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 .
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].
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” . Table 2 summarizes animal models of EBS.
|Cow||Naturally occurring (a heterozygous missense mutation)||Not mentioned|||
|Mouse||Tg (expressing truncated protein)||Neonatal death|||
|Mouse||KI (an inducible model)||Not mentioned|||
|Mouse||Conditional KO||Neonatal death|||
|Mouse||KI (expressing EBS-Ogna mutation)||Normal|||
|Mouse||Conditional KO||Not mentioned|||
|Dog||Naturally occurring (a homozygous splice donor site mutation)||Neonatal death|
(6 of 9 affected dogs)
|Mouse||Partial ablation (expressing ectodomain of β4 integrin)||Neonatal death|||
|Mouse||Conditional KO||Not mentioned|||
|Mouse||KO||Prolonged survival in 20%|
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 . Typically, type I and type II keratins form heteropolymers that function in cells . 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 . 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 . 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 ,
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 . This RNAi strategy is promising and will be further validated in clinical trials.
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 . Among the many transcript isoforms, plectin 1a is the one that is mainly expressed in epidermal keratinocytes . In addition to 5’ transcript complexity, plectin has a rodless splicing variant . 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 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) . 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).
Dystonin, encoded by
α6/β4 integrins are hemidesmosomal components that are encoded by
4. Target proteins in suprabasal EBS
Desmoplakin is a plakin family protein located in desmosome  (Figure 2). Two isoforms (desmoplakins I and II) are generated through alternative splicing . Desmoplakin I is mainly expressed in the heart, whereas desmoplakin II is abundant in the skin . 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
Plakophilin-deficient EBS is listed in the newest classification of EB . This entity has also been called ectodermal dysplasia-skin fragility syndrome (ED-SF). An excellent review on this EBS subtype was published recently . 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 . It is speculated that the role of plakophilin-1 in translation and proliferation is involved in abnormalities in skin appendages of ED-SF patients .
Mice models in which plakophilin-1 is defective have not been reported. However, there is a naturally occurring canine model with
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.
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