Postgrad Med J: first published as 10.1136/pgmj.70.829.775 on 1 November 1994. Downloaded from

Postgrad Med J (1994) 70, 775 - 779 i) The Fellowship of Postgraduate Medicine, 1994

Leading Article in human skin disease H.P. Stevens and M.H.A. Rustin

Departments ofDermatology, The Royal Free Hospital and School ofMedicine, Pond Street, London NW3 2QG, UK

Introduction The molecular biology of these monogenetic skin have a major protective and structural role diseases has been approached in two ways. The first which comprises 90% of the total of the was initiated by ultrastructural observations pos- differentiated . All keratins have the tulating mutations in the structural of the same basic structure (Figure 1) and are numbered cell so that linkage and keratin mutations could be on the basis of their migration by two-dimensional extrapolated. The second approach has been by the gel electrophoresis.' The common structural com- use of transgenic mice technology to produce the ponents of the keratin polypeptide (Figure 1) are a of human blistering skin diseases with central a-helical rod which is comprised of four specific keratin gene mutations. segments (lA, 1B, 2A, 2B), lying between each of Over the last 10 years dermatology has been in these four segments is a non-helical linkage seg- the forefront of academic research examining the ment (LI, L12, L2), and in the type two keratins the genetic basis a-helical ofmonogenetic diseases and has used rod is flanked at each end by a homology copyright. the powerfully combined approaches of molecular region (H1, H2).2'3 biology, morphological studies, immunohis- The keratins (K) provide the intermediate tochemist.y and biochemical studies. The key to filament network that forms the of these developments has been the polymerase chain epithelial cells. Specific pairs of type I (K9-K 19; reaction (PCR) which has made linkage analysis small acidic proteins) and type II (KI -K8; larger and gene sequencing possible. The target for basic or neutral proteins) keratins are coexpressed the hereditary genodermatoses were identified during various stages of epithelial differentiation. using biochemical, immunohistochemical and In the absence of the corresponding keratin part- positional cloning techniques which has given ner, single keratins are degraded within the cell.

molecular genetics the power to unravel the nature The keratins expressed are fundamental to the http://pmj.bmj.com/ ofthe keratin gene mutations. Keratin mutations in cellular differentiation and of the a number of genodermatoses (epidermolytic epithelial cell.4 These coexpressed keratin polypep- ; simplex, tides form dimers with a coiled-coil structure in a Weber- Cockayne, Koebner and epidermolytic 1:1 ratio. The dimers polymerize to form tetramers. palmoplantar ) have now been deter- These tetramers in turn polymerize to form mined and all have two common features. The first, intermediate filaments (10 nm in diameter) of the epidermolysis or blistering, is a prominent his- cytoskeleton. The process of heterodimer forma- tological feature. Secondly, the mutations all lie in tion is believed to result from molecular interac- on October 1, 2021 by guest. Protected four highly conserved subdomains common to all tions in the highly conserved regions at the begin- the keratins. These subdomains are important in ning and the end of the keratin a-helical rod filament assembly. Mutations at these critical domains. points result in perturbation of keratin assembly, In an analogous fashion to the switching from and result in epidermolysis, seen in both the fetal to adult haemoglobin after birth, the keratin affected individuals as well as in transgenic mice. expression is influenced by the maturation and terminal differentiation of the keratinocytes in the from which the cells are derived. K8 and The keratin cytoskeleton K18 are the primary epithelial keratins expressed in the fetus and in all simple epithelia. K5 and K14 are The keratins comprise a heterogeneous group of first detectable in embryonic based cells and are the more than 30 distinct proteins. The cellular primary keratins expressed by all keratinocytes in stratified non-secreting epithelia in which cells high Correspondence: M.H.A. Rustin, B.Sc., M.D., M.R.C.P. levels of expression are seen. In stratified Received: 20 April 1994 epithelia the keratin expression profile changes Postgrad Med J: first published as 10.1136/pgmj.70.829.775 on 1 November 1994. Downloaded from

