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1. Epidermolysis bullosa simplex diseases and K5/K14
2. Keratoderma disorders caused by keratin mutations
3. Hair and nail defects caused by keratin mutations
4. Keratin disorders affecting other tissues
5. Possible pathology linked to simple epithelial keratin mutations
1. Epidermolysis bullosa simplex diseases and K5/K14
Epidermolysis bullosa (EB) describes a heterogeneous group of heritable skin-blistering disorders in which the epidermis comes away from the connective tissue due to a tissue breakdown in the epidermis or dermis. About 1 in 20,000 people suffer from some form of EB. EB is categorized into three main sub-types, depending upon the level of the skin in which the splitting and blistering occurs.
In dystrophic EB (DEB), recessive or dominant, the breakage occurs just below the basement membrane and the molecular cause is now known to be a range of defects in collagen VII (COL7A1).
In junctional EB (JEB), the split occurs within the basal lamina, and can be caused by any one of six genes so far: one of the three genes contributing to laminin V (LAMA3, LAMB2, LAMC2) (in the lethal or Herlitz form), the two genes contributing to a6b4 integrin (ITGB4, ITGA6)(JEB with pyloric atresia) or collagen 17 (COL17A1).
In epidermolysis bullosa simplex (EBS), blistering is due to fragility of the basal layer of epidermal keratinocytes, caused by mutations in the genes for keratins 5 (KRT5) or 14 (KRT14). By electron microscopy it can be seen that the split in the epidermis in EBS occurs within the basal keratinocyte itself, generally within the sub-nuclear cytoplasm. EBS was the first human inherited blistering disorder to be characterized at a molecular level and was also the first human disease recognized to be caused by intermediate filament mutations.
There are three main subtypes of EBS, all caused by mutations in K5 or K14:
Epidermolysis bullosa simplex, Weber-Cockayne type (EBS-WC; OMIM #131800) Weber-Cockayne EBS is regarded as the mildest form of EBS. Weber and subsequently Cockayne were the first authors to describe a subtype of epidermolysis bullosa simplex (EBS Weber-Cockayne; EBS-WC) in which blistering is usually limited to the hands and feet. Affected individuals often also suffer from palmo-plantar keratoderma (thickening of the skin on the hands and feet). The onset of blistering in patients with EBS-WC is usually in early childhood, when the child begins to walk. As with several other keratin disorders, the disorder can be temperature dependent with a worsening of symptoms in the summer months. Also called Cockayne-Touraine type epidermolysis bullosa, EBDCT. Associated type I or type II intermediate filament proteins: K5, K14 [Refs]
Epidermolysis bullosa simplex, Dowling-Meara type (EBS-DM; OMIM #131760) The Dowling-Meara type (EBS-DM), originally reported in 1954, is the most severe EBS subtype. Blisters arise in clusters (herpetiform blisters) at any body site, usually beginning within the first five days of life. The hands and feet are most severely affected, and patients with EBS-DM often also have palmoplantar keratoderma, nail dystrophy and oral ulceration. EBS-DM can be fatal in neonates due to extensive skin loss. As with other forms of EBS the blistering tends to improve in adolescence and adulthood, but the palmoplantar keratoderma tends to become more marked with age. Unlike EBS-K and EBS-WC, patients do not usually display significant seasonal variation. The diagnosis of EBS-DM is confirmed by the typical appearance on electron microscopy of an intraepidermal cleavage plain plus electron-dense aggregates (formed by non-filamentous keratin protein) within the cytoplasm of basal layer epidermal keratinocytes. Associated type I or type II intermediate filament proteins: K5, K14 [Refs]
Causative K5/K14 mutations in EBS are mostly dominant
A convergence of differing approaches led to the discovery of keratin mutations in EBS. Expression of mutated keratins in cultured cells had been shown to produce keratin aggregates. The characteristic aggregates formed in vivo in cells of patients with EBS-DM were shown to consist of keratin by immunoelectron microscopy. When mutant K5/K14 genes were expressed in the skin of transgenic mice, the mice had fragile blistering skin strikingly similar to EBS-DM. Shortly after these key observations, mutations in K14 and also K5 were identified in EBS patients.
In 1991 three groups working independently almost simultaneously reported causative mutations in EBS. Genetic linkage between EBS-K and the type I keratin gene cluster on chromosome 17q was demonstrated and the causative mutation (L384P) discovered in the 2B segment of the K14 rod domain. The first EBS-DM mutations (R125H) were discovered in the highly-conserved helix initiation motif at the beginning of helix 1A of K14. The DNA encoding this tenth codon (an arginine) of the first (1A) section of the central rod domain contains a CpG dinucleotide that is conserved in all type I keratins and represents a mutation hotspot in all these proteins. Similarly, a mutation in the conserved helix termination motif of K5 was reported in a large EBS-DM family.
