In a father and son with pachyonychia congenita type 1 (167200), Smith
et al. (2000) identified heterozygosity for a 371T-G transversion in the
KRT16 gene, resulting in a leu124-to-arg (L124R) substitution in the 1A
domain of the K16 polypeptide. The mutation was not found in 50
unrelated controls. Expression of mutant K16 in the PtK2 epithelial cell
line produced complete collapse of the endogenous keratin cytoskeleton
into dense aggregates.

.0008
PACHYONYCHIA CONGENITA TARDA, TYPE 1
KRT16, LYS354ASN

In a girl with late-onset pachyonychia congenita tarda type 1 (167200),
Connors et al. (2001) reported a lys354-to-asn (K354N) mutation in the
central 2B domain of the KRT16 polypeptide. The amino acid substitution
resulted from a 1062A-T transversion in exon 6. The authors noted that
this was the first time a mutation had been described in this location
in a keratin other than KRT14. KRT14 mutations in region 2B (e.g.,
148066.0005 and 148066.0012) result in milder phenotypes. It was unclear
whether the position of the mutation was sufficient to explain the
late-onset PC phenotype.

.0009
PACHYONYCHIA CONGENITA, TYPE 1
KRT16, MET121THR

In a patient with sporadic pachyonychia congenita type 1 (167200),
Terrinoni et al. (2001) reported a met121-to-thr (M121T) mutation in the
KRT16 protein that arose from a 362T-C transition. This mutation in the
1A domain is also referred to as M4T.

.0010
PACHYONYCHIA CONGENITA, TYPE 1
KRT16, LEU128GLN

In a patient with sporadic pachyonychia congenita type 1 (167200),
Terrinoni et al. (2001) reported a leu128-to-gln (L128Q) mutation in the
KRT16 protein that arose from a 383T-A transversion. This mutation in
the 1A domain is also referred to as L11Q.

.0011
PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC, FOCAL
KRT16, 23-BP DEL, NT1244 AND 1-BP DEL, 1270G

In a 3-generation family with mild focal nonepidermolytic palmoplantar
keratoderma (FNEPPK; 613000), Smith et al. (2000) identified
heterozygosity for a complex deletion in exon 6 of the KRT16 gene,
involving a 23-bp deletion (1244del23) together with a 1-bp deletion
downstream (1270delG), resulting in a deletion of 8 residues and a
substitution of 2 residues in the conserved helix termination motif
(HTM) of the K16 polypeptide. Expression of the deleted K16 in the PtK2
epithelial cell line produced aggregates larger than those seen with an
L124R mutation (148067.0007), and some residual endogenous keratin was
seen in filamentous form, implying that the deletion mutation may render
the mutant K16 protein less able to integrate into and disrupt the
endogenous network, thus resulting in a milder phenotype.

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

2. Connors, J. B.; Rahil, A. K.; Smith, F. J. D.; McLean, W. H. I.;
Milstone, L. M.: Delayed-onset pachyonychia congenita associated
with a novel mutation in the central 2B domain of keratin 16. Brit.
J. Derm. 144: 1058-1062, 2001.

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

4. McLean, W. H. I.: Personal Communication. Philadelphia, Pa.
2/26/1997.

5. McLean, W. H. I.; Rugg, E. L.; Lunny, D. P.; Morley, S. M.; Lane,
E. B.; Swensson, O.; Dopping-Hepenstal, P. J. C.; Griffiths, W. A.
D.; Eady, R. A. J.; Higgins, C.; Navsaria, H. A.; Leigh, I. M.; Strachan,
T.; Kunkeler, L.; Munro, C. S.: Keratin 16 and keratin 17 mutations
cause pachyonychia congenita. Nature Genet. 9: 273-278, 1995.

6. Paladini, R. D.; Takahashi, K.; Gant, T. M.; Coulombe, P. A.:
cDNA cloning and bacterial expression of the human type I keratin
16. Biochem. Biophys. Res. Commun. 215: 517-523, 1995.

