1. Introduction
Epidermolysis bullosa (EB) is a heterogeneous group of congenital disorders characterized by skin blister formation. EB is subdivided into three main subtypes (EB simplex (EBS), junctional EB (JEB) and dystrophic EB (DEB)) and one minor subtype (Kindler syndrome (KS)), according to the level of skin split [1].
The EBS subtype can be defined as EBS with blisters within epidermal basal keratinocytes or above, and it is distinguished from other subtypes whose levels of blister formation are deeper (JEB and DEB) or variable (KS). Mutations in several genes have been identified as being responsible for EBS phenotypes. The clinical manifestations of EBS vary greatly depending on the causative genes. Some EBS subtypes are mild and tend to improve with age, whereas others are severe and often associated with early demise and/or other organ involvement. This chapter introduces the clinical and histological characteristics and classifications of EBS. Subsequently, each protein that is defective in EBS is discussed, as are animal models of the disease.
2. Overview of epidermolysis bullosa simplex
Mutations in genes encoding keratinocyte components involved in the organization of the cytoskeleton or cell-cell junctions are responsible for EBS. EBS can be subclassified into basal and suprabasal according to the level of skin split [1, 2] (Table 1).
Basal EBS is caused by defects in skin basement membrane (BMZ) proteins. Figure 1 diagrams the skin BMZ. Among the BMZ components, keratin 5/14 and plectin are the main targets in EBS [3, 4]. A few EBS cases have been reported to have mutations in
In contrast, suprabasal EBS is associated with abnormalities in desmosomal proteins (Figure 2). So far, plakophilin-1, plakoglobin and desmoplakin are known to be the target proteins of suprabasal EBS [2, 9-11].
EBS | Suprabasal EBS | |
Basal EBS | ||
Animal models have been used to clarify the function of some proteins and to develop new therapies for human diseases. Animal models of EB were reviewed recently [12, 13]. However, some new animal models have emerged since then [14, 15], and other transgenic mice with abnormalities in desmosomal proteins should be added to the list of EB animal models because of the introduction of the concept of “suprabasal EBS” [1]. Table 2 summarizes animal models of EBS.
Causative Gene | Species | Type | Survival | Reference |
Mouse | KO | Neonatal death | [16] | |
Cow | Naturally occurring (a heterozygous missense mutation) | Not mentioned | [17] | |
Mouse | Tg (expressing truncated protein) | Neonatal death | [18] | |
Mouse | KO | Neonatal death | [19] | |
Mouse | KI | Neonatal death | [20] | |
Mouse | KI (an inducible model) | Not mentioned | [20] | |
Mouse | KO | Neonatal death | [21] | |
Mouse | Conditional KO | Neonatal death | [22] | |
Mouse | KI (expressing EBS-Ogna mutation) | Normal | [14] | |
Mouse | KO | Not mentioned | [23] | |
Mouse | KO | Embryonicdeath | [24] | |
Mouse | Conditional KO | Not mentioned | [25] | |
Dog | Naturally occurring (a homozygous splice donor site mutation) | Neonatal death (6 of 9 affected dogs) | [15] | |
Mouse | KO | Embryonicdeath | [26] | |
Mouse | KO | Neonatal death | [27] | |
Mouse | KO | Neonatal death | [28] | |
Mouse | Partial ablation (expressing ectodomain of β4 integrin) | Neonatal death | [29] | |
Mouse | Conditional KO | Not mentioned | [30] | |
Mouse | KO | Prolonged survival in 20% of mice | [31] |
3. Target proteins in basal EBS
3.1. Keratin 5/14
Recent brilliant reviews have addressed keratins and EBS [3, 32]. Here we focus on the history, mutation analysis, animal models and future therapeutics of keratin-associated EBS from the physician’s point of view.