776 H.P. STEVENS & M.H.A. RUSTIN

Type I

V1 1A LI lB L12 2A L2 2B V2

EH (K1O) EBS (K14) ft It

EPPK (K9) XT

T-1pe II V1 Hl 1A Ll 1B _~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.L12 2A L2 2B H2 V2

EH (Kl) 4 EBS (K5) it

Figure 1 A demonstration ofthe clustering ofknown sites ofpoint (arrows) in the type I and type II keratins in epidermolysis bullosa simplex (EBS), epidermolytic hyperkeratosis (EH) and epidermolytic palmoplantarcopyright. hyperkeratosis (EPPK). with the passage ofthe from the basal Epidermolytic hyperkeratosis to suprabasal layers of the .7'8 In the basal layer, whilst the keratinocyte is in contact Epidermolytic hyperkeratosis (EH) is a group of with the , K5 and K14 are inherited skin diseases which include bullous con- expressed. In the suprabasal layers of the skin, K1 genital ichthyosiform erythroderma (BCIE), ich- and KIO are expressed, and in the stratified thyosis hystrix of Curth-Macklin (IHCM) and squamous oral and genital mucosa K6 and K16 are bullosa of Siemens (IBS). In EH the http://pmj.bmj.com/ expressed.' K6 and K16 are also expressed by basal cells are normal, and there is suprabasal hyperproliferative and hyperkeratotic epithelia tonofilament clumping which appears to be the such as on the palm and sole and during wound primary event with secondary cytolysis of the healing.' suprabasal cells, blister formation and hyperkeratosis.9 BCIE presents soon after birth with eryth-

Disordered cytoskeleton roderma and severe blistering, the denuded areas on October 1, 2021 by guest. Protected healing rapidly with recurrent episodes ofblistering The first suggestion of keratin mutations being on the background of erythroderma. With time, a involved in the pathogenesis of the autosomal verrucous hyperkeratosis becomes progessively dominant skin diseases came from ultrastructural more prominent with a linear distribution in the studies. This was facilitated by the realization ofthe flexures." Immunohistochemical staining with genetic concept that recessive disorders were most specific monoclonal antibodies to keratin polypep- commonly the result of enzyme deficiencies, whilst tides demonstrated tonofilament abnormalities dominant disorders usually resulted from defects in only in the stratified epithelia in which keratins KI regulatory or structural proteins.9"'0 The reasoning and KIO are expressed, but not in cultured behind this concept is that a reduction in enzyme keratinocytes or non-stratified epithelia. concentration of 50% will not significantly affect Immunoelectron microscopy demonstrated that, metabolic function, but an alteration in the among the keratins detected in the suprabasal physical properties of 50% of a specific structural epidermis, the clumped tonofilaments pre- protein could result in major morphological distur- dominantly expressed KI and KlO.'2 Linkage bance as in sickle cell disease. studies of large pedigree with BCIE have mapped Postgrad Med J: first published as 10.1136/pgmj.70.829.775 on 1 November 1994. Downloaded from