7. 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.

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

9. Shamsher, M. K.; Navsaria, H. A.; Stevens, H. P.; Ratnavel, R.
C.; Purkis, P. E.; McLean, W. H.; Cook. L. J.; Griffiths, W. A. D.;
Geschmeissner, S.; Spurr, N.; Leigh, I. M.: Novel mutations in keratin
16 gene underly focal nonepidermolytic palmoplantar keratoderma (NEPPK)
in two families. Hum. Mol. Genet. 4: 1875-1881, 1995.

10. Smith, F. J. D.; Del Monaco, M.; Steijlen, P. M..; Munro, C. S..;
Morvay, M.; Coleman, C. M.; Rietveld, F. J. R.; Uitto, J.; McLean,
W. H. I.: Novel proline substitution mutations in keratin 16 in two
cases of pachyonychia congenita type 1. Brit. J. Derm. 141: 1010-1016,
1999.

11. Smith, F. J. D.; Fisher, M. P.; Healy, E.; Rees, J. L.; Bonifas,
J. M.; Epstein, E. H., Jr.; Tan, E. M. L.; Uitto, J.; McLean, W. H.
I.: Novel keratin 16 mutations and protein expression studies in
pachyonychia congenita type 1 and focal palmoplantar keratoderma. Exp.
Derm. 9: 170-177, 2000.

12. Smith, F. J. D.; McKusick, V. A.; Nielsen, K.; Pfendner, E.; Uitto,
J.; McLean, W. H. I.: Cloning of multiple keratin 16 genes facilitates
prenatal diagnosis of pachyonychia congenita type 1. Prenatal Diag. 19:
941-946, 1999.

13. Stevens, H. P.; Kelsell, D. P.; Spurr, N. K.; Bishop, D. T.; Purkis,
P. E.; Griffiths, W. A. D.; Rustin, M. H. A.; Leigh, I. M.: Keratin
staining and linkage of non-epidermolytic focal palmoplantar keratodermas
(PPK) to 17q. (Abstract) Brit. J. Derm. 131: 425, 1994.

14. Terrinoni, A.; Smith, F. J. D.; Didona, B.; Canzona, F.; Paradisi,
M.; Huber, M.; Hohl, D.; David, A.; Verloes, A.; Leigh, I. M.; Munro,
C. S.; Melino, G.; McLean, W. H. I.: Novel and recurrent mutations
in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia
congenita. J. Invest. Derm. 117: 1391-1396, 2001.

*FIELD* CN
Marla J. F. O'Neill - updated: 5/11/2010
Patricia A. Hartz - updated: 11/19/2009
Marla J. F. O'Neill - updated: 8/12/2009
Marla J. F. O'Neill - updated: 7/10/2009
Patricia A. Hartz - updated: 6/22/2007
Victor A. McKusick - updated: 2/22/2005
Gary A. Bellus - updated: 4/28/2003
Gary A. Bellus - updated: 3/13/2003
Gary A. Bellus - updated: 4/18/2002
Gary A. Bellus - updated: 4/12/2000
Victor A. McKusick - updated: 1/19/2000
Victor A. McKusick - updated: 3/28/1997

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

*FIELD* ED
wwang: 05/11/2010
terry: 5/11/2010
mgross: 12/2/2009
terry: 11/19/2009
wwang: 9/3/2009
terry: 8/12/2009
terry: 7/13/2009
carol: 7/10/2009
wwang: 7/2/2007
terry: 6/22/2007
carol: 4/18/2006
carol: 1/17/2006
wwang: 3/9/2005
terry: 2/22/2005
alopez: 4/28/2003
alopez: 3/27/2003
alopez: 3/13/2003
alopez: 3/10/2003
alopez: 4/18/2002
alopez: 4/12/2000
carol: 1/28/2000
mcapotos: 1/27/2000
mcapotos: 1/24/2000
terry: 1/19/2000
terry: 5/29/1998
alopez: 7/29/1997
terry: 7/7/1997
mark: 4/14/1997
terry: 3/28/1997
terry: 3/18/1997
terry: 3/26/1996
mark: 1/5/1996
mark: 1/4/1996
mark: 6/26/1995
carol: 3/15/1995
mimadm: 4/29/1994
warfield: 4/12/1994
supermim: 3/16/1992
carol: 10/9/1991

