Epidermolysis Bullosa Simplex with Mottled Pigmentation Resulting from a Recurrent Mutation in KRT14

Harel, Avikam; Bergman, Reuven; Indelman, Margarita; Sprecher, Eli

doi:10.1038/sj.jid.5700296

Cited by 39 publications

(39 citation statements)

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“…Recently, a recurrent mutation in the 1A domain of K14 (p.Met119Thr) has been disclosed in EBS-MP, that aVects a highly conserved residue that is involved in KIF formation. p.Met119Thr has been reported in various forms of EBS (Cummins et al 2001) suggesting the existence of modifying traits in EBS (Harel et al 2006). Although the pathomechanisms underlying the unique phenotype is still elusive, the non-helical head domain of K5 has been implicated in melanosome transport (Irvine et al 2001) which could explain the pigmentary changes and the ultrastructural Wnding of increased melanosomes within basal keratinocytes, dermal macrophages and Schwann cells (Uitto et al 2007).…”

Section: Epidermolysis Bullosa Simplexmentioning

confidence: 98%

The molecular basis of human keratin disorders

Arin

2009

Hum Genet

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Keratins are cytoskeletal proteins that provide structural support to epithelial cells and tissues. Perturbation causes cell and tissue fragility and accounts for a large number of genetic disorders in humans. In humans, 54 functional keratin genes exist and 21 different keratin genes including hair keratins and hair follicle-specific epithelial keratins have been associated with hereditary disorders. Moreover, keratins have been implicated in more complex traits such as liver disease and inflammatory bowel disease. Understanding the molecular basis of keratin disorders has been the basis for improved diagnosis with prognostic implications, genetic counseling and prenatal testing for severe disorders. Besides their mechanical role, keratins have newly identified functions in apoptosis, cell growth, tissue polarity, wound healing and tissue remodeling. Improved understanding of the regulatory functions of keratins may offer novel approaches to overcome current treatment limitations.

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Section: Epidermolysis Bullosa Simplexmentioning

confidence: 98%

The molecular basis of human keratin disorders

Arin

2009

Hum Genet

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“…82) or K14 (e.g., Met119→Thr; ref. 83). The 1649delG allele of K5 can also result in EBS-Migr, and this too is characterized by the appearance of hyper- or hypopigmented skin patches in adults (76).…”

Section: Figurementioning

confidence: 99%

Epidermolysis bullosa simplex: a paradigm for disorders of tissue fragility

2009

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Epidermolysis bullosa (EB) simplex is a rare genetic condition typified by superficial bullous lesions that result from frictional trauma to the skin. Most cases are due to dominantly acting mutations in either keratin 14 (K14) or K5, the type I and II intermediate filament (IF) proteins tasked with forming a pancytoplasmic network of 10-nm filaments in basal keratinocytes of the epidermis and in other stratified epithelia. Defects in K5/K14 filament network architecture cause basal keratinocytes to become fragile and account for their trauma-induced rupture. Here we review how laboratory investigations centered on keratin biology have deepened our understanding of the etiology and pathophysiology of EB simplex and revealed novel avenues for its therapy.Introduction to epidermolysis bullosa simplex Epidermolysis bullosa (EB) is a grouping of rare genetic conditions in which bullous lesions (fluid-filled cavities, or blisters, larger than 0.5 cm) affecting primarily the skin arise after exposure to mechanical trauma (1). Three major forms of EB have been defined using clinical and histological criteria. The dystrophic, junctional, and simplex forms of EB are characterized by loss of tissue integrity in the upper dermis, at the dermo-epidermal interface, and within the epidermis, respectively (Figure 1) (2, 3). With rare exceptions, EB simplex is inherited in an autosomal dominant fashion. Although EB simplex is the most frequently occurring form of EB (approximately 1 case per 25,000 live births), it also is the least severe (2, 4-6). In this Review, we summarize current knowledge of the etiology and pathophysiology of EB simplex, discuss what this condition tells us about the properties and roles of keratin, and outline progress toward therapeutic intervention.In EB simplex, trauma-induced loss of tissue integrity consistently occurs within the basal layer of epidermal keratinocytes (Figures 1 and 2). The inherited defect renders basal keratinocytes fragile, causing them to rupture when the epidermis (and, in some cases, other stratified epithelia) is subjected to mechanical stress (Figures 1 and 2). Associated skin pigmentation anomalies can occur (see below), but terminal epithelial cell differentiation and epidermal barrier function appear normal.Several clinical variants of EB simplex have been described. The most frequent and widely known variants - EB simplex-generalized (EBS-generalized; in which the distribution of blistering is "generalized" over the body), EB simplex-localized (in which the distribution of blistering is "localized," e.g., primarily restricted to hands and feet), and EB simplex Dowling-Meara (EBS-DM; in which blisters are also generalized but show a distinct "herpetiform" or clustered pattern) - differ primarily according to the distribution, frequency, and severity of skin blistering over the body (Table 1). These variants also show key ultrastructural differences ( Figure 3) and vary in the involvement of other epithelia and their prognosis (Table 1). Other forms of EB simplex are les...