KERATIN GENE MUTATIONS IN HUMAN SKIN DISEASE 777

to the keratin gene clusters on 12q tissue and cultured keratinocytes demonstrated suggesting keratin gene mutations are also respon- tonofilament clumping in the normal skin, outer sible for BCIE.'3 Subsequently, keratin gene muta- hair root sheaths, sweat ducts, and sebaceous tions in Kl and K10 have been confirmed in a glands.26 All these epithelia express K5 and K14 number of mutation hot spots on the keratin whereas no tonofilament clumping was demon- polypeptide.14-19 strated in tissues not expressing these keratins. Immunogold electron microscopy confirmed that the basal cell tonofilament clumps were strongly Epidermolysis bullosa labelled with monoclonal antibodies to K5 and K14, and only slightly reactive suprabasally to Epidermolysis bullosa (EB) represents a large and K 10.26 heterogeneous group of diseases characterized by (II) Junctional EB is characterized by more blistering or erosions occurring in response to severe blistering of the skin and mucous mem- mechanical trauma. Electron microscopy has been branes, which can result in nail dystrophy and loss fundamental in our understanding of these of nails. Unlike EBS the eroded areas heal slowly genodermatoses according to the initial plane of with scarring and it may be fatal in infancy. blistering three main groups of EB can be distin- Abnormalities of kalinin/ 5 expression, a guished.20'2' lamina lucida protein expressed by basal a. In EB simplex (EBS) intra-epithelial blistering keratinocytes, have been demonstrated in Herlitz's results from cytolysis of the basal cells. junctional EB;27 subsequently, kalinin/laminin 5 b. In junctional EB cytolysis occurs in the lamina mutations have been demonstrated in Herlitz's lucida with resultant blister formation but no junctional EB.28,29 abnormality of tonofilament structure has been (III) DEB is usually apparent from birth with demonstrated. severe blistering occurring over the entire skin c. In dystrophic EB (DEB) there are no ultrastruc- surface, mucous membranes, pharyngeal and

tural tonofilament abnormalities and cytolysis oesophageal mucosa in response to minor trauma. copyright. occurs below the level ofthe lamina densa at the The erosions heal slowly with much scarring result- level of the anchoring fibrils. ing in syndactyly and oesophageal strictures. The (I) EBS can be subdivided into three main split in DEB occurs at the level of the anchoring groups: Weber-Cockayne EBS, Koebners EBS fibrils which are comprised of VII and and Dowling-Meara EBS. adhere the lamina densa to the underlying der- Weber-Cockayne EBS is the commonest and mis.30'3' Immunofluorescent labelling with mono- least severe form of EBS and presents with blister- clonal antibodies to collagen VII have demon- ing confined to sites of greatest trauma, such as the strated reduced or absent collagen VII staining in hands and feet. Children tend not to be affected these patients.32-3" A mutation in the type VII

until they start to walk and the blistering tends to collagen gene (COL7AI) has subsequently been http://pmj.bmj.com/ be worse in warm weather. In Weber-Cockayne demonstrated in Hallopeau-Siemens DEB, which EBS linkage studies have mapped affected families shows no detectable collagen VII polypeptide.38 to the keratin gene cluster on 12 and, as the disease is restricted to the palmoplantar Elegant studies with transgenic mice have dem- epidermis, have suggested that site-specific keratins onstrated that specific K14 mutations can produce such as K9 or K16 may be involved.22-24 the full range phenotypes of EBS seen in man. The blistering in patients with Koebner EBS Furthermore, a strong correlation was found occurs within the first few weeks of life but again between the degree of keratin tonofilament disrup- on October 1, 2021 by guest. Protected develops at sites of trauma. In Koebner EBS the tion and the severity of the disease. In those tonofilament clumping and condensation observed phenotypes with only subtle disruption of the in these patients was so minor that it was con- tonofilament cytoskeleton but in the absence of sidered to be the consequence ofthe cytolysis rather tonofilament clumping, cytolysis still occurred.39'40 than the cause of it. These studies produced some of the best evidence Dowling-Meara EBS is the most uncommon for a structural role for the intermediate filament and most severe form of EBS, and presents at birth network in cellular integrity. or in early infancy with grouped and generalized Keratin sequencing in Weber-Cockayne and skin blistering at sites of mild skin trauma. In Dowling-Meara subtypes of EBS have demon- addition there is an associated palmoplantar strated K5 and K14 mutations in all the pedigrees hyperkeratosis, nail dystrophy and oral ulcera- thus far examined.'7 39 41-47 The sites of the muta- tion.25 Tonofilament clumping of the basal cells is a tion within the keratin polypeptide show significant prominent histological feature of the Dowl- clustering at certain points that appear to be ing-Meara subtype. In Dowling-Meara subtype important in maintaining the integrity of the of EBS, electron microscopic studies using fresh intermediate filament network.43 Postgrad Med J: first published as 10.1136/pgmj.70.829.775 on 1 November 1994. Downloaded from