MIM 167200
*RECORD*
*FIELD* NO
167200
*FIELD* TI
#167200 PACHYONYCHIA CONGENITA, TYPE 1; PC1
;;PACHYONYCHIA CONGENITA, JADASSOHN-LEWANDOWSKY TYPE;;
read moreJADASSOHN-LEWANDOWSKY SYNDROME
PACHYONYCHIA CONGENITA TARDA, TYPE 1, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
pachyonychia congenita type 1 (PC1) can be caused by heterozygous
mutation in the keratin-16 gene (KRT16; 148067) on chromosome 17 or in
the keratin-6A gene (KRT6A; 148041) on chromosome 12.

Pachyonychia congenita type 2, or the Jackson-Lawler (PC2; 167210), can
be caused by mutation in the KRT17 gene (148069) on chromosome 17 or in
the KRT6B gene (148042) on chromosome 12.

See 260130 for a possible autosomal recessive form of pachyonychia
congenita.

CLINICAL FEATURES

Pachyonychia congenita is characterized by onychogryposis,
hyperkeratosis of the palms, soles, knees and elbows, tiny cutaneous
horns in many areas, and leukoplakia of the oral mucous membranes.
Hyperhidrosis of the hands and feet is usually present. Murray (1921)
found 7 affected in 3 generations. Kumer and Loos (1935) found 24
affected in 5 generations. McKusick (1971) observed an apparent new
mutation with transmission from father to son in a Jewish family.

Laryngeal changes requiring tracheostomy for respiratory distress during
childhood were reported by Stieglitz and Centerwall (1983) in father and
son. Feinstein et al. (1988) classified 168 reported cases into 4 types,
of which type IV, present in 7.2% of the cases, had laryngeal lesions,
hoarseness, mental retardation, hair anomalies, and alopecia. Paller et
al. (1991) described a late-onset form in which typical subungual
hyperkeratoses began during the teenage years. Leukokeratosis and
keratoderma of the palms and soles were associated. The family history
of 3 of the 5 patients was consistent with autosomal dominant
inheritance.

Gorlin et al. (1976) suggested that 2 distinct syndromes are subsumed
under the designation pachyonychia congenita. PC1, the
Jadassohn-Lewandowsky type, shows oral leukokeratosis. PC2, the Jackson
and Lawler type, has natal teeth and epidermoid cysts (cylindromas), but
no oral leukoplakia. Corneal dystrophy may be a feature exclusively of
the Jackson-Lawler type. Both disorders are clearly autosomal dominant.

On the basis of a study of 13 patients with PC1 or PC2, Terrinoni et al.
(2001) concluded that the presence of pilosebaceous cysts following
puberty is the best indicator of PC2; prepubescent patients are more
difficult to classify due to the lack of cysts. Natal teeth are
indicative of PC2, although their absence does not preclude the PC2
diagnosis.

Leachman et al. (2005) analyzed clinical, pathologic, and genetic data
from the literature in 2 research registries. They found that more than
97% of PC cases exhibited fingernail and toenail thickening, and painful
plantar keratoderma. Prospective evaluation of 57 PC patients from 41
families revealed variable clinical findings: hyperhidrosis (79%), oral
leukokeratosis (75%), follicular keratosis (65%), palmar keratoderma
(60%), cutaneous cysts (35%), hoarseness or laryngeal involvement (16%),
coarse or twisted hair (26%), early primary tooth loss (14%), and
presence of natal or prenatal teeth (2%). Stratification of these data
by keratin mutation confirmed the increased incidence of cyst formation
and natal teeth among PC2 patients, although cysts were more commonly
seen in PC1 patients than had previously reported (25-33%). Previously
unreported clinical features of PC included development of painful oral
and nipple lesions during breastfeeding, copious production of waxy
material in ears, and inability to walk without an ambulatory aid (50%).