Keratin is one of the most abundant components of the epithelial cytoskeleton [33]. Typically, type I and type II keratins form heteropolymers that function in cells [34]. Keratin 5 (K5) and keratin 14 (K14) are specifically expressed in epidermal basal cells [34, 35] (Figure 1). In the 1980’s, disorganization of those keratins was recognized in the basal keratinocytes of EBS patients [36, 37]. From those findings, it had been hypothesized that EBS patients have mutations in
There are several subtypes of keratin-associated EBS, as described in Table 3 [1]. Classical and common EBS subtypes, in which traits are autosomal-dominantly inherited, are Dowling-Meara type EBS (EBS-DM), non Dowling-Meara type (EBS-gen-non-DM) and localized type (EBS-loc), from the severest to the mildest. Ultrastructurally, basal keratinocytes of EBS-DM are characterized by keratin aggregates [42]. Hot spots of the mutations in
The pathogenesis of EBS development through keratin mutations has also been demonstrated in animal models (Table 2). Following the discovery of transgenic mice overexpressing mutated K14 described above [18],
Therapeutic interventions for EBS have been confined to palliative modalities. However, recent innovations in RNA interference have led to therapeutic strategies for dominant-negative disorders including keratin-associated EBS, where aberrant mutated keratin is knocked down while normal keratin synthesis on another allele is left intact [46]. This RNAi strategy is promising and will be further validated in clinical trials.
3.2. Plectin
A comprehensive review paper has addressed EBS and plectin [4], although there have been several advances in this field since then [14, 47-49].
Plectin is a cross-linking protein between the cytoskeleton and membranous proteins including hemidesmosomal components (Figure 1). Plectin has been known to have many transcript isoforms that differ from each other in N-terminal sequences at the protein level [50]. Among the many transcript isoforms, plectin 1a is the one that is mainly expressed in epidermal keratinocytes [51]. In addition to 5’ transcript complexity, plectin has a rodless splicing variant [52]. There are several EBS subtypes that are caused by plectin deficiencies (Table 4).
In the mid-1990’s, mutations in the gene encoding plectin (
In 2005, two groups independently reported a new EBS subtype with
The reason
The next big question was whether EBS-MD and EBS-PA can occur simultaneously in a single patient or those two distinct EBS subtypes are mutually exclusive. Recently, one case was reported to have the phenotype of both EBS-MD and EBS-PA (EBS-MD-PA) [48]. The patient had truncation mutations at the last exon of
Apart from autosomal recessive EBS subtypes associated with
Animal models of plectin-deficient EBS have been generated (Table 2).
3.3. BPAG1-e
Dystonin, encoded by
3.4. Miscellaneous
Mutations in
α6/β4 integrins are hemidesmosomal components that are encoded by
4. Target proteins in suprabasal EBS
4.1. Desmoplakin
Desmoplakin is a plakin family protein located in desmosome [55] (Figure 2). Two isoforms (desmoplakins I and II) are generated through alternative splicing [65]. Desmoplakin I is mainly expressed in the heart, whereas desmoplakin II is abundant in the skin [66]. In the early 1990’s, desmoplakin was determined as a major autoantigen in paraneoplastic pemphigus [67, 68]. Mutations in the gene encoding desmoplakin,
There are two desmoplakin-associated EBS model animals (Table 2). The fact that
4.2. Plakophilin-1
Plakophilin-deficient EBS is listed in the newest classification of EB [1]. This entity has also been called ectodermal dysplasia-skin fragility syndrome (ED-SF). An excellent review on this EBS subtype was published recently [10]. The first case of ED-SF and the mutations in the gene encoding plakophilin-1,
The desmosomal expression of plakophilin-1 (Figure 2) accounts for skin fragility and histological features of skin specimens characterized by widening of spaces between keratinocytes. However, the phenotype of ectodermal dysplasia may not be explained solely by desmosomal proteins. Recently, plakophilin-1 has been identified as a regulator of protein synthesis and proliferation through a pathway associated with eIF4A1 [74]. It is speculated that the role of plakophilin-1 in translation and proliferation is involved in abnormalities in skin appendages of ED-SF patients [74].
Mice models in which plakophilin-1 is defective have not been reported. However, there is a naturally occurring canine model with
4.3. Plakoglobin
5. Summary
Many genes are involved in the manifestations of EBS, as described in this chapter. The most common subtype is keratin-associated EBS caused by dominant-negative effects of aberrant mutated protein. RNAi strategies will be used in future clinical trials, although it is not easy to apply such therapies for all patients, because each patient has a different mutation. Tailor-made strategies will be required to correct each EBS mutation.
Other EBS subtypes are generally complicated with organ malfunction. The task of clinicians is to predict the prognosis of each EBS cases based on the causative genes. It is imperative to clarify what organs, other than the skin, will suffer dysfunction in each EBS case.
References
- 1.
Fine J. D Eady R. A Bauer E. A Bauer J. W Bruckner-tuderman L Heagerty A Hintner H Hovnanian A Jonkman M. F Leigh I Mcgrath J. A Mellerio J. E Murrell D. F Shimizu H Uitto J Vahlquist A Woodley D Zambruno G The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB J Am Acad Dermatol.2008 58 6 931 950 - 2.
Pigors M Kiritsi D Krumpelmann S Wagner N He Y Podda M Kohlhase J Hausser I Bruckner-tuderman L Has C Lack of plakoglobin leads to lethal congenital epidermolysis bullosa: a novel clinico-genetic entity Hum Mol Genet.2011 20 9 1811 1819 - 3.
Coulombe P. A Kerns M. L Fuchs E Epidermolysis bullosa simplex: a paradigm for disorders of tissue fragility J Clin Invest.2009 119 7 1784 1793 - 4.
Rezniczek G. A Walko G Wiche G Plectin gene defects lead to various forms of epidermolysis bullosa simplex. Dermatol Clin.2010 28 1 33 41 - 5.
Huber M Floeth M Borradori L Schacke H Rugg E. L Lane E. B Frenk E Hohl D Bruckner-tuderman L Deletion of the cytoplasmatic domain of BP180/collagen XVII causes a phenotype with predominant features of epidermolysis bullosa simplex. J Invest Dermatol.2002 118 1 185 192 - 6.
Jonkman M. F Pas H. H Nijenhuis M Kloosterhuis G Steege G Deletion of a cytoplasmic domain of integrin beta4 causes epidermolysis bullosa simplex. J Invest Dermatol.2002 119 6 1275 1281 - 7.
Groves R. W Liu L Dopping-hepenstal P. J Markus H. S Lovell P. A Ozoemena L Lai-cheong J. E Gawler J Owaribe K Hashimoto T Mellerio J. E Mee J. B Mcgrath J. A A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex. J Invest Dermatol.2010 130 6 1551 1557 - 8.
Liu L Dopping-hepenstal P. J Lovell P. A Michael M Horn H Fong K Lai-cheong J. E Mellerio J. E Parsons M Mcgrath J. A Autosomal recessive epidermolysis bullosa simplex due to loss of BPAG J Invest Dermatol.1 e expression.2012 Pt 1):742-744. - 9.
Mcgrath J. A Bolling M. C Jonkman M. F Lethal acantholytic epidermolysis bullosa Dermatol Clin.2010 28 1 131 135 - 10.
Mcgrath J. A Mellerio J. E Ectodermal dysplasia-skin fragility syndrome Dermatol Clin.2010 28 1 125 129 - 11.
Desmosomal genodermatoses. Br J Dermatol.Petrof G Mellerio J. E Mcgrath J. A 2012 166 1 36 45 - 12.
Bruckner-tuderman L Mcgrath J. A Robinson E. C Uitto J Animal models of epidermolysis bullosa: update J Invest Dermatol. 2010;2010 130 6 1485 1488 - 13.
Natsuga K Shinkuma S Nishie W Shimizu H Animal models of epidermolysis bullosa. Dermatol Clin.2010 28 1 137 142 - 14.
Walko G Vukasinovic N Gross K Fischer I Sibitz S Fuchs P Reipert S Jungwirth U Berger W Salzer U Carugo O Castanon M. J Wiche G Targeted proteolysis of plectin isoform 1a accounts for hemidesmosome dysfunction in mice mimicking the dominant skin blistering disease EBS-Ogna. PLoS Genet.2011 e1002396 EOF - 15.
Olivry T Linder K. E Wang P Bizikova P Bernstein J. A Dunston S. M Paps J. S Casal M. L Deficient plakophilin-1 expression due to a mutation in PKP1 causes ectodermal dysplasia-skin fragility syndrome in Chesapeake Bay retriever dogs. 2012 e32072 EOF - 16.
Peters B Kirfel J Bussow H Vidal M Magin T. M Complete cytolysis and neonatal lethality in keratin 5 knockout mice reveal its fundamental role in skin integrity and in epidermolysis bullosa simplex Mol Biol Cell.2001 12 6 1775 1789 - 17.
Ford C. A Stanfield A. M Spelman R. J Smits B Ankersmidt-udy A. E Cottier K Holloway H Walden A Al-wahb M Bohm E Snell R. G Sutherland G. T A mutation in bovine keratin 5 causing epidermolysis bullosa simplex, transmitted by a mosaic sire J Invest Dermatol.2005 124 6 1170 1176 - 18.
Vassar R Coulombe P. A Degenstein L Albers K Fuchs E Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease 1991 64 2 365 380 - 19.
Lloyd C Yu Q. C Cheng J Turksen K Degenstein L Hutton E Fuchs E The basal keratin network of stratified squamous epithelia: defining K15 function in the absence of K14. J Cell Biol.1995 129 5 1329 1344 - 20.
Cao T Longley M. A Wang X. J Roop D. R An inducible mouse model for epidermolysis bullosa simplex: implications for gene therapy J Cell Biol.2001 152 3 651 656 - 21.
Andra K Lassmann H Bittner R Shorny S Fassler R Propst F Wiche G Targeted inactivation of plectin reveals essential function in maintaining the integrity of skin, muscle, and heart cytoarchitecture Genes Dev.1997 11 23 3143 3156 - 22.
Conditional targeting of plectin in prenatal and adult mouse stratified epithelia causes keratinocyte fragility and lesional epidermal barrier defects. J Cell Sci.Ackerl R Walko G Fuchs P Fischer I Schmuth M Wiche G 2007 Pt 14):2435-2443. - 23.
Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration. Cell.Guo L Degenstein L Dowling J Yu Q. C Wollmann R Perman B Fuchs E 1995 81 2 233 243 - 24.
Desmoplakin is required early in development for assembly of desmosomes and cytoskeletal linkage. J Cell Biol.Gallicano G. I Kouklis P Bauer C Yin M Vasioukhin V Degenstein L Fuchs E 1998 143 7 2009 2022 - 25.
Desmoplakin is essential in epidermal sheet formation. Nat Cell Biol.Vasioukhin V Bowers E Bauer C Degenstein L Fuchs E 2001 3 12 1076 1085 - 26.
Embryonic heart and skin defects in mice lacking plakoglobin. Dev Biol.Bierkamp C Mclaughlin K. J Schwarz H Huber O Kemler R 1996 180 2 780 785 - 27.
Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. J Cell Biol.Dowling J Yu Q. C Fuchs E 1996 134 2 559 572 - 28.
Epithelial detachment due to absence of hemidesmosomes in integrin beta 4 null mice. Nat Genet.Van Der Neut R Krimpenfort P Calafat J Niessen C. M Sonnenberg A 1996 13 3 366 369 - 29.
Cell cycle and adhesion defects in mice carrying a targeted deletion of the integrin beta4 cytoplasmic domain. Embo J.Murgia C Blaikie P Kim N Dans M Petrie H. T Giancotti F. G 1998 17 14 3940 3951 - 30.
Keratinocytes display normal proliferation, survival and differentiation in conditional betaRaymond K Kreft M Janssen H Calafat J Sonnenberg A 4 integrin knockout mice. J Cell Sci.2005 Pt 5):1045-1060. - 31.