778 H.P. STEVENS & M.H.A. RUSTIN

Epidermolytic (Vorner The locations of keratin gene mutations in the subtype) keratin polypeptide are clustered at a number of mutational 'hot spots' along the keratin polypep- Epidermolytic palmoplantar keratoderma (EPPK) tide. The sites for the point mutations seen in EH, is an autosomal dominant skin disease in which EBS and EPPK are surprisingly restricted to there is diffuse palmoplantar hyperkeratosis with particular domains of the keratin chain and also an erythematous edge. The characteristic his- particular points within that chain are susceptible tological feature is that of perinuclear epider- to mutation. These mutation 'hot spots' lie in the molysis and suprabasal clumping of tonofilaments H 1, 1A, L12 and 2B domains of the keratin chain. but without frank blister formation. Linkage For the mutations so far identified, no domain is studies have mapped the gene to the keratin gene specific for any particular disease type, and a cluster on 17q.48-' On the basis ofthe restriction of similar mutation in a different keratin appears to the disease to the palmoplantar epidermis K9 was produce a different clinical disease. predicted as the probable site of mutation in these With our greater understanding of intermediate pedigrees.48 K9 mutations have now been demon- filament structure and function, the differences strated in a number of pedigrees with EPPK. 50'5 between naturally occurring keratin polymor- phisms and pathological keratins is being unravelled. The mutational 'hot spots' give impor- tant information on the highly conserved regions in Conclusions intermediate filament structure and assembly. Our understanding ofkeratin polypeptide struc- In those diseases in which a keratin gene mutation ture and function is still in its infancy. We do not has been demonstrated there are a number of know the nature of the molecular interactions that ultrastructural similarities in common. Firstly, are responsible for the maintenance ofthe integrity epidermolysis is a characteristic feature of all the of the cellular cytoskeleton nor how the keratin genodermatoses in which a ke'ratin gene mutation gene mutations that have been demonstrated in has been demonstrated. Secondly, tonofilament man alter this function. Future developments in thecopyright. clumping is seen in many ofthese diseases. Thirdly, elucidation of the cause of this important group of hyperkeratosis is a feature of EH, epidermolytic diseases must rely on tissue culture and experimen- palmoplantar hyperkeratosis, and some types of tation at the cellular level. Intermediate filaments EB (Dowling-Meara). This would be in keeping are an important structural component ofevery cell with the demonstrated keratin gene mutations in the body and a better understanding of having similar functional consequences for the intermediate filament function in the skin may have biophysical properties of the intermediate filament important implications for the treatment of a wide network and cellular integrity. range of human disease. http://pmj.bmj.com/ References 1. Moll, R., Franke, W.W., Schiller, D.L., Geiger, B. & Krepler, 7. Kopan, R. & Fuchs, E. A new look into an old problem: R. The catalog ofhuman : patterns ofexpression keratins as tools to investigate determination, mor- in normal epithelia, tumors, and cultured cells. Cell 1982,31: phogenesis, and differentiation in skin. Genes Develop 1989, 11-24. 3: 1-15. 2. Parry, D.A.D. Primary and secondary structure ofIF protein 8. Roop, D.R., Huitfeldt, H., Kilkenny, A. & Yuspa, S.H. chains and modes of molecular aggregation. In: Goldman, Regulated expression of differentiation-associated keratins R.D. & Steinert, P.M. (eds) Cellular and Molecular Biology of in cultured epidermal cells detected by monospecific on October 1, 2021 by guest. Protected Intermediate Filaments. Plenum Press, New York, 1990, antibodies to unique peptides of mouse epidermal keratins. pp. 175-204. Differentiation 1987, 35: 143-150. 3. Conway, J.F. & Parry, D.A.D. Intermediate filament struc- 9. Anton-Lamprecht, J. Genetically induced abnormalities of ture: 3. Analysis ofsequence homologies. Int J Biol Macromol epidermal differentiation and ultrastructure in ichthyoses 1988, 10: 79-98. and epidermolysis: pathogenesis, heterogeneity, fetal 4. Lu, X. & Lane, E.B. Retrovirus-mediated transgenic keratin manifestation, and prenatal diagnosis. J Invest Dermatol expression in cultured fibroblasts: specific domain functions 1983, 81: 149S- 156S. in keratin stabilization and filament formation. Cell 1990,62: 10. McKusick, V.A. Mendelian Inheritance in Man. Catalogs of 681-696. Autosomal Dominant, Autosomal Recessive, and X-linked 5. Dale, B., Holbrook, K.A., Kimball, J.R., Hoff, M. & Sun, Phenotypes, 3rd edn. Johns Hopkins Press, Baltimore, 1971. T.-T. Expression of epidermal keratins and during 11. Brocq, L. Erythrodermie congenitale ichthyosiforme avec human fetal skin development. J Cell Biol 1985, 101: hyperepidermotrophie. Ann Dermatol Syph 1902, 4: 1-31. 1257-1269. 12. Ishida-Yamamoto, A., McGrath, J.A., Judge, M.R., Leigh, 6. Jackson, B.W., Grund, C., Schmid, E., Burki, K., Franke, I.M., Lane, E.B. & Eady, R.A. Selective involvement of W.W. & Illmensee, K. Formation of cytoskeletal elements keratins Ki and K10 in the cytoskeletal abnormality of during mouse embryogenesis. Intermediate filaments of the epidermolytic hyperkeratosis (bullous congenital ich- type and in preimplantation em- thyosiform erythroderma). J Invest Dermatol 1992, 99: 9-26. bryos. Differentiation 1980, 17: 161-179. Postgrad Med J: first published as 10.1136/pgmj.70.829.775 on 1 November 1994. Downloaded from