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“…3 Although EBS has been shown to result from mutations in at least six genes including KRT5, KRT14, PLEC1, PKP1, DSP and ITGB4 coding for keratin 5, keratin 14, plectin, plakophilin 1, desmoplakin and a6b4 integrin, respectively, mutations in KRT5 and KRT14 are considered to cause almost all cases of EBS. 4 Patients with recessive EBS represent approximately 5% of EBS mutations. 5 To our knowledge, there are 13 previously reported cases of autosomal recessive EBS with a KRT14 mutation: four with nonsense mutations, three with deletion mutations, two with missense mutations, one with a splice site mutation, one that was compound heterozygous for nonsense and missense mutations, one with a deletion ⁄inser-tion mutation, and one with a duplication mutation.…”

Section: Resultsmentioning

confidence: 99%

A novel homozygous keratin 14 mutation in a patient with autosomal recessive epidermolysis bullosa simplex and squamous cell carcinoma of the tongue

Baek

Lee

et al. 2010

British Journal of Dermatology

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Epidermolysis bullosa simplex (EBS) is a group of inherited skin disorders characterized by lysis of basal keratinocytes leading to the development of intraepidermal blisters from mild trauma. 1 EBS is known to be an autosomal dominant disorder; however, a few recessive cases have been reported. In EBS, the risk of cutaneous malignancy is not higher than in the normal population. 2 We present a patient who showed generalized blistering after minor trauma followed by brownish reticulated hyperpigmentation and squamous cell carcinoma of the tongue. We identified a novel homozygous KRT14 mutation (E392X) inherited in an autosomal recessive fashion. Case and methodsA 41-year-old Korean man was referred because of a lifelong tendency to develop blisters on his whole body in response to minimal trauma. Three months before admission, he detected a painful ulcerative mass on his lateral tongue and was diagnosed with squamous cell carcinoma. Clinical examination showed scattered blisters and superficial erosions on the sites of previous trivial trauma such as the trunk, extremities and palms ( Fig. 1a), generalized brownish reticulated patches ( Fig. 1b), punctuate keratoderma of the palms (Fig. 1c) and relatively diffuse keratoderma of the soles (Fig. 1d), hallux valgus deformities of the great toes, and dystrophic toenails (Fig. 1e). Hair and eyes were not affected. He was the son of unaffected parents of Korean origin without apparent consanguinity and he denied any of his relatives having a blistering disease. There was a history of frequent blistering of his tongue at the tumour site and a history of multiple dental caries. From early childhood, the patient developed palmoplantar punctuate hyperkeratosis and dystrophic toenails. Skin fragility had not lessened with age. All laboratory tests were negative or within normal limits. Histological examination revealed a subepidermal blister on staining with haematoxylin and eosin. Direct immunofluorescence was negative for IgG, IgM, IgA, C3, C4 and fibrinogen. Electron microscopy confirmed reduced keratin filaments and lysis of the basal keratinocytes. Mutation analysis was performed by polymerase chain reaction amplification of all the exons of the keratin 5 and keratin 14 genes from genomic DNA. Results and discussionA homozygous guanine to thymine transition at residue 1174 of the KRT14 genomic sequence was identified (Fig. 2). This nonsense mutation converts a glutamate residue at codon 392 to a stop codon. To exclude the possibility of selective amplification of one allele, we performed restriction fragment length polymorphism analysis with 50 unrelated controls and confirmed a homozygous mutation (Data S1; see Supporting information). However, due to the absence of parental DNA there is still a remote possibility of heterozygosity. The patient was diagnosed with autosomal recessive EBS with a novel homozygous KRT14 mutation.EBS is usually inherited in an autosomal dominant fashion, but there are several types which are inherited in an autosomal recessive fashion such...

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Epidermolysis Bullosa Simplex with Mottled Pigmentation Resulting from a Recurrent Mutation in KRT14

Cited by 39 publications

References 30 publications

The molecular basis of human keratin disorders

The molecular basis of human keratin disorders

Epidermolysis bullosa simplex: a paradigm for disorders of tissue fragility

A novel homozygous keratin 14 mutation in a patient with autosomal recessive epidermolysis bullosa simplex and squamous cell carcinoma of the tongue

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