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Chamcheu JC, Siddiqui IA, Syed DN et al.Keratin gene mutations in disorders of human skin and its appendages. Arch Biochem Biophys 508:123-137

Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
Archives of Biochemistry and Biophysics (Impact Factor: 3.04). 12/2010; 508(2):123-37. DOI: 10.1016/j.abb.2010.12.019
Source: PubMed

ABSTRACT Keratins, the major structural protein of all epithelia are a diverse group of cytoskeletal scaffolding proteins that form intermediate filament networks, providing structural support to keratinocytes that maintain the integrity of the skin. Expression of keratin genes is usually regulated by differentiation of the epidermal cells within the stratifying squamous epithelium. Amongst the 54 known functional keratin genes in humans, about 22 different genes including, the cornea, hair and hair follicle-specific keratins have been implicated in a wide range of hereditary diseases. The exact phenotype of each disease usually reflects the spatial expression level and the types of mutated keratin genes, the location of the mutations and their consequences at sub-cellular levels as well as other epigenetic and/or environmental factors. The identification of specific pathogenic mutations in keratin disorders formed the basis of our understanding that led to re-classification, improved diagnosis with prognostic implications, prenatal testing and genetic counseling in severe keratin genodermatoses. Molecular defects in cutaneous keratin genes encoding for keratin intermediate filaments (KIFs) causes keratinocytes and tissue-specific fragility, accounting for a large number of genetic disorders in human skin and its appendages. These diseases are characterized by keratinocytes fragility (cytolysis), intra-epidermal blistering, hyperkeratosis, and keratin filament aggregation in severely affected tissues. Examples include epidermolysis bullosa simplex (EBS; K5, K14), keratinopathic ichthyosis (KPI; K1, K2, K10) i.e. epidermolytic ichthyosis (EI; K1, K10) and ichthyosis bullosa of Siemens (IBS; K2), pachyonychia congenita (PC; K6a, K6b, K16, K17), epidermolytic palmo-plantar keratoderma (EPPK; K9, (K1)), monilethrix (K81, K83, K86), ectodermal dysplasia (ED; K85) and steatocystoma multiplex. These keratins also have been identified to have roles in apoptosis, cell proliferation, wound healing, tissue polarity and remodeling. This review summarizes and discusses the clinical, ultrastructural, molecular genetics and biochemical characteristics of a broad spectrum of keratin-related genodermatoses, with special clinical emphasis on EBS, EI and PC. We also highlight current and emerging model tools for prognostic future therapies. Hopefully, disease modeling and in-depth understanding of the molecular pathogenesis of the diseases may lead to the development of novel therapies for several hereditary cutaneous diseases.

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    • "In epidermolysis bullosa simplex, an inherited connective tissue disorder, mutant forms of the keratin proteins KRT5 and KRT14 lead to severe blistering of the skin in response to injury. Keratin forms long intermediate filaments that provide structure to the epidermis of the skin (Chamcheu et al., 2011a). Disease-associated mutations in keratin cause the protein to misfold and aggregate, particularly in response to mechanical stress (Russell et al., 2004; Werner et al., 2004). "
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    ABSTRACT: For a protein to function appropriately, it must first achieve its proper conformation and location within the crