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Keratins and their associated skin disorders

European Journal of Dermatology. Volume 17, Number 2, 123-9, March-April 2007, Review article

DOI : 10.1684/ejd.2007.0123

Summary

Author(s) : Meral J Arin, Felix B Mueller , Department of Dermatology, University of Cologne, Kerpener Strasse 62, 50924 Cologne, Germany.

Summary : Keratins are the largest group of intermediate filament proteins that are expressed in the cytoplasm of epithelial cells. They form a cytoskeletal scaffold that maintains cell and tissue integrity and provides vital mechanical support to epithelia. Mutations in 19 different keratin genes have so far been identified as the cause of at least 15 different genetic diseases. Identification of the molecular basis of the keratin disorders has contributed to definite diagnoses and has facilitated genetic counselling. Better understanding of the structure, function and regulatory mechanisms of keratins will be the basis for the development of novel therapeutic approaches to overcome the current treatment limitations.

Keywords : keratin, genodermatosis, mutation

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ARTICLE

Auteur(s) : Meral J Arin, Felix B Mueller

Department of Dermatology, University of Cologne, Kerpener Strasse 62, 50924 Cologne
Germany

accepté le 8 Decembre 2006

The epidermis is a self-renewing tissue where stem cells within the basal layer give rise to keratinocytes that are committed to terminal differentiation. This process of epidermal differentiation is characterised by major changes in the expression of keratins, structural proteins that build up a three-dimensional cytoskeletal scaffold of intermediate filaments in the cytoplasm of epithelial cells [1].Keratins are classified into two groups according to their biochemical properties, type I or acidic keratins (keratins K9-K20 and Ha trichocyte keratins) and type II basic keratins (keratins K1-K8 and Hb trichocyte keratins). Just recently, a revised nomenclature has been proposed that accommodates functional genes and pseudogenes and offers the incorporation of keratins from other mammalian species. This nomenclature is divided into three categories: (1) epithelial keratins, (2) hair keratins, (3) keratin pseudogenes [2].Keratins share a common domain structure with other intermediate filament proteins [3] and contain an alpha-helical central rod domain that is interrupted by non-helical linkers and flanked by amino-terminal head and carboxy-terminal tail domains (figure 1). The start of the 1A rod domain and the end of the 2B rod domain, the so-called helix initiation (HIP) and helix termination peptides (HTP), respectively, are highly conserved among the different keratins and play a pivotal role in keratin intermediate filament assembly and elongation [4]. These helix boundary peptides represent genetic “hot spots” for mutations in almost all hereditary keratin disorders. Variations in the head and tail domains account for much of the diversity among the individual keratin proteins within one group. It thus appears likely that these domains play an important role in adapting keratin polymers to the requirements of the cell they are located in. The simplest soluble unit of keratin intermediate filament proteins is a tetramer of two antiparallel heterodimers that consist of one type I and one type II keratin molecule. From this cytoplasmic pool of subunits linear protofilaments are formed that associate pairwise to protofibrils. Four of these protofibrils build up the mature 10-12 nm intermediate filament [5].Epidermal keratinization is a tightly regulated process that enables epidermal cells to withstand mechanical stress and leads to the formation of the cornified cell envelope as a protective barrier against the environment and water loss. During this process, keratins are expressed that are highly specific for the state of differentiation. In the basal layer, keratinocytes express the keratin pair K5 and K14. As the cells move out of the proliferative compartment, K5 and K14 are down-regulated while the differentiation-specific keratins, K1 and K10 are expressed [6]. These suprabasal keratins account for 85% of the total protein of the fully differentiated squames that are sloughed from the skin surface. There are a number of keratins with a restricted tissue distribution, such as K9 in suprabasal cells of palmoplantar skin and K2e which is found in keratinocytes of the upper spinous and granular layers of the epidermis [7]. Non-cornifying cells of the stratified mucosa express K4 and K13 and suprabasal cells of the corneal epithelia express K3 and K12. In normal epidermis, keratin 6 and 16 expression is restricted to the outer root sheath of the hair follicle, nail bed, palmoplantar skin and the suprabasal layer of the orogenital mucosa. K17 is expressed in the nail bed, hair follicle, sebaceous glands, and other epidermal appendages [8]. K6, K16 and K17 are rapidly induced by stress and wounding.Over the past decade, the genetic bases of a number of structural genodermatoses have been elucidated. The largest group are caused by mutations in keratin genes. Mutations in 19 different keratin genes have so far been identified as the cause of at least 15 different genetic diseases (Table 1).Most disorders are transmitted in an autosomal dominant mode, although there are some reports of recessive transmission. In some keratin disorders, the site of mutation and amino acid substitution may allow prediction of the phenotype [9]. As more mutations are being reported, genotype-phenotype correlations have become more complex [10]. Environmental, genetic and epigenetic modifiers may account for the clinical heterogeneity and knowledge of these variations is important for molecular diagnosis and genetic counselling.A complete catalogue with details of all reported mutations in human keratins can be found at the Intermediate Filament Mutation Database (http://www.interfil.org).