Reports of K5 and K14 mutations in EBS-WC followed soon after, and these indicated a genotype-phenotype correlation between the location of the mutation within the keratin protein and the severity of the EBS disorder. In contrast to the severe EBS-DM mutations, the EBS-WC mutations in K5/K14 did not involve the two ends of the rod domain (the helix boundary motifs). In milder forms of EBS, causative mutations generally occur outside the helix boundary motifs and filaments appear essentially normal by EM.
Recessive EBS subtypes (OMIM #601001)
Epidermolysis bullosa simplex is most often expressed as an autosomal dominant trait but there have been a few reports of recessive EBS. These are also caused by mutations in the KRT5 or KRT14 genes.
The first of these was a point mutation in the 1A domain of K14, (A144E) outside the helix initiation motif. This mutation produced a very mild Weber-Cockayne-like phenotype in homozygotes whereas the parents who were heterozygous carriers of the mutation were clinically unaffected. This type of mutation has not been reported since, probably because of the rarity of recessive phenotypes and the very mild nature of this phenotype.
More cases of recessive EBS have proved to be “knock-outs” of K14, mostly showing severe generalised blistering due to complete ablation of K14 expression, with tonofilaments (keratin filament bundles) absent from basal keratinocytes on electron microscopy. K5 (the assembly partner of K14) was still detectable by immunohistochemistry, immuno-electron microscopy and immunoblotting, but K14 protein was undetectable. In one case, a homozygous 2-nucleotide deletion (313del2) led to a premature stop codon and truncation of K14 in the V1 region of the head domain. K14 mRNA was undetectable in patients’ skin due to nonsense-mediated decay of the incompletely translated mRNA. In a simultaneous publication, a homozygous nonsense mutation was described in K14 (Y204X), leading to a premature termination codon in the 1B domain and complete loss of K14 expression and identical clinical findings.
These first "knockouts" of an epidermal keratin in humans were especially interesting as it had been predicted, from mouse model phenotypes, that ablation of K14 would be fatal. (Mice lacking K14 died by the age of three months not because of skin blistering, which recovers in mice following hair growth, but rather due to oesophageal damage.) In a third severe recessive EBS family the causative defect was loss of K14 expression due to a homozygous splice site mutation. There are several affected members in this family, including individuals in the seventh decade of life, so that the phenotype would appear to be less severe in humans. It was postulated that increased expression of K15 has a compensatory effect in humans, whereas expression of this keratin appears to decrease with age in mice, possibly explaining the fatality of the K14 deficient mice. A fourth kindred has now been reported with a homozygous nonsense mutation in the helix 2 domain of K14 leading to K14 ablation and severe recessive EBS.
• Recessive epidermolysis bullosa simplex (REBS; OMIM #601001)
Associated type I or type II intermediate filament proteins: K14
[Refs]
• Recessive epidermolysis bullosa simplex, Koebner type (REBS-K; OMIM #131900)
Associated type I or type II intermediate filament proteins: K5, K14
[Refs]
• Recessive epidermolysis bullosa simplex, Weber-Cockayne type (REBS-WC; OMIM #131800)
Associated type I or type II intermediate filament proteins: K14
[Refs]
Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP; OMIM #131960) Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP) is a subtype of EBS characterized by skin blistering, mottled pigmentation of the trunk and limbs, punctate hyperkeratoses of the palms and soles, and dystrophic nails. Histologically and ultrastructurally, the blistering in EBS-MP closely resembles that found in EBS-WC, EBS-K and EBS-DM in that there is a subnuclear split through the basal keratinocytes. The genetic basis of many cases of EBS-MP has been found to be due to a heterozygous point mutation, P25L, in the V1 region of the non-helical head domain of K5. In vitro filament assembly studies using the mutant K5 reveal only slight deleterious effects and expression of the mutant K5 produced keratin filament networks indistinguishable from wild type. It remains unclear how this mutation acts to disrupt keratin filaments although it points to a subtle and hitherto undetected role for the V1 domain in filament dynamics. How these particular mutations produce pigmentary changes is equally unclear but these findings suggest that additional functions may reside in the head and tail domains of intermediate filaments. Associated type I or type II intermediate filament proteins: K5, K14 [Refs]
Dowling-Degos disease (DDD; OMIM #179850) Individuals with this disorder develop disfiguring reticulate patterns of hyperpigmentation after puberty, plus dark hyperkeratotic papules in skin flexural regions. Basal keratinocytes accumulate melanin in an irregular way compared to normal cells, and the contours of the dermo-epidermal junction may also be abnormal, with extended irregular rete peg development. Hair and nails are normal, and abnormalities in melanocytes are not implicated. Reticulate pigmentation disorders of Kitamura and Dowling-Degos may be manifestations of the same disorder. This dominant disorder appears to be caused by haploinsufficiency of K5, making it the second type of mutation pointing to a function of keratins in regulating melanosome distribution in keratinocytes (see EBS-MP, above). No homozygous knock-out mutations of K5 have ever been identified in humans, and mouse model experiments concur with this to suggest that complete loss of K5 is lethal. This disorder provides the first direct evidence of a haploinsufficiency in a keratin. Also called Dowling-Degos-Kitamura disease; reticular pigment anomaly of the flexures; Kitamura reticulate acropigmentation. Associated type I or type II intermediate filament proteins: K5 [Refs]
In the context of identifying pathogenic keratin mutations, the following disorders should also be noted:
Epidermolysis bullosa simplex and limb girdle muscular dystrophy (MD-EBS; OMIM #226670)
This autosomal recessive disorder is characterized by EBS-like skin blistering plus progressive limb-girdle muscular dystrophy. However it is not caused by keratin mutations. It was found to be caused by mutations in the plakin (or cytolinker) family member plectin, and so is fundamentally distinct from the EBS types described above. The plakins are a diverse family of multifunctional proteins known for their ability to connect different elements of the cytoskeleton with one another. Plectin contributes to the structural integrity of the hemidesmosome junctions that attach keratinocytes to the extracellular matrix of the basal lamina. Ultrastructurally, the effects of defective plectin on the epidermis can appear similar to the effects of keratin mutations of EBS, although in MD-EBS the epidermis splits in the very lowest part of the basal cytoplasm, through the hemidesmosome plaque, which is usually reduced in thickness. In small infants it can therefore be difficult to distinguish this condition from EBS caused by keratin mutations, but its different etiology becomes apparent as the muscular dystrophy develops with age.
Epidermolysis bullosa simplex, Ogna type (EBS-Ogna; OMIM #131950)
This disorder, extensively analysed by Gedde-Dahl in a large Norwegian kinship in the 1970s, and subsequently identified elsewhere, is now known to be associated with plectin mutations. It is therefore probably a variant of the MD-EBS type of disorder.
Epidermolysis bullosa simplex with maternal somatic and germline mosaicism Mosaicism has been described in a family with epidermolysis bullosa simplex. Associated type I or type II intermediate filament proteins: K5 [Refs] Epidermolysis bullosa simplex with migratory circinate erythema (EBS-MCE; OMIM #609352) Epidermolysis bullosa simplex with the involvement of an unusual migratory circinate erythema with multiple vesicles on the area affected by the erythema. The lesions, which appeared from birth primarily on the hands, feet, and legs healed with brown pigmentation but no scarring. Associated type I or type II intermediate filament proteins: K5 [Refs] Epidermolysis bullosa simplex with severe palmoplantar hyperkeratosis Epidermolysis bullosa simplex with additional phenotype of a severe palmoplantar hyperkeratosis. Associated type I or type II intermediate filament proteins: K5 [Refs] Epidermolysis bullosa simplex, Köebner type (EBS-K; OMIM #131900) Kobner reported a form of EBS with blisters predominantly on the hands and feet but also with widespread blistering elsewhere. Blisters usually occur on the hands and feet and limbs within the first week of life and sometimes become more widespread on the trunk. Blistering usually becomes limited to the hands and feet in adult life, but blistering may still occur at sites of friction or trauma. As with EBS-WC, there is a marked seasonal variation in severity of blistering. Associated type I or type II intermediate filament proteins: K5, K14 [Refs]
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2. Keratoderma disorders caused by keratin mutations
Bullous erythroderma ichthyosiformis congenita of Brocq, bullous congenital ichthyosiform erythroderma, epidermolytic hyperkeratosis (BCIE/EHK; OMIM #113800) This disorder is characterized by redness (erythroderma), blistering (bullous) and hypertrophy (ichthyosis-like) of the skin. Blistering lesions are seen at birth or soon after, similar to EBS, and can be fatal in newborn infants because of secondary infection. Blistering subsides with age but patients develop progressively thickened hyperkeratotic skin, especially at flexures. In severe cases this hyperkeratosis can be crippling. Histologically, suprabasal cell layers of the epidermis can be seen to be frequently ruptured and it may be this chronic intraepidermal wounding that triggers the hyperproliferation leading to thickened skin. By electron microscopy, the keratin filament bundles are often clumped, frequently giving the appearance of a dense perinuclear shell. The disorder is caused by autosomal dominant mutations in K1 or K10, the two major keratins expressed in suprabasal layers of keratinocytes in epidermis and other body sites where cornifying stratified squamous