KERATIN GENE MUTATIONS IN HUMAN SKIN DISEASE 779

13. Compton, J.G., DiGiovanna, J.J., Santucci, S.K. et al. 34. Bruckner-Tuderman, L., Mitsuhashi, Y., Schnyder, U.W. & Linkage of epidermolytic hyperkeratosis to the type II Bruckner, P. Anchoring fibrils and type VII collagen are keratin gene cluster on chromosome 1 2q. Nature Genet 1992, absent from the skin in severe recessive dystrophic epider- 1: 301-305. molysis bullosa. J Invest Dermatol 1989, 93: 3-9. 14. Cheng, J., Syder, A.J., Yu, Q.-C., Letai, A., Paller, A.S. & 35. Bruckner-Tuderman, L., Niemi, K.M., Kero, M., Schnyder, Fuchs, E. The genetic basis ofepidermolytic hyperkeratosis: a U.W. & Reunala, T. Type VII collagen is expressed but disorder of differentiation-specific epidermal keratin genes. anchoring fibrils are defective in dystrophic epidermolysis Cell 1992, 70: 811-820. bullosa inversa. Br J Dermatol 1990, 122: 383-390. 15. Chipev, C.C., Korge, B.P., Markova, N. et al. A 36. Fine, J.D., Horiguchi, Y., Stein, D.H., Esterly, N.B. & Leigh, leucine-proline mutation in the HI subdomain of keratin I I.M. Intraepidermal type VII collagen. Evidence for abnor- causes epidermolytic hyperkeratosis. Cell 1992, 70: 821-882. mal intracytoplasmic processing of a major basement mem- 16. Chipev, C.C., Yang, J.-M., DiGiovanna, J.J., Steinert, P.M., brane protein in rare patients with dominant and possibly Compton, J.G. & Bale, S.J. Preferential sites in localised recessive forms ofdystrophic epidermolysis bullosa. mutated in epidermolytic hyperketatosis. Am J Human Genet J Am Dermatol 1990, 22: 188-195. 1994, 54: 179- 190. 37. Konig, A., Lauharanta, J. & Bruckner-Tuderman, L. 17. McLean, W.H.I., Eady, R.A.J., Dopping-Hepenstal, P.J.C. Keratinocytes and fibroblasts from a patient with mutilating et al. Mutations in the rod domain of keratins 1 and 10 in dystrophic epidermolysis bullosa synthesize drastically bullous congenital ichthyosiform erythroderma (BCIE). J reduced amounts ofcollagen VII: lack ofeffect oftransform- Invest Dermatol 1994, 102: 24-30. ing growth factor P. J Invest Dermatol 1992, 99: 808-812. 18. Rothnagel, J.A., Dominey, A.M., Dempsey, L.D. et al. 38. Hilal, L., Rochat, A., Duquesnoy, P. et al. A homozygous Mutations in the rod domains of keratins 1 and 10 in - in the type VII collagen gene (COL7A 1) in epidermolytic hyperkeratosis. Science 1992, 257: 1128- 1130. Hallopeau-Siemens dystrophic epidermolysis bullosa. 19. Yang, J.