Humanization of autoantigen. Nat Med.Nishie W Sawamura D Goto M Ito K Shibaki A Mcmillan J. R Sakai K Nakamura H Olasz E Yancey K. B Akiyama M Shimizu H 2007 13 3 378 383 - 32.
Defining keratin protein function in skin epithelia: epidermolysis bullosa simplex and its aftermath. J Invest Dermatol.Coulombe P. A Lee C. H 2012 Pt 2):763-775. - 33.
Parry DAD, Rogers MA, Wright MW. New consensus nomenclature for mammalian keratins. J Cell Biol.Schweizer J Bowden P. E Coulombe P. A Langbein L Lane E. B Magin T. M Maltais L Omary M. B 2006 174 2 169 174 - 34.
The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell.Moll R Franke W. W Schiller D. L Geiger B Krepler R 1982 31 1 11 24 - 35.
The 50- and 58-kdalton keratin classes as molecular markers for stratified squamous epithelia: cell culture studies. J Cell Biol.Nelson W. G Sun T. T 1983 97 1 244 251 - 36.
Abnormal organization of keratin intermediate filaments in cultured keratinocytes of epidermolysis bullosa simplex. Arch Dermatol Res.Kitajima Y Inoue S Yaoita H 1989 281 1 5 10 - 37.
Epidermolysis bullosa herpetiformis Dowling-Meara. Report of a case and pathomorphogenesis. Dermatologica.Anton-lamprecht I Schnyder U. W 1982 164 4 221 235 - 38.
Jr. Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities. Science.Bonifas J. M Rothman A. L Epstein E. H 1991 254 5035 1202 1205 - 39.
Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses. Cell.Coulombe P. A Hutton M. E Letai A Hebert A Paller A. S Fuchs E 1991 66 6 1301 1311 - 40.
A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature.Lane E. B Rugg E. L Navsaria H Leigh I. M Heagerty A. H Ishida-yamamoto A Eady R. A 1992 356 6366 244 246 - 41.
The Human Intermediate Filament Database: comprehensive information on a gene family involved in many human diseases. Hum Mutat.Szeverenyi I Cassidy A. J Chung C. W Lee B. T Common J. E Ogg S. C Chen H Sim S. Y Goh W. L Ng K. W Simpson J. A Chee L. L Eng G. H Li B Lunny D. P Chuon D Venkatesh A Khoo K. H Mclean W. H Lim Y. P Lane E. B 2008 29 3 351 360 - 42.
Epidermolysis bullosa simplex (Dowling-Meara type) is a genetic disease characterized by an abnormal keratin-filament network involving keratins K5 and K14. J Invest Dermatol.Ishida-yamamoto A Mcgrath J. A Chapman S. J Leigh I. M Lane E. B Eady R. A 1991 97 6 959 968 - 43.
Keratin 14 point mutations at codon 119 of helix 1A resulting in different epidermolysis bullosa simplex phenotypes. J Invest Dermatol.Cummins R. E Klingberg S Wesley J Rogers M Zhao Y Murrell D. F 2001 117 5 1103 1107 - 44.
Consequences of two different amino-acid substitutions at the same codon in KRT14 indicate definitive roles of structural distortion in epidermolysis bullosa simplex pathogenesis. J Invest Dermatol.Natsuga K Nishie W Smith B. J Shinkuma S Smith T. A Parry D. A Oiso N Kawada A Yoneda K Akiyama M Shimizu H 2011 131 9 1869 1876 - 45.
Functional testing of keratin 14 mutant proteins associated with the three major subtypes of epidermolysis bullosa simplex. Exp Dermatol.Sorensen C. B Andresen B. S Jensen U. B Jensen T. G Jensen P. K Gregersen N Bolund L 2003 12 4 472 479 - 46.