epithelium is seen. Thus the mutations are analogous to those in K5/K14, but the phenotypic difference arises from the different subpopulation of tissue cells that synthesize K1/K10 as major structural proteins. Also, mutations described in BCIE tend to be limited to the ends of the central helical rod domains, analogous to EBS-DM. It has been suggested that the nature of the keratin mutations may predict phenotype in BCIE, with keratin 1 mutations giving rise to a phenotype with severe palmoplantar hyperkeratosis whilst keratin 10 mutations cause a phenotype lacking palmoplantar involvement, but these correlations await confirmation with further mutation studies. A nevoid variant of BCIE has long been recognized where typical BCIE lesions occur in the distribution of Blaschko's lines. This variant has been variously labeled as ichthyosis hystrix and linear epidermolytic hyperkeratosis. Female patients with this disorder occasionally give birth to children affected with generalised BCIE. A further subtlety of the BCIE story was the discovery of a heterozygous point mutation of K10 similar to those found in BCIE in this nevoid form. This mutation was not detected in normal skin suggesting that the condition is due to a post-zygotic mutation in early development. Patients with nevoid variant who have affected children presumably have underlying gonadal as well as cutaneous mosaicism. To date BCIE is the only human keratin disease to exhibit mosaicism. Associated type I or type II intermediate filament proteins: K1, K10 [Refs]
Diffuse non-epidermolytic palmoplantar keratoderma (OMIM #600962)
In addition to the BCIE phenotypes described above, a K1 mutation has been reported in a single pedigree as causative of diffuse non-epidermolytic palmoplantar keratoderma. This mutation lies outside of the central rod domain and lies within a 22 amino acid motif referred to as the ISIS box (after part of the sequence) which is conserved in many type II keratins. The residue involved, K73I, is the residue most frequently found to be involved in cross-linking of the cornified cell envelope by transglutaminases. This ISIS box sequence has also been postulated to play a pivotal role in desmoplakin binding so the K73I substitution may act by disrupting K1 interaction with other molecules.
Epidermolytic palmoplantar keratoderma (EPPK; OMIM #144200) EPPK is an autosomal dominant genodermatosis first described by Vörner in 1901 and is characterized by epidermolytic hyperkeratosis confined to the palmar and plantar epidermis. The clinical appearances of waxy hyperkeratosis limited to the palms and soles surrounded by an erythematous border are virtually diagnostic of EPPK. This can sometimes include the involvement of knuckle pads. Keratin 9 is expressed in a very specific manner limited to palms and soles, making this a prime candidate for EPPK. Recently, genetic linkage of EPPK to the type I keratin cluster was demonstrated and with the cloning of the K9 cDNA and corresponding gene, KRT9, missense mutations have been identified in a number of EPPK families. The expression partner of K9 has not been characterized but is thought to be a K1 isoform, there are no reports in the literature of EPPK linked to the type II keratin locus but the pattern of mutations in other keratin diseases would predict that some families will be found. EPPK is possibly one of the commoner keratin diseases with an incidence of at least 4.4 per 100,000 in Northern Ireland (Irvine and McKenna, unpublished observation). To date all reported mutations in K9 have been located in the 1A domain. Associated type I or type II intermediate filament proteins: K1, K9, K10, K16 [Refs]
Palmoplantar keratoderma, nonepidermolytic (NEPPK; OMIM #600962) Non-epidermolytic palmoplantar keratoderma (NEPPK) shows a characteristic phenotype of focal palmoplantar keratoderma with oral, genital, and follicular lesions. The Unna-Thost form of palmoplantar keratoderma is clinically identical to Vorner disease but can be distinguished histologically by the absence of epidermolysis. This disorder has been associated with mutations in the KRT16 and KRT1 genes. Clinical manifestations of NEPPK are similar to those of pachyonychia congenital type 1, which is also associated with KRT16. Associated type I or type II intermediate filament proteins: K1 [Refs]
Palmoplantar keratoderma, nonepidermolytic (focal) (FNEPPK; OMIM #600962) Skin disease affecting the palms and soles in focal regions without lysis of the epidermis. Associated type I or type II intermediate filament proteins: K16 [Refs]
Ichthyosis hystrix, Curth-Mackin type (IHCM; OMIM #146590) This kind of ichthyosis hystrix is a disorder in which localized thickening or keratoderma can give the appearance of ridges or spikes on the skin surface. EM examination shows thick shells of keratin filaments packed around the nuclei of suprabasal keratinocytes in the epidermis. Mutations in K1 and K10 have both been linked to this disorder, suggesting that cell fragility underlies its pathology. The hyperkeratosis may be triggered by frequent intraepidermal cell breakages, which the tissue responds to, as to a wound, with increased proliferation. However there are other cases in which both keratin gene clusters, on chromosomes 12 and 17, have been apparently excluded by linkage analysis, suggesting that mutation in another gene may also give a similar phenotype. Associated type I or type II intermediate filament proteins: K1 [Refs]