- Pachyonychia Congenita Tarda, Type 1

Pachyonychia congenita with late onset of symptoms has been described by
several authors (Paller et al., 1991; Iraci et al., 1993; Lucker and
Steijlen, 1995; Mouaci-Midoun et al., 1996; Hannaford and Stapleton,
2000) and has been referred to as pachyonychia congenita tarda. There
has been some debate as to whether these late-onset cases represent a
separate genetic syndrome or a variant form of PC1. Connors et al.
(2001) described a young girl with clinical features of pachyonychia
congenita type 1 that was unusual in that the typical skin and nail
changes were not noted until the age of 6 years. Direct sequencing of
the KRT16 gene revealed a novel lys354 to asn mutation (K354N;
148067.0008) in the central 2B domain of the KRT16 polypeptide.
Mutations in this region of KRT16 had not been described, but had been
described in homologous regions of KRT14 (148066) in the milder Koebner
(131900) and Weber-Cockayne (131800) variants of epidermolysis simplex.
It was unclear whether the position of the mutation was sufficient to
explain the late-onset phenotype.

DIAGNOSIS

- Prenatal Diagnosis

Using a genomic PCR system, Smith et al. (1999) carried out the first
prenatal diagnosis of Jadassohn-Lewandowsky syndrome using CVS material
and correctly predicted a normal fetus.

MOLECULAR GENETICS

In a sporadic case of pachyonychia congenita type 1, Smith et al. (1999)
identified heterozygosity for a 3-bp deletion (148067.0001) in the KRT16
gene.

In affected members of a Slovenian family segregating PC1, Bowden et al.
(1995) identified heterozygosity for a 3-bp deletion in the KRT6A gene
(148041.0001).

*FIELD* SA
Akesson (1967); Cohn et al. (1976); Franzot et al. (1981); Jadassohn
and Lewandowsky (1906); Joseph (1964); Witkop and Gorlin (1961)
*FIELD* RF
1. Akesson, H. O.: Pachyonychia congenita in six generations. Hereditas 58:
103-110, 1967.

2. Bowden, P. E.; Haley, J. L.; Kansky, A.; Rothnagel, J. A.; Jones,
D. O.; Turner, R. J.: Mutation of a type II keratin gene (K6a) in
pachyonychia congenita. Nature Genet. 10: 363-365, 1995.

3. Cohn, A. M.; McFarlane, J. F.; Knox, J.: Pachyonychia congenita
with involvement of the larynx. Arch. Otolaryng. 102: 233-235, 1976.

4. Connors, J. B.; Rahil, A. K.; Smith, F. J. D.; McLean, W. H. I.;
Milstone, L. M.: Delayed-onset pachyonychia congenita associated
with a novel mutation in the central 2B domain of keratin 16. Brit.
J. Derm. 144: 1058-1062, 2001.

5. Feinstein, A.; Friedman, J.; Schewach-Millet, M.: Pachyonychia
congenita. J. Am. Acad. Derm. 19: 705-711, 1988.

6. Franzot, J.; Kansky, A.; Kavcic, S.: Pachyonychia congenita (Jadassohn-Lewandowsky
syndrome): a review of 14 cases in Slovenia. Dermatologica 160:
462-472, 1981.

7. Gorlin, R. J.; Pindborg, J. J.; Cohen, M. M., Jr.: Syndromes of
the Head and Neck. New York: McGraw-Hill (pub.) (2nd ed.): 1976.
Pp. 600-603.

8. Hannaford, R. S.; Stapleton, K.: Pachyonychia congenita tarda. Australas.
J. Derm. 41: 175-177, 2000.

9. Iraci, S.; Bianchi, L.; Gatti, S.; Carrozzo, A. M.; Bettini, D.;
Nini, G.: Pachyonychia congenita with late onset of nail dystrophy--a
new clinical entity? Clin. Exp. Derm. 18: 478-480, 1993.