Development of allele-specific therapeutic siRNA for keratin 5 mutations in epidermolysis bullosa simplex. J Invest Dermatol.Atkinson S. D Mcgilligan V. E Liao H Szeverenyi I Smith F. J Moore C. B Mclean W. H 2011 131 10 2079 2086 - 47.
Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex. Hum Mutat.Natsuga K Nishie W Akiyama M Nakamura H Shinkuma S Mcmillan J. R Nagasaki A Has C Ouchi T Ishiko A Hirako Y Owaribe K Sawamura D Bruckner-tuderman L Shimizu H 2010 31 3 308 316 - 48.
Plectin deficiency leads to both muscular dystrophy and pyloric atresia in epidermolysis bullosa simplex. Hum Mutat.Natsuga K Nishie W Shinkuma S Arita K Nakamura H Ohyama M Osaka H Kambara T Hirako Y Shimizu H 2010 E1687 1698 - 49.
Epidermolysis Bullosa Simplex Ogna Revisited. J Invest Dermatol.Kiritsi D Pigors M Tantcheva-poor I Wessel C Arin M. J Kohlhase J Bruckner-tuderman L Has C 2012 - 50.
Unusual 5’ transcript complexity of plectin isoforms: novel tissue-specific exons modulate actin binding activity. Hum Mol Genet.Fuchs P Zorer M Rezniczek G. A Spazierer D Oehler S Castanon M. J Hauptmann R Wiche G 1999 8 13 2461 2472 - 51.
Plectin-isoform-specific rescue of hemidesmosomal defects in plectin (-/-) keratinocytes. J Invest Dermatol.Andra K Kornacker I Jorgl A Zorer M Spazierer D Fuchs P Fischer I Wiche G 2003 120 2 189 197 - 52.
Plectin transcript diversity: identification and tissue distribution of variants with distinct first coding exons and rodless isoforms. Genomics.Elliott C. E Becker B Oehler S Castanon M. J Hauptmann R Wiche G 1997 42 1 115 125 - 53.
Loss of plectin causes epidermolysis bullosa with muscular dystrophy: cDNA cloning and genomic organization. Genes Dev.Mclean W. H Pulkkinen L Smith F. J Rugg E. L Lane E. B Bullrich F Burgeson R. E Amano S Hudson D. L Owaribe K Mcgrath J. A Mcmillan J. R Eady R. A Leigh I. M Christiano A. M Uitto J 1996 10 14 1724 1735 - 54.
Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. Nat Genet.Smith F. J Eady R. A Leigh I. M Mcmillan J. R Rugg E. L Kelsell D. P Bryant S. P Spurr N. K Geddes J. F Kirtschig G Milana G De Bono A. G Owaribe K Wiche G Pulkkinen L Uitto J Mclean W. H Lane E. B 1996 13 4 450 457 - 55.
Plakins in development and disease. Exp Cell Res.Sonnenberg A Liem R. K 2007 313 10 2189 2203 - 56.
Epidermolysis bullosa simplex associated with pyloric atresia is a novel clinical subtype caused by mutations in the plectin gene (PLEC1). J Mol Diagn.Nakamura H Sawamura D Goto M Nakamura H Mcmillan J. R Park S Kono S Hasegawa S Paku S Nakamura T Ogiso Y Shimizu H 2005 7 1 28 35 - 57.
Plectin gene mutations can cause epidermolysis bullosa with pyloric atresia. J Invest Dermatol.Pfendner E Uitto J 2005 124 1 111 115 - 58.
Integrin beta 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia. Nat Genet.Vidal F Aberdam D Miquel C Christiano A. M Pulkkinen L Uitto J Ortonne J. P Meneguzzi G 1995 10 2 229 234 - 59.
G. A homozygous mutation in the integrin alpha6 gene in junctional epidermolysis bullosa with pyloric atresia. J Clin Invest.Ruzzi L Gagnoux-palacios L Pinola M Belli S Meneguzzi G D Alessio M Zambruno 1997 99 12 2826 2831 - 60.