Cyclic ichthyosis with epidermolytic hyperkeratosis (CIEH; OMIM #607602) Affected individuals show palmoplantar hypokeratosis overlaid with periodic flares of developing erythematous scaly round patches which can expand and cover large areas of the skin, lasting for a few weeks to several months before subsiding and disappearing, leaving only the hyperkeratosis. It is associated with mutations in either K1 or K10, and the filament proteins show abnormal cytoplasmic protein aggregates. There is no obvious explanation for the additional phenotype of erythematous plaques that these individuals develop. Associated type I or type II intermediate filament proteins: K10 [Refs]
Greither's syndrome (GS; OMIM #144200) Greither's syndrome is a form of diffuse non-epidermolytic type palmoplantar keratoderma, inherited in an autosomal dominant pattern. Diffuse PPK with erythema and scaling is usually associated with hyperhidrosis. Transgrediens is always present with a characteristic extension of the keratoderma to the ventral aspect of the wrist and the Achilles tendon. Two unrelated families have been described with mutations in KRT1. Associated type I or type II intermediate filament proteins: K1 [Refs]
Striate palmoplantar keratoderma (SPPK; OMIM #607654) Striate palmoplantar keratoderma is a rare autosomal dominant disorder affecting the palms and soles. Focal and linear streaks of hyperkeratosis run the length of the fingers giving this disorder a clinically distinct feature. Genetic heterogeneity has been demonstrated for SPPK with pathogenic mutations associated with desmoplakin (DSP), desmoglein 1 (DSG1) and also KRT1. Associated type I or type II intermediate filament proteins: K1 [Refs]
Ichthyosis bullosa of Siemens (IBS; OMIM #146800) This form, first described in 1937 by Siemens, is a much milder type of epidermolytic hyperkeratosis than BCIE of Brocq. It is predominantly localized to the flexures. Ichthyosis bullosa of Siemens, or IBS, can be distinguished from BCIE by the absence of erythroderma and a characteristic shedding or molting of the superficial outer layers of the epidermis, called the Mauserung phenomenon. This said, mild BCIE and severe IBS can be very difficult to distinguish clinically and some authors disputed the existence of IBS as a discrete entity until it was characterized at a molecular level. Tonofilament (keratin filament bundles) aggregation and cytolysis in IBS is limited to the upper spinous and granular cell layers of the epidermis, a pattern of involvement which is consistent with the known expression pattern of K2e late in epidermal differentiation. The first report of linkage to the keratin cluster on chromosome was followed by three simultaneous reports of mutations in K2e. Rothnagel et al found mutations in four families with IBS and in two that were initially misdiagnosed as BCIE. One mutation, a potential Methyl-CpG deamination (E493K), accounts for a disproportionate number of cases reported and probably represents a mutational hotspot in IBS. Associated type I or type II intermediate filament proteins: K2 [Refs]
Dermatopathia pigmentosa reticularis (DPR; OMIM #125595) Dermatopathia pigmentosa reticularis (DPR) is an autosomal dominant disorder very similar to Naegeli-Franceschetti-Jadassohn syndrome in presentation. Patients show a reticulate pattern of hyperpigmentation of the epidermis, together with a reduced ability to sweat, palmoplantar keratoderma and lack dermatoglyphics (fingerprint lines). They may also exhibit minor developmental defects in their hair and skin. It is distinct from NFJS in that the pigmentation defect persists throughout life, and is accompanied by partial alopecia but not dental defects. The disease has been mapped to a heterozygous nonsense mutation in K14 that results in a premature termination codon near the beginning of the protein sequence. Associated type I or type II intermediate filament proteins: K14 [Refs] Naegeli-Franceschetti-Jadassohn syndrome (NFJS; OMIM #161000) Naegeli-Franceschetti-Jadassohn Syndrome (NFJS) is an autosomal dominant disorder that presents primarily with a reticulate pattern of hyperpigmentation of the epidermis that disappears with age. In addition, patients experience reduced sweating (hypohydrosis), palmoplantar keratoderma and lack of dermatoglyphics (fingerprint lines). They may also exhibit minor developmental defects in their hair and skin; tooth development can be severely affected, with early loss of teeth. Naegeli syndrome shares many features with dermatopathia pigmentosa reticularis. The disease has been linked to heterozygous nonsense mutations of K14 resulting in very early termination of translation a short way into the head domain. Associated type I or type II intermediate filament proteins: K14 [Refs] Palmoplantar keratoderma and mild ichthyosis (PPK) Skin disease affecting the palms and soles with a mild scaling phenotype. Associated type I or type II intermediate filament proteins: K1 [Refs]