Bullous Congenital Ichthyosiform Erythroderma (BCIE) (OMIM 113800)

Bullous congenital ichthyosiform erythroderma (BCIE), also known as epidermolytic hyperkeratosis (EHK) is transmitted in an autosomal dominant fashion, yet a high frequency of spontaneous mutations (up to 50%) occur. EHK presents at birth or shortly thereafter as erythema, blistering, and peeling (figure 2C). Erythroderma and blistering diminish during the first year of life and hyperkeratoses develop, predominantly over the flexural areas of the extremities (figure 2D). There is notable perinatal mortality and childhood morbidity from epidermal erosions and infections. Clinical heterogeneity is high between BCIE families, but the disease phenotype is constant between affected members of the same family. The various clinical presentations of EHK can be separated into two primary types based on the presence or absence of severe palmoplantar hyperkeratosis, including non-palmoplantar EHK (without severe palm/sole hyperkeratosis) and palmoplantar EHK (with severe palm/sole hyperkeratosis) [11]. Clumping of keratin filaments in the suprabasal layers of the epidermis leads to lysis of suprabasal keratinocytes and a thickened stratum corneum. Several point mutations in the genes for the suprabasal keratins, K1 and K10, have been identified [12-14]. The majority of the mutations in K10 are located in the same codon, affecting an evolutionarily highly conserved arginine residue. Interestingly, the same arginine residue has been found to be mutated in KRT14 in the Dowling-Meara form of epidermolysis bullosa simplex (EBS-DM), the most severe form of EBS. Mutations in milder cases have been found in less conserved regions outside or within the rod domain. Defects in keratin 1 are associated with palmoplantar EHK; defects in keratin 10 are mostly associated with the non-palmoplantar variants [11].

Just recently, a recessive form of EHK has been reported with a severe phenotype due to a homozygous nonsense mutation of the KRT10 gene, resulting in degradation of the KRT10 transcript and complete absence of keratin K10 protein in the epidermis and cultured keratinocytes of homozygous patients [15].

Epidermal nevus of the epidermolytic hyperkeratotic type (OMIM 600648) is a mosaic form of BCIE that is due to postzygotic, spontaneous mutations in KRT1 and KRT10 that occur during embryogenesis. Affected skin alternates with normal skin, and the distribution of the patchy or linear skin lesions is often along the lines of Blaschko. Vertical transmission of the mutation is possible if the germline is involved, causing generalized BCIE in the affected offspring [16].

Cyclic ichthyosis with EHK (OMIM 607602) is also reported as annular ichthyosis variant of EHK with polycyclic psoriasiform plaques. It presents at birth with redness and superficial erosions that improve during the first months of life and are replaced by scaling and palmoplantar keratoderma. Flares of annular, scaly plaques that coalesce and persist for several weeks are characteristic. Between the flares, the skin is normal except for hyperkeratoses on palms and soles. Mutations in the end of the 2B rod domain of KRT1 have been identified in this variant of EHK [17].
Table 1 Expression pattern of keratins and the associated human disorders. The designation of the keratins is used according to the current nomenclature of keratins [2], the former designation is given in brackets. ^{*, ¶} indicates diseases for which mutations have been found in only one of a keratin pair

Type II	Type I	Expression pattern	Human disease
K1*	K10^¶	suprabasal cells of cornified squamous epithelia	Bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis
Autosomal recessive epidermolytic hyperkeratosis^¶
Diffuse non-epidermolytic palmoplantar keratoderma*
Ichthyosis hystrix Curth-Macklin*
Palmoplantar keratoderma with tonotubules*
K3	K12	Corneal epithelium	Meesmann corneal epithelial dystrophy
K4	K13	suprabasal cells of non-cornified squamous epithelia	White sponge nevus
K5*	K14^¶	basal cells of stratified epithelia	Epidermolysis bullosa simplex types Weber-Cockayne, Koebner, Dowling-Meara
Autosomal-recessive Epidermolysis bullosa simplex^¶
EBS with mottled pigmentation*
Dowling-Degos disease*
K6a	K16*	suprabasal orogenital mucosa; palmoplantar epidermis; epidermal appendages, epidermal expression induced by trauma/wound healing	Pachyonychia congenita type I
Focal non-epidermolytic PPK*
K6b	K17*	like K6a/K16	Pachyonychia congenita type II
Steatocystoma multiplex*
K2 (K2e)		Upper spinous and granular layer of cornified squamous epithelia	Ichthyosis bullosa of Siemens
	K9	Suprabasal layers of palmoplantar epidermis	Epidermolytic palmoplantar keratoderma
K8	K18	Simple epithelia	Various liver diseases, inflammatory bowel disease
K31 (Ha1)	K81 (Hb1)*	Hair shaft	Monilethrix*
K33 (Ha3)	K83 (Hb3)*
K36 (Ha6)	K86 (Hb6)*

Ichthyosis hystrix of Curth-Macklin (OMIM 146590)

Ichthyosis hystrix of Curth-Macklin is a rare autosomal dominant disorder characterised by verrucous hyperkeratosis and palmoplantar keratoderma, but displays no skin fragility. This ichthyosis is clinically heterogeneous since palmoplantar keratoderma can be present [18] or absent [19, 20]. Peculiar ultrastructural features consist of bi-nucleated cells without signs of epidermolysis or keratin clumping. In one family with IHCM, a mutation in the V2 domain of KRT1 has been identified. In contrast to keratin mutations affecting the alpha-helical rod domains that disturb oligomerization and filament assembly, the V2 mutation apparently does not inhibit keratin intermediate filament (KIF) formation. The study suggests a critical function for the keratin 1 tail domain in mediating the supramolecular organization of KIF and a role in cornified cell envelope formation [18].

Palmoplantar Keratoderma, epidermolytic and non-epidermolytic (OMIM 144200, 600962)

Palmoplantar keratoderma (PPK) is characterised by hyperkeratotic skin changes confined to palms and soles and can be grouped clinically into three distinct patterns: diffuse, focal and punctate. Epidermolytic palmoplantar keratoderma is an autosomal dominant disorder characterised by a thick and diffuse palmoplantar hyperkeratosis (figure 2F) developing in the first months after birth. The severity of hyperkeratosis varies markedly between families and among members of the same family. Additional features frequently seen are knuckle pad-like keratoses over the flexural areas of the finger joints and clubbing of the nails [21]. The Vörner type is clinically identical to the form described by Unna-Thost but both forms can be distinguished histologically by presence or absence of epidermolytic hyperkeratosis and at the ultrastructural level by presence or absence of suprabasal keratin filament clumping, respectively [22]. Histological re-investigation of the kindred originally described by Thost in 1880 revealed features of epidermolytic hyperkeratosis, suggesting that the two conditions are in fact a single entity [23]. However, cases exist with diffuse PPK and without keratin clumping. Both epidermolytic (Vörner) and non-epidermolytic (Unna-Thost) forms have been observed with various mutations in the HIP and HTP of keratins K1 and K9, but not all Vörner type patients reveal KRT9 mutations [24, 25]. KRT1 mutations in non- epidermolytic PPK affect the amino-terminal variable end region which is implicated in supramolecular interactions of keratin filaments.

Focal non-epidermolytic PPK can occur as a symptom of pachyonychia congenita type I (PC-1, see below) but has also been described as an isolated trait. Mutations in KRT16 can be found in both the isolated and the PC-1 associated variant [26].

Palmoplantar Keratoderma with tonotubules

Just recently, autosomal-dominant palmoplantar keratoderma has been described with a peculiar ultrastructural finding consisting of tubular keratin structures in the cytoplasm of suprabasal cells. A novel mutation at the beginning of the 1B domain of K1 was identified in two unrelated families. The unusual gain-of-function mutation points to a subtle role of the 1B domain in mediating filament-filament interactions with regular periodicity [27].

Ichthyosis Bullosa of Siemens (IBS) (OMIM 146800)

Ichthyosis bullosa of Siemens is a dominant autosomal ichthyotic disease characterised by the absence of congenital erythroderma and by milder blistering than usually seen with BCIE although clinical distinction can be very difficult. The fragility of the epidermis is more superficial with shedding that leads to characteristic denuded areas (molting or Mauserung phenomenon) and hyperkeratoses with a lichenified appearance over the flexural areas [28]. Tonofilament clumping is confined to the upper spinous and granular layers of the epidermis consistent with the tissue expression of K2. Mutations in the helix termination motif of K2 have been identified and probably this region represents a genetic “hot spot”. Interestingly, KRT2 mutations were found as the underlying genetic defect in families previously misdiagnosed as EHK [29].

Pachyonychia Congenita (PC); Type I Jadassohn-Lewandowsky Pachyonychia Congenita (OMIM 167200); Type II Jackson-Sertoli Pachyonychia Congenita (OMIM 167210)

Pachyonychia congenita (PC) is a group of autosomal dominant dysplasias characterised by hypertrophic nail dystrophy accompanied by other features of ectodermal dysplasia. In pachyonychia congenita type I (PC-1), hypertrophic nail dystrophy is accompanied by focal palmoplantar keratoderma and variable features of oral leukokeratosis and follicular keratosis. In the Jackson-Sertoli form (PC-2, also known as Jackson-Lawler type), pachyonychia and mild focal keratoderma are accompanied by multiple pilosebaceous cysts that develop after puberty. Pilosebaceous cysts are caused by hyperkeratosis of the infundibulum and accompanying sebaceous gland. Natal teeth and hair abnormalities are associated features but are not fully penetrant. Corneal dystrophy may be a feature exclusively found in PC-2. In contrast to PC-1, PC-2 has minimal oral involvement and milder keratoderma and multiple steatocystomas [30].

PC-1 has been associated with mutations in the genes for K6a and K16 which are expressed in the nail bed and nail fold as well as in palmoplantar skin and oral mucosa. Keratins K6b and K17 which are mutated in pachyonychia congenita type II are found in the nail bed, hair follicle, eccrine glands and in palmoplantar skin [31-33]. Overlapping clinical features of PC-1 and PC-2 have been shown to result from a deleterious mutation in KRT6a [34]. A mutation in KRT16 was found in an unilateral palmoplantar nevus [35].

Steatocystoma multiplex (OMIM 184500)

Patients with steatocystoma multiplex habour multiple, up to 2000 round to oval cystic tumors that are widely distributed on the trunk, arms, thighs and scrotum. Mutations in KRT17 have been found and it was suggested that steatocystoma multiplex and pachyonychia congenita should be considered to be at opposite ends of phenotypic expression of the same disorder [36].

Monilethrix (OMIM 158000)

Monilethrix is an autosomal dominant disorder with a variable clinical presentation, from dystrophic hair confined to a small area to almost total alopecia. Beaded hair shafts are characteristic and are caused by periodic narrowing of the shaft [37]. Hairs break at the constricted sites which results in varying degrees of alopecia with short and sparse scalp hair. Perifollicular hyperkeratosis is a consistent feature and nail defects may be present. Ultrastructural examination of affected hair shows structural defects in the cortex and clumps of the structural proteins of the hair shaft, the hair keratins. Mutations in the hair cortex keratins KRTHB1, KRTHB3 and KRTHB6, now denoted KRT81, KRT83 and KRT86 have been identified [38]. Just recently, mutations in desmoglein 4 (DSG4) have been disclosed [39].

Epidermolysis bullosa simplex (EBS; OMIM 131800, 131900, 131760)

Epidermolysis bullosa simplex comprises a group of autosomal dominant disorders that are characterised by the development of intraepidermal blisters upon minor mechanical trauma [40]. According to the clinical extent and the severity of symptoms, EBS is subdivided into three major subtypes. The most common and mildest form is epidermolysis bullosa simplex-Weber Cockayne (EBS-WC; OMIM 131800) where blistering is limited to the hands and feet. Blisters are not present at birth, but develop later after an identifiable traumatic event. Secondary infections of blistering lesions on the feet are the most common complication. The Köbner type (EBS-K; OMIM 131900) manifests usually within the first months of life. Blistering is generalized, but relatively mild and hands and feet are usually affected. In the most severe subtype, the Dowling-Meara form (EBS-DM; OMIM 131760) extensive blistering in a grouped, “herpetiform” fashion manifests at birth and erosions and areas of denuded skin are present (figure 2A). Serous and hemorrhagic blisters develop on the entire skin, but most frequently on palms and soles, around the mouth, on the trunk and neck. Oral mucosal involvement, progressive palmoplantar keratosis and nail dystrophies are common. Usually the lesions heal without scarring, however inflammation especially of hemorrhagic blisters may be followed by milia formation (figure 2B). EBS-DM with extensive involvement may be associated with death in the neonatal period. Ultrastructural examination of skin biopsies shows the characteristic clumps of keratin intermediate filaments in the cytoplasm of basal keratinocytes [41].

Mutations in the basal keratins, KRT5 and KRT14 have been identified in EBS [42-44]. The clinical severity is related to the location of the mutations and the degree to which these mutations perturb keratin structure. EBS-DM mutations are generally restricted to the helix boundary peptides of K5 and K14 which marks the importance of these structures for keratin intermediate filament assembly and elongation. However, conservative amino acid changes within these regions as well as complete disintegration of their amino acid sequences by frame shift mutations may result in milder disease phenotypes [45]. In the Köbner and Weber-Cockayne forms of EBS, point mutations tend to be within the non-helical linker domains or within the central rod domains [10, 46].

Autosomal recessive EBS (OMIM 601001) is rare and presents as mild generalized blistering. The underlying defects are premature termination codons in keratin 14 leading to a functional knockout of this keratin [47].

EBS with mottled pigmentation (OMIM 131960) is an autosomal dominant subtype of EBS where pigmentation is an additional feature. Patients present with skin blistering from birth resembling EBS-K and in addition develop hyper- and hypopigmented spots on the trunk and limbs. Palmoplantar keratoses and nail dystrophy are associated features. A mutation in the V1 domain of keratin 5 has been disclosed [48], but it remains unclear how this mutation causes the pigmentary changes.

Dowling Degos disease (DDD; OMIM 179850)

Dowling Degos disease is an autosomal dominant disorder characterised by progressive reticulate hyperpigmentation that manifests after puberty and hyperkeratotic brown papules located in the flexural folds. Loss of function mutations in keratin 5 have been identified and are the first mutations that lead to haploinsufficiency in a keratin gene [49]. The pigmentary changes in EBS with mottled pigmentation and DDD suggest a distinct role of keratin 5 in melanosome transport.

Extracutaneous keratin disorders

White sponge nevus of Cannon (WSN; OMIM 193900)

White sponge nevus can affect vagina, rectum and the nasal cavity by thickened, white lesions. The plaques often undergo periods of remission and exacerbation. Mutations in the mucosal keratins K4 and K13 cause this disorder [50, 51].

Meesmann corneal dystrophy (OMIM 122100)

Meesmann corneal dystrophy is an autosomal dominant disorder due to mutations in the cornea-specific keratins K3 and K12. Heterozygous missense mutations in these genes were found in large German and Northern Irish kindreds [52]. The condition usually appears in the first years of life with signs of irritation. Vision is only rarely impaired to a serious degree.

Therapeutic approaches

Advancements in the understanding of the molecular pathophysiology of the keratin disorders have provided the basis for the efforts to develop effective gene und protein therapy approaches. Most keratin diseases are transmitted in a dominant mode, i.e. a normal copy of the gene is present and its function is disrupted by the dominant-negative effect of the mutant gene. Thus, gene therapy approaches have to selectively deactivate the mutant allele. Several approaches are being explored, such as mRNA deactivation by the use of ribozymes, small catalytic RNA molecules that can cleave specific target mRNA sequences [53, 54] or based on siRNA (short inhibitory RNA) technology [55]. Development of chimeric gene repair oligonucleotides, small DNA-RNA hybrid molecules that can target and correct a specific mutation, has been exploited in vivo in mice with albinism and shows promising results [56]. Interestingly, data from mouse models for epidermolytic hyperkeratosis and epidermolysis bullosa simplex suggest that amelioration of the phenotype can be achieved by partial suppression of the mutant allele or overexpression of the normal allele, thus altering the ratio of wild-type to mutant protein [57, 58]. Another potential approach is ectopic expression of other intermediate filament proteins, such as desmin. Since these type III intermediate filament proteins cannot polymerize with keratins, they are not affected by the keratin mutations. This approach has been taken in keratin 5 knockout mice to supplement the abnormal keratin cytoskeleton, but was not able to rescue the severe lethal phenotype [59]. It is tempting to speculate that in the future therapeutic approaches with drugs that can down-regulate the expression of the mutant keratin may be beneficial.

Acknowledgements

This work was supported by network grants of the BMBF (Bundesministerium für Bildung und Forschung), Network for Ichthyoses and Related Keratinization disorders, NIRK and Network Epidermolysis bullosa to MJA.

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