-M., Chipev, C.C., DiGiovanna, J.J. et al. Mutations Nature Genet 1993, 5: 287-293. in the HI and IA domains in the gene in 39. Coulombe, P.A., Hutton, M.E., Vassar, R. & Fuchs, E. A epidermolytic hyperkeratosis. J Invest Dermatol 1994, 102: function for keratins and a common thread among different 17-23. types of epidermolysis bullosa simplex diseases. J Cell Biol 20. Gedde-Dahl, T.J. Epidermolysis bullosa syndromes. Curr 1991, 115: 1661-1674. Prob Dermatol 1987, 16: 129-145. 40. Vassar, R.C.P.A., Degenstein, L., Abers, K. & Fuchs, E. 21. Gedde-Dahl, T.J. Sixteen types of epidermolysis bullosa. On Mutant keratin expression in transgenic mice causes marked the clinical discrimination, therapy and prenatal diagnosis. abnormalities resembling a human genetic skin disease. Cell Acta Dermatovenereol 1981, Suppi 95: 74-87. 1991, 64: 365-380. 22. Bonifas, J.M., Rothman, A.L. & Epstein, E.H. Epidermolysis 41. Coulombe, P.A., Hutton, M.E., Letai, A., Hebert, A., Paller, bullosa simplex: evidence in two familities for keratin gene A. & Fuchs, E. Point mutations in human genes of copyright. abnormalities. Science 1991, 254: 1202-1205. epidermolysis bullosa simplex patients: genetic and func- 23. Hoyheim, B., Gedde-Dahl, T. & Olaisen, B. Linkage studies tional analyses. Cell 1991, 66: 1301-131 1. in epidermolysis bullosa simplex. J Invest Dermatol 1992, 98: 42. Stephens, K., Sybert, V.P., Wijsman, E.M., Ehrlich, P. & 397a. Spencer, A. A keratin 14 mutational hot spot for epider- 24. Epstein, E.H.J., Molecular genetics ofepidermolysis bullosa. molysis bullosa simplex, Dowling-Meara: implications for Science 1992, 256: 799-804. diagnosis. J Invest Dermatol 1993, 101: 240-243. 25. Dowling, G.B. & Meara, R.H. Epidermolysis bullosa resemb- 43. Smith, F.J.D., Morley, R.M., Rugg, E.L. et al. Clustering of lingjuvenile herpetiformis. BrJDermatol 1954,66: epidermolysis bullosa simplex mutations in relation to 139- 143. disease phenotype: data from Weber-Cockayne EBS. J 26. Ishida-Yamamoto, A., McGrath, J.A., Chapman, S.J., Invest Dermatol 1993, 101: 481a. Leigh, I.M., Lane, E.B. & Eady, R.A.J. Epidermolysis 44. Hovnanian, A., Pollack, E. Hilal, L. et al. A missense bullosa simplex is a (Dowling-Meara type) genetic disease mutation in the rod domain of keratin 14 associated with http://pmj.bmj.com/ characterized by an abnormal keratin-filament network recessive epidermolysis bullosa simplex. Nature Genet 1993, involving keratins K5 and K14. J Invest Dermatol 1991, 97: 3: 327-332. 959-968. 45. Humphries, M.M., Sheils, D.M., Farrar, G.J. et al. A 27. Meneguzzi Gea. Kalinin is abnormally expressed in epithelial mutation (Met-Arg) in the (K14) gene basement membranes of Herlitz's junctional epidermolysis responsible for autosomal dominant epidermolysis bullosa bullosa patients. Exp Dermatol 1993, 1: 221-229. simplex. Human Mutation 1993, 2: 37-42. 