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3. Hair and nail defects caused by keratin mutations
Pachyonychia congenita type 1 (PC-1; OMIM #167200) Pachyonychia congenita (PC) describes a group of inherited ectodermal abnormalities whose most prominent clinical feature is hypertrophic nail dystrophy. There are two forms, the Jadassohn-Lewandowsky type (PC-1) and the Jackson-Lawler type (PC-2), which can be distinguished by the presence of one of two subsets of additional phenotypic traits. In the PC-1 form, pachyonychia (thickened nails) is accompanied by severe focal keratoderma, especially on the foot soles. This painful feature is usually the dominant aspect of the disorder in adults and can significantly affect quality of life. White plaques in the mouth (oral leukokeratosis) are also observed, as is follicular keratosis and hoarseness, but these are not fully penetrant and may occur in both PC-1 and PC-2. PC-2 is associated with mutations in keratins K6a or K16, normally regarded as stress response keratins which in normal skin are induced during wound healing. The distribution of the epithelial fragility phenotype closely matches the tissues known to express high amounts of K6a/K16 constitutively, i.e. not only in response to stress. However, cytolysis of cells expressing K6a/K16 as a result from the compromised function of the keratin filaments probably triggers a wound response, and thus additional synthesis of K6a/K16, which may exacerbate the condition.
There can be significant phenotypic variation between families carrying these mutations, as is being recognized for many keratinopathies. K16 mutations can present as focal keratoderma without nail changes or other features of PC-1. The reason for these phenotypic differences is not clear but appears to be unrelated to the specific genetic mutation and is therefore thought to be due to the action of additional unknown modifying genes. Associated type I or type II intermediate filament proteins: K6a, K16, K17 [Refs]
Pachyonychia congenita type 2 (PC-2; OMIM #167210) The Jackson-Lawler type of pachyonychia congenital, PC-2, is also characterized by grossly thickened finger and toe nails, but can be distinguished from PC-1 by the additional presence of (i) multiple steatocysts (developing in association with the pilosebaceous tract) which begin to appear at puberty, (ii) milder focal keratoderma than in PC-1, (iii) pili torti (twisted hairs) and (iv) natal teeth (teeth already erupted at birth). The presence of natal teeth is the least common phenotypic characteristic and its causal mechanism is not yet understood. PC-2 is caused by mutations in K6b and K17. Genetic linkage analysis in a large Glaswegian PC-2 family first indicated a type I keratin defect, and the mutation in this family was later found to be a point mutation in the 1A domain of K17. K17 mutations are now known to be consistently associated with the PC-2 phenotype, as are less frequently mutations in K6b, now known to be the expression partner of K17. Like K6a/K16, K6b/K17 are also considered to be stress response proteins although their genes are regulated by slightly different factors. K6a/K17 are also constitutively expressed in certain tissues and subpopulations of cells, irrespective of stress, and it is these tissues which are at risk of cytolysis when mutations in the genes KRT6A and KRT17 are present. Associated type I or type II intermediate filament proteins: K6b, K17 [Refs]
Monilethrix (OMIM #158000) Monilethrix is an autosomal dominant disorder characterized by varying degrees of alopecia (hair loss) and beaded hairs with an alternating structure of elliptical nodes and constrictions (internodes). The affected hairs are more susceptible to fracturing and weathering. The most common clinical presentation is alopecia with marked variation between individuals, even between members of the same family. Perifollicular hyperkeratosis is a consistent feature and keratosis pilaris is a common clinical accompaniment, as are nail abnormalities such as koilonychia, lamellar splitting and brittleness. Ultrastructural analysis of affected hair shafts showed defects in the microfibrillar structure of the hair shaft itself. This pointed to the trichocyte keratins, the structural keratins of the hair shaft, as the prime candidates for this disorder. The first mutations in a human hair keratin (trichocyte keratin Hb6, now called K86) were reported in two families in 1997. Monilethrix mutations have also been reported in another type II hair keratin, Hb1 (now K81), which is coexpressed with Hb6/K86 in cortical trichocytes of the hair shaft. As with many of the keratin disorders, monilethrix exhibits a wide degree of clinical variation within families, suggesting a role for environmental factors or disease modifying genes. Associated type I or type II intermediate filament proteins: K81, K83, K86 [Refs]
Pseudofolliculitis barbae (PB)
Sequence variants in the hair follicle-restricted keratin K6hf (now called K75) have been shown to be associated with an increase the risk of developing pseudofolliculitis barbae, a condition in which shaving leads to ingrown hair follicles and a tendency to follicular infections. This is not a direct causative association however.