Jr. A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations. J Invest Dermatol.Koss-harnes D Hoyheim B Anton-lamprecht I Gjesti A Jorgensen R. S Jahnsen F. L Olaisen B Wiche G Gedde-dahl T 2002 118 1 87 93 - 61.
Molecular heterogeneity of the bullous pemphigoid antigens as detected by immunoblotting. J Immunol.Labib R. S Anhalt G. J Patel H. P Mutasim D. F Diaz L. A 1986 136 4 1231 1235 - 62.
Human bullous pemphigoid antigen (BPAG1). Amino acid sequences deduced from cloned cDNAs predict biologically important peptide segments and protein domains. J Biol Chem.Sawamura D Li K Chu M. L Uitto J 1991 266 27 17784 17790 - 63.
Cloning and primary structural analysis of the bullous pemphigoid autoantigen BP180. J Invest Dermatol.Giudice G. J Emery D. J Diaz L. A 1992 99 3 243 250 - 64.
Mutations in the 180-kD bullous pemphigoid antigen (BPAG2), a hemidesmosomal transmembrane collagen (COL17A1), in generalized atrophic benign epidermolysis bullosa. Nat Genet.Mcgrath J. A Gatalica B Christiano A. M Li K Owaribe K Mcmillan J. R Eady R. A Uitto J 1995 11 1 83 86 - 65.
Isolation of cDNAs encoding desmosomal plaque proteins: evidence that bovine desmoplakins I and II are derived from two mRNAs and a single gene. Proc Natl Acad Sci U S A.Green K. J Goldman R. D Chisholm R. L 1988 85 8 2613 2617 - 66.
Loss of desmoplakin isoform I causes early onset cardiomyopathy and heart failure in a Naxos-like syndrome. J Med Genet.Uzumcu A Norgett E. E Dindar A Uyguner O Nisli K Kayserili H Sahin S. E Dupont E Severs N. J Leigh I. M Yuksel-apak M Kelsell D. P Wollnik B 2006 e5. - 67.
rd, Mutasim D, Ariss-Abdo L, et al. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med.Anhalt G. J Kim S. C Stanley J. R Korman N. J Jabs D. A Kory M Izumi H Ratrie H 1990 323 25 1729 1735 - 68.
GJ. Human autoantibodies against desmoplakins in paraneoplastic pemphigus. J Clin Invest.Oursler J. R Labib R. S Ariss-abdo L Burke T O Keefe E. J Anhalt 1992 89 6 1775 1782 - 69.
Skin and heart: une liaison dangereuse. Exp Dermatol.Bolling M. C Jonkman M. F 2009 18 8 658 668 - 70.
van den Berg MP, Ter Horst HJ, Timmer A, Pas HH. Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. Am J Hum Genet.Jonkman M. F Pasmooij A. M Pasmans S. G 2005 77 4 653 660 - 71.
Lethal acantholytic epidermolysis bullosa due to a novel homozygous deletion in DSP: expanding the phenotype and implications for desmoplakin function in skin and heart. Br J Dermatol.Bolling M. C Veenstra M. J Jonkman M. F Diercks G. F Curry C. J Fisher J Pas H. H Bruckner A. L 2010 162 6 1388 1394 - 72.
Insights from a desmoplakin mutation identified in lethal acantholytic epidermolysis bullosa. J Invest Dermatol.Hobbs R. P Han S. Y Van Der Zwaag P. A Bolling M. C Jongbloed J. D Jonkman M. F Getsios S Paller A. S Green K. J 2010 130 11 2680 2683 - 73.
Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome. Nat Genet.Mcgrath J. A Mcmillan J. R Shemanko C. S Runswick S. K Leigh I. M Lane E. B Garrod D. R Eady R. A 1997 17 2 240 244 - 74.
Plakophilin 1 stimulates translation by promoting eIF4A1 activity. J Cell Biol.Wolf A Krause-gruszczynska M Birkenmeier O Ostareck-lederer A Huttelmaier S Hatzfeld M 2010 188 4 463 471