28. -Aberdam, D., Galliano, M.-F., Vailly, J. et al. Herlitz's 46. Chen, M.A., Bonifas, J.M., Matsumara, K., Blumenfield, A. junctional epidermolysis bullosa is linked to mutations in the & Epstein, E.H. A novel 3-nucleotide deletion in the helix 2B gene (LAMC2) for the y2 subunit of necein/kalinin region of keratin-14 in epidermolysis bullosa simplex - (LAMININ-5). Nature Genet 1994, 6: 299-304. AE375. Hum Molec Genet 1993, 2: 1971-1973. on October 1, 2021 by guest. Protected 29. Pulkkinen, L., Christiano, A.M., Airenne, T., Haakana, H., 47. Dong, W., Ryynanen, M. & Uitto, J. Identification of a Tryggvason, K. & Uitto, J. Mutations in the 12 chain gene leucine-to-proline mutation in the gene in a family (LAMC2) of kalinin/laminin 5 in the junctional forms of with the generalized Koebner type of epidermolysis bullosa epidermolysis bullosa. Nature Genet 1994, 6: 293-298. simplex. Human Mutation 1993, 2: 94-102. 30. Saki, L.Y., Keene, D.R., Morris, N.P. & Burgeson, R.E. 48. Reis, A., Kuster, W., Eckardt, R. & Sperling, K. Mapping of Type VII collagen is a major structural component of a gene for epidermolytic palmoplantar keratoderma to the anchoring fibrils. J Cell Biol 1986, 103: 1577-1586. region of the acidic keratin gene cluster at 17ql2-q21. 31. Burgeson, R.E., Lunstrum, G.P., Rokosova, B., Rimberg, Human Genet 1992, 90: 113-116. C.S., Rosenbaum, L.M. & Keene, D.R. The structure and 49. Rognaev, E.I., Rogaev, E.A., Ginter, E.K. et al. Identifica- function of type VII collagen. Ann N Y Acad Sci 1990, 580: tion ofthe genetic for palmaris et plantaris on 32-43. near the RARA and keratin type 1 genes. 32. Leigh, I.M., Eady, R.A., Heagerty, A.H., Purkis, R.E., Nature Genet 1993, 5: 158-162. Whitehead, P.A. & Burgeson, R.E. Type VII collagen is a 50. Torchard, D., Blanchet-Bardon, C., Serova, 0. et al. Epider- normal component ofepidermal basement membrane, which molytic palmoplantar keratoderma cosegregates with a shows altered expression in recessive dystrophic epider- muation in a pedigree with breast and ovarian molysis bullosa. J Invest Dermatol 1988, 90: 639-642. cancer. Nature Genet 1994, 6: 106-110. 33. Bruckner-Tuderman, L., Ruegger, S., Odermatt, B., Mit- 51. Reis, A., Hennies, H.-C., Langbein, L. et al. Keratin 9 gene suhashi, Y. & Schnyder, U.W. Lack of type VII collagen in mutations in epidermolytic palmoplantar keratoderma unaffected skin of patients with severe recessive dystrophic (EPPK). Nature Genet 1994, 6: 174-179. epidermolysis bullosa. Dermatol 1988, 176: 57-64.