Ectodermal Dysplasia, 'Pure' Hair-Nail Type (OMIM #602032) Ectodermal dysplasia that involves only the hair and the nails. Associated type I or type II intermediate filament proteins: K85 [Refs]
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4. Keratin disorders affecting other tissues
White sponge nevus of Cannon (WSN; OMIM #193900) This rather benign disorder affects the non-cornifying stratified squamous epithelial barrier tissues, and is characterized by white plaques and patches of loose skin in the mouth, often in the lining of the cheek along the buccal occlusal line. It is often picked up on dental check-ups. This oral leukokeratosis is similar to that of PC-1 caused by mutations in K6a or K16. The loose skin is caused by fragility in the suprabasal cells of the buccal epithelium, which is due to dominant negative mutations in the major oral suprabasal keratins K4 and K13. Anal and genital epithelia can also be affected, as these tissues also express K4/K13 as they differentiate. The first mutations in K4 and K13 were reported simultaneously in 1995. Associated type I or type II intermediate filament proteins: K4, K13 [Refs]
Corneal dystrophy, juvenile epithelial, of Meesmann; Meesmann Corneal Dystrophy (MCD; OMIM #122100) Meesmann corneal dystrophy is a bilaterally symmetrical, autosomal dominant disorder of the corneal epithelium, caused by mutations in K3 or K12. It can only be seen on magnification and has a characteristic slit lamp appearance of many fine, round epithelial cysts. Children are usually asymptomatic; the cysts become visible by twelve months of age and increase in number throughout life. In adulthood, rupture of the corneal microcysts begins to cause erosions, producing clinical symptoms such as photophobia, contact lens intolerance and intermittent reduction of visual acuity. Histological examination shows a disorganized and thickened epithelium with widespread cytoplasmic vacuolation and small, round, intraepithelial cysts filled with debris. Electron microscopy reveals cytoplasmic inclusions within the corneal keratinocytes, presumably keratin aggregates. Corneal keratins (K3 and K12) were thus prime candidates for causative mutations and the first mutations in KRT3 and KRT12 were reported in 1997. All K12 and K3 mutations reported to date have been within the helix boundary peptides. Associated type I or type II intermediate filament proteins: K3, K12 [Refs]
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5. Possible pathology linked to simple epithelial keratin mutations
Inflammatory bowel disease (IBD; OMIM #266600) Inflammatory bowel disease covers a heterogeneous group of disorders in which the intestinal epithelium becomes chronically eroded. It is quite common, affecting around 1/400 people in a study conducted in the US. It includes both Crohn disease and ulcerative colitis, and early onset of ulcerative colitis is associated with a high risk of colon cancer in later years. There is a clear genetic component involved in susceptibility to these disorders but despite huge efforts, the exact molecular basis of these diseases remains unknown. A number of factors suggested that keratin mutations might be involved, specifically simple keratins K8 and K18: linkage to chromosomal loci which include the keratins (IBD2 on chromosome 12, OMIM #601458), a hyperproliferative colon phenotype seen in mice with K18 ablated, and not least, the apparent lack of any recognized disease involvement of mutations in these two keratins in spite of large numbers of pathogenic mutations recorded for the other family members. A small number of mutations in the KRT8 gene have been observed in a UK patient group containing both ulcerative colitis and Crohn disease patients, affecting 5% of a Scottish population examined. K8 G62C was found in 3/100, but since these are polygenic disorders with racial bias in their etiology, more studies will be required to establish the significance of these results. Associated type I or type II intermediate filament proteins: K8 [Refs]