10. Jadassohn, J.; Lewandowsky, F.: Pachyonychia congenita.In: Jacobs
Ikonographia Dermatologica. Berlin: Urban and Schwarzenberg (pub.)
1: 1906. P. 29.

11. Joseph, H. L.: Pachyonychia congenita. Arch. Derm. 90: 594-603,
1964.

12. Kumer, L.; Loos, H. O.: Ueber Pachyonychia congenita (Typus Riehl). Wien.
Klin. Wschr. 48: 174-178, 1935.

13. Leachman, S. A.; Kaspar, R. L.; Fleckman, P.; Florell, S. R.;
Smith, F. J. D.; McLean, W. H. I.; Lunny, D. P.; Milstone, L. M.;
van Steensel, M. A. M.; Munro, C. S.; O'Toole, E. A.; Celebi, J. T.;
Kansky, A.; Lane, E. B.: Clinical and pathological features of pachyonychia
congenita. J. Invest. Derm. Symp. Proc. 10: 3-17, 2005.

14. Lucker, G. P. H.; Steijlen, P. M.: Pachyonychia congenita tarda. Clin.
Exp. Derm. 20: 226-229, 1995.

15. McKusick, V. A.: Pachyonychia congenita in father and son. Birth
Defects Orig. Art. Ser. VII(8): 274-275, 1971.

16. Mouaci-Midoun, N.; Cambiaghi, S.; Abimelec, P.: Pachyonychia
congenita tarda. J. Am. Acad. Derm. 35: 334-335, 1996.

17. Murray, F. A.: Congenital anomalies of the nails. Four cases
of hereditary hypertrophy of the nail bed associated with a history
of erupted teeth at birth. Brit. J. Derm. 33: 409-412, 1921.

18. Paller, A. S.; Moore, J. A.; Scher, R.: Pachyonychia congenita
tarda: a late-onset form of pachyonychia congenita. Arch. Derm. 127:
701-703, 1991.

19. Smith, F. J. D.; McKusick, V. A.; Nielsen, K.; Pfendner, E.; Uitto,
J.; McLean, W. H. I.: Cloning of multiple keratin 16 genes facilitates
prenatal diagnosis of pachyonychia congenita type 1. Prenatal Diag. 19:
941-946, 1999.

20. Stieglitz, J. B.; Centerwall, W. R.: Pachyonychia congenita (Jadassohn-Lewandowsky
syndrome): a seventeen-member, four-generation pedigree with unusual
respiratory and dental involvement. Am. J. Med. Genet. 14: 21-28,
1983.

21. Terrinoni, A.; Smith, F. J. D.; Didona, B.; Canzona, F.; Paradisi,
M.; Huber, M.; Hohl, D.; David, A.; Verloes, A.; Leigh, I. M.; Munro,
C. S.; Melino, G.; McLean, W. H. I.: Novel and recurrent mutations
in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia
congenita. J. Invest. Derm. 117: 1391-1396, 2001.

22. Witkop, C. J., Jr.; Gorlin, R. J.: Four hereditary mucosal syndromes. Arch.
Derm. 84: 762-771, 1961.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Mouth];
Oral leukokeratosis

SKIN, NAILS, HAIR:
[Skin];
Palmoplantar hyperkeratosis;
Follicular hyperkeratosis;
[Nails];
Onychogryposis

MISCELLANEOUS:
Genetic heterogeneity

MOLECULAR BASIS:
Caused by mutation in the keratin 16 gene (KRT16, 148067.0001);
Caused by mutation in the keratin 6A gene (KRT6A, 148041.0001)

*FIELD* CN
Kelly A. Przylepa - revised: 03/08/2008

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

*FIELD* ED
joanna: 03/08/2008

*FIELD* CN
Victor A. McKusick - updated: 1/17/2006
Gary A. Bellus - updated: 4/23/2003
Victor A. McKusick - updated: 3/13/1998
Victor A. McKusick - updated: 3/25/1997

