Inherited defects in keratins

doi:10.1016/j.clindermatol.2004.09.014

Clinics in Dermatology

Volume 23, Issue 1, January–February 2005, Pages 6-14

https://doi.org/10.1016/j.clindermatol.2004.09.014 Get rights and content

Abstract

In the years following the initial reports of keratin gene mutations in epidermolysis bullosa simplex, great strides have been made in understanding the basic biology of human keratins and in understanding the etiology and pathogenesis of a number of specific human single gene disorders. A total of 19 human keratin genes is now linked to specific diseases. This article summarizes current knowledge in relation to basic keratin biology, known disease associations, and genotype correlation in this diverse and complex group of conditions.

Section snippets

Keratins: basic biology

The cytoplasm of animal cells is structured by scaffolding composed of actin microfilaments, microtubules, and intermediate filaments. The largest group within the intermediate filament family is the keratins (types I and II intermediate filament proteins), which are expressed specifically in the cytoplasm of epithelial cells where they form a dense meshwork of 10-nm filaments (Fig. 1).¹ In 1977, work on sheep wool keratins had suggested a classification of keratins into 2 subtypes. This

Genetic disorders due to mutations in human keratins

Since 1991, mutations in several keratin genes have been found to cause a variety of human diseases affecting the epidermis and other epithelial structures (Table 1). Epidermolysis bullosa simplex (EBS) was the first keratin disease to be identified with mutations in both the K5 and K14 genes rendering basal epidermal keratinocytes less resilient to trauma and resulting in skin fragility.7., 8., 9. Since mutations were identified in the basal cell keratins, the total number of keratin genes

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Cited by (15)

KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-α-induced apoptosis and causes Naegeli-Franceschetti- Jadassohn syndrome
2008, Journal of Investigative Dermatology
Citation Excerpt :
Mutations in KRT14 have previously been shown to underlie a different inherited disorder, epidermolysis bullosa simplex (EBS; MIM 131800, 131760, 131900). Indeed, more than 60 autosomal dominant and recessive mutations in KRT14 (http://www.interfil.org) have been reported in this skin fragility disorder, which is characterized by blistering of the skin following mechanical trauma (Irvine, 2005). In contrast to NFJS, loss of dermatoglyphics has never been reported in EBS, and abnormal pigmentation has been limited to a rare EBS subtype (EBS with mottled pigmentation) (Uttam et al., 1996; Horiguchi et al., 2005; Harel et al., 2006).
Naegeli–Franceschetti–Jadassohn syndrome (NFJS) is a rare autosomal dominant disorder characterized by loss of dermatoglyphics, reticulate hyperpigmentation of the skin, palmoplantar keratoderma, abnormal sweating, and other developmental anomalies of the teeth, hair, and skin. We recently demonstrated that NFJS is caused by heterozygous nonsense or frameshift mutations in the E1/V1-encoding region of KRT14, but the mechanisms for their deleterious effects in NFJS remain elusive. In this study, we further expand the spectrum of NFJS-causing mutations and demonstrate that these mutations result in haploinsufficiency for keratin 14 (K14). As increased apoptotic activity was observed in the epidermal basal cell layer in NFJS patients and as previous data suggested that type I keratins may confer resistance to tumor necrosis factor-α (TNF-α)-induced apoptosis in epithelial tissues, we assessed the effect of down-regulation of KRT14 expression on apoptotic activity in keratinocytes. Using a HaCaT cell-based assay, we found that decreased KRT14 expression is associated with increased susceptibility to TNF-α-induced apoptosis. This phenomenon was not observed when cells were cultured in the presence of doxycycline, a known negative regulator of TNF-α-dependant pro-apoptotic signaling. Collectively, our results indicate that NFJS results from haploinsufficiency for K14 and suggest that increased susceptibility of keratinocytes to pro-apoptotic signals may be involved in the pathogenesis of this ectodermal dysplasia syndrome.
Epidermolysis Bullosa
2008, Neonatal Dermatology
Dyskeratosis as a histologic feature in epidermolysis bullosa simplex-Dowling Meara
2007, Journal of the American Academy of Dermatology
Citation Excerpt :
Both diseases are also characterized histologically by various degrees of dyskeratosis.8,9,20 In contrast with diseases of the desmosomal plaque,21 abnormal organization of the cell cytoskeleton in EBS-DM and other keratin diseases is the direct consequence of dominant mutations affecting the structure and function of keratin molecules.6 Although rare keratin mutations have been shown to cause cutaneous disorders resulting from haplo-insufficiency,22 in most cases these mutations exert a so-called dominant negative effect, with mutant molecules interfering with the function of wild type keratins and leading to destabilization of the keratin filament network resulting in filament aggregation and clumping.23
Intracellular keratin aggregation and clumping is a characteristic ultrastructural feature in epidermolysis bullosa simplex (EBS)-Dowling Meara (DM) yet without histologic correlates in routinely stained specimens.
We sought to detect histologic clues to keratin aggregation and clumping in the involved epidermis of EBS-DM.
Four cases of EBS-DM caused by dominant keratin (KRT)5 and KRT14 mutations were studied histologically and ultrastructurally. The histologic slides of 11 additional EBS cases (9 Weber-Cockayne subtypes and two Koebner subtypes) were also reviewed histologically.
Intracytoplasmic aggregation and clumping of tonofilaments were observed ultrastructurally in all 4 EBS-DM cases. Intracytoplasmic eosinophilic homogenizations and inclusions (ie, dyskeratosis) in individual keratinocytes were detected histologically in 3 of the 4 EBS-DM cases, but in none of the 9 EBS-Weber-Cockayne cases or the two EBS-Koebner cases.
This was a relatively small studied group.
The histopathological detection of dyskeratosis in individual keratinocytes may provide a valuable clue to keratin aggregation and clumping, and to the diagnosis in EBS-DM.
Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: Two allelic ectodermal dysplasias caused by dominant mutations in KRT14
2006, American Journal of Human Genetics
Naegeli-Franceschetti-Jadassohn syndrome (NFJS) and dermatopathia pigmentosa reticularis (DPR) are two closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation, thickening of the palms and soles (palmoplantar keratoderma), abnormal sweating, and other subtle developmental anomalies of the teeth, hair, and skin. To decipher the molecular basis of these disorders, we studied one family with DPR and four families with NFJS. We initially reassessed linkage of NFJS/DPR to a previously established locus on 17q11.2-q21. Combined multipoint analysis generated a maximal LOD score of 8.3 at marker D17S800 at a recombination fraction of 0. The disease interval was found to harbor 230 genes, including a large cluster of keratin genes. Heterozygous nonsense or frameshift mutations in KRT14 were found to segregate with the disease trait in all five families. In contrast with KRT14 mutations affecting the central α-helical rod domain of keratin 14, which are known to cause epidermolysis bullosa simplex, NFJS/DPR-associated mutations were found in a region of the gene encoding the nonhelical head (E1/V1) domain and are predicted to result in very early termination of translation. These data suggest that KRT14 plays an important role during ontogenesis of dermatoglyphics and sweat glands. Among other functions, the N-terminal part of keratin molecules has been shown to confer protection against proapoptotic signals. Ultrastructural examination of patient skin biopsy specimens provided evidence for increased apoptotic activity in the basal cell layer where KRT14 is expressed, suggesting that apoptosis is an important mechanism in the pathogenesis of NFJS/DPR.
Medical Genetics and Genomics: Questions for Board Review
2022, Medical Genetics and Genomics: Questions for Board Review
Identification of a founder mutation in KRT14 associated with Naegeli–Franceschetti–Jadassohn syndrome
2020, British Journal of Dermatology

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Inherited defects in keratins

Abstract

Section snippets

Keratins: basic biology

Genetic disorders due to mutations in human keratins

J. Invest. Dermatol.

J. Invest. Dermatol.

Cell

J. Am. Acad. Dermatol.

J. Invest. Dermatol.

Cell

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Biol. Chem.

J. Invest. Dermatol.

Am. J. Hum. Genet.

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Invest. Dermatol.

Curr. Opin. Cell Biol.

Intermediate filaments

Keratins

Human keratin diseases: the increasing spectrum of disease and specificity of genotype-phenotype correlation

Br. J. Dermatol.

K6irs1, K6irs2, K6irs3, and K6irs4 represent the inner-root-sheath–specific type II epithelial keratins of the human hair follicle

J. Invest. Dermatol.