Liver disease K8 and K18 are the major keratins expressed in gastrointestinal epithelia, including the gut, liver and pancreas, and liver disease is often accompanied by accumulations of keratin protein (e.g. Mallory bodies). Transgenic mice with K18 mutations develop chronic hepatitis, suggesting keratin 18 as a candidate gene in patients with cirrhosis of the liver. Occasionally patients with cryptogenic cirrhosis of the liver are found to have mutations in K18 or K8. A K18 mutation (H127L) was found with this disease in a single patient. This mutation was located in the L1 domain of K18, a site where there has been no analogous mutations described in any other keratin. Mutations found in K8 are also not in the hot-spots identified in the skin keratins. The most frequent mutation is G62C in K8 (in 3 out of 55 patients), and K8 Y53H was also found in 2/55 patients. Subsequently, occasional rare mutations in K8 have turned up in other liver disorders including alcoholic hepatitis, biliary atresia, primary biliary cirrhosis, fulminant hepatitis and hepatitis B and C livers. The situation is very similar to that pertaining in inflammatory bowel disease; all these mutations can be shown to disturb keratin function in laboratory experiments, and the hypothesis is that in vivo these mutations may be risk factors for liver disease. Associated type I or type II intermediate filament proteins: K8, K18 [Refs]
Pancreatitis Pancreatitis has been associated with many different genes, but a recent addition to this list is the simple keratins K8/K18. Rare mutations in simple keratins have been identified in patients with pancreatitis. Associated type I or type II intermediate filament proteins: K8 [Refs]
Diseases of keratin-associated molecules
The intermediate filament cytoskeleton directly associates with a number of subcellular structures, including desmosomes, hemidesmosomes and proteins of the cornified cell envelope. In recent years, epidermal fragility diseases have begun to emerge which are due to mutations in molecules of these attachment complexes. Mutations which cause loss of plectin, a high-molecular weight intermediate filament-binding protein, have been shown to cause EBS with muscular dystrophy (EB-MD or MD-EBS), demonstrating the essential role of this protein in hemidesmosomes and in mediating cytoskeletal cross-linking in muscle. Similarly, loss of plakophilin, has been shown to lead to a phenotype of skin fragility and ectodermal dysplasia, revealing that this molecule is an essential link in keratin-desmosome association. In both these cases, essential biological functions for widely expressed proteins have been elucidated from the study of rare genetic disorders.
Acute fulminant hepatitis Liver disease. Associated type I or type II intermediate filament proteins: K18 [Refs] Cryptogenic cirrhosis (OMIM #215600) Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrotic scar tissue as well as regenerative nodules, leading to progressive loss of liver function. Associated type I or type II intermediate filament proteins: K8, K18 [Refs] Hepatic artery thrombosis Liver disease. Associated type I or type II intermediate filament proteins: K18 [Refs] Noncryptogenic cirrhosis (OMIM #215600) Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrotic scar tissue as well as regenerative nodules, leading to progressive loss of liver function. Associated type I or type II intermediate filament proteins: K8 [Refs] Primary biliary cirrhosis (PBC; OMIM 109720) Primary biliary cirrhosis is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts (bile canaliculi) within the liver. Liver damage is caused when bile builds up over time (cholestasis). This can lead to scarring, fibrosis, cirrhosis, and ultimately liver failure. Associated type I or type II intermediate filament proteins: K18 [Refs] Viral hepatitis Viral liver disease. Associated type I or type II intermediate filament proteins: K8 [Refs]
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6. Others Pseudofolliculitis barbae (PFB) Sequence variants in the hair follicle-restricted keratin K6hf (now called K75) have been shown to be associated with an increased risk of developing pseudofolliculitis barbae, a condition in which shaving leads to ingrown hair follicles and a tendency to follicular infections. This is not a direct causative association however. Associated type I or type II intermediate filament proteins: K75 [Refs] Steatocystoma multiplex (SM; OMIM #184500) At least one form of steatocystoma multiplex is associated with mutations in keratins K6b/K17 and as such is closely related to PC-2. Patients develop multiple steatocysts over their body, with or without mild nail changes and with or without mild focal keratoderma. Steatocystoma multiplex (sebaceous cysts) appears to be a milder consequence of mutations in K6b/K17 than PC-2. This is reminiscent of the relationship between EBS Dowling-Meara and EBS Weber-Cockayne. Families presenting with steatocystoma multiplex may have mutations in K17 without abnormalities of nails or other ectodermal structures. However there is no clear relationship between these phenotypic variations and the location of the mutations within the gene/protein, and the variability is therefore thought to be due to the action of additional unknown modifying genes. Associated type I or type II intermediate filament proteins: K17 [Refs] [Back to index] Last modified: August 27 2008 16:55:00. |