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

*FIELD* ED
carol: 01/10/2014
carol: 7/8/2013
alopez: 7/3/2013
terry: 4/30/2010
terry: 12/16/2009
carol: 2/11/2009
carol: 4/18/2006
carol: 1/17/2006
terry: 1/17/2006
carol: 6/23/2005
cwells: 11/7/2003
tkritzer: 9/29/2003
alopez: 4/23/2003
alopez: 4/12/2000
carol: 1/28/2000
carol: 7/29/1998
alopez: 5/5/1998
alopez: 3/13/1998
terry: 3/10/1998
alopez: 3/25/1997
terry: 3/18/1997
terry: 6/30/1995
carol: 3/15/1995
mimadm: 1/14/1995
pfoster: 4/1/1994
warfield: 3/3/1994
supermim: 3/16/1992

MIM 613000
*RECORD*
*FIELD* NO
613000
*FIELD* TI
#613000 PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC, FOCAL; FNEPPK
;;FOCAL NONEPIDERMOLYTIC PALMOPLANTAR KERATODERMA;;
read moreKERATODERMA, FOCAL NONEPIDERMOLYTIC PALMOPLANTAR
*FIELD* TX
A number sign (#) is used with this entry because of evidence that focal
nonepidermolytic palmoplantar keratoderma (FNEPPK) is caused by
heterozygous mutation in the KRT16 gene (148067) on chromosome 17q.

Focal forms of PPK associated with esophageal carcinoma (TOC; 148500)
and with gingival hyperplasia (148730) have been described.

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

CLINICAL FEATURES

Stevens et al. (1994) studied one 2-generation and two 3-generation
families in which focal NEPPK segregated as an autosomal dominant with
an age of onset of 6 to 7 years. Affected individuals developed large,
hard, compact painful masses of keratin at sites of recurrent friction
on the feet and hands. Blistering occurred in hot weather upon walking
approximately 1 mile. The onychocorenal band was widened with multiple
splinter hemorrhages, keratosis pilaris was seen on the arms and legs,
and a whitish opalescence over the hard palate, buccal mucosa, and glans
penis of circumcised males.

Kelsell et al. (1995) reported a large 4-generation Caucasian pedigree
segregating autosomal dominant focal NEPPK associated with orogenital
hyperkeratosis. Patients presented at 6 to 7 years of age with
development of large, hard, compact painful masses of keratin,
particularly on the soles and other areas of repeated mechanical trauma.
Skin biopsies from 2 affected individuals confirmed the nonepidermolytic
pattern of PPK.

Smith et al. (2000) examined 6 affected members from a 3-generation
family with mild FNEPPK, in which the keratoderma was confined to the
weight-bearing areas of the soles, with no evidence of palmar
keratoderma, nail changes, or oral leukokeratosis. Histologic analysis
of a plantar skin biopsy showed no signs of epidermolysis, consistent
with the diagnosis of FNEPPK.

MAPPING

In a multigenerational family with autosomal dominant focal NEPPK,
Stevens et al. (1994) performed segregation analysis using markers
flanking the keratin gene clusters at chromosomes 12q and 17q; they
excluded linkage to chromosome 12q, but obtained a Z-score of 3.2 (theta
= 0.0) on chromosome 17q12-q21.

In a large, 4-generation Caucasian pedigree with focal NEPPK, Kelsell et
al. (1995) excluded linkage to markers on chromosome 12q11-q12, but
obtained a lod score of 3.25 on chromosome 17q12-q21 with 3-point
analysis involving a microsatellite marker within intron 4 of the KRT9
gene (607606) and D17S855 (theta = 0.0).

MOLECULAR GENETICS

In 2 families with identical clinical phenotypes of focal NEPPK with
follicular and orogenital hyperkeratosis, 1 of which was the large
multigenerational family with linkage to chromosome 17q12-q21 previously
studied by Stevens et al. (1994), Shamsher et al. (1995) sequenced the
KRT16 gene and identified heterozygosity for 2 different missense
mutations in affected individuals (148067.0002 and 148067.0003,
respectively). The mutations were not found in unaffected family members
or in 30 unrelated controls. Shamsher et al. (1995) noted that the
manifestations of focal NEPPK are very similar to those of pachyonychia
congenita, with the only significant difference being the extent of nail
involvement; see, e.g., pachyonychia congenita type 1 (PC1; 167200), in
which mutation in the KRT16 gene has also been found (148067.0001).

McLean (1997) noted that the 2 families studied by Shamsher et al.
(1995) had mild nail changes similar to those that occur in a much more
severe form in pachyonychia congenita, and concluded that expression of
nail dystrophy in addition to palmoplantar keratoderma is not dependent
on the specific mutation, as this has been found to vary greatly within
large families. Because of the marked phenotypic variability observed in
all keratin diseases, even among persons with the same mutation, McLean
(1997) suggested that there are probably modifier genes and/or
environmental influences yet to be defined.

In a 3-generation family with mild FNEPPK, Smith et al. (2000)
identified a complex deletion (148067.0011) in the KRT16 gene. The
authors noted that the deletion, which removes a keratin-16 helix
termination motif (HTM), unexpectedly resulted in a relatively mild
phenotype. In vitro studies suggested that loss of the HTM sequence may
render the mutant protein less capable of contributing to filament
assembly and thus decrease its dominant-negative effect.

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

2. McLean, W. H. I.: Personal Communication. Philadelphia, Pa.
2/26/1997.

3. Shamsher, M. K.; Navsaria, H. A.; Stevens, H. P.; Ratnavel, R.
C.; Purkis, P. E.; Kelsell, D. P.; McLean, W. H. I.; Cook, L. J.;
Griffiths, W. A. D.; Geschmeissner, S.; Spurr, N.; Leigh, I. M.:
Novel mutations in keratin 16 gene underly focal nonepidermolytic
palmoplantar keratoderma (NEPPK) in two families. Hum. Molec. Genet. 4:
1875-1881, 1995.

4. Smith, F. J. D.; Fisher, M. P.; Healy, E.; Rees, J. L.; Bonifas,
J. M.; Epstein, E. H., Jr.; Tan, E. M. L.; Uitto, J.; McLean, W. H.
I.: Novel keratin 16 mutations and protein expression studies in
pachyonychia congenita type 1 and focal palmoplantar keratoderma. Exp.
Derm. 9: 170-177, 2000.

5. Stevens, H. P.; Kelsell, D. P.; Spurr, N. K.; Bishop, D. T.; Purkis,
P. E.; Griffiths, W. A. D.; Rustin, M. H. A.; Leigh, I. M.: Keratin
staining and linkage of non-epidermolytic focal palmoplantar keratodermas
(PPK) to 17q. (Abstract) Brit. J. Derm. 131: 425 only, 1994.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Mouth];
Whitish opalescence of hard palate;
Whitish opalescence of buccal mucosa

GENITOURINARY:
[External genitalia, male];
Whitish opalescence of glans penis in circumcised males

SKIN, NAILS, HAIR:
[Skin];
Large hard compact painful masses of keratin at sites of recurrent
friction on palms and soles;
Keratosis pilaris of arms and legs;
HISTOLOGY:;
Hyperkeratosis of stratum corneum;
No cytolysis or abnormal keratohyalin granules;
ELECTRON MICROSCOPY:;
No aggregated tonofilaments;
No large keratohyalin granules;
[Nails];
Widened onychocorenal band;
Splinter hemorrhages

MOLECULAR BASIS:
Caused by mutation in the keratin 16 gene (KRT16, 148068.0002)

*FIELD* CD
Marla J. F. O'Neill: 4/26/2013

*FIELD* ED
joanna: 04/26/2013

*FIELD* CD
Marla J. F. O'Neill: 9/2/2009

*FIELD* ED
carol: 01/10/2014
wwang: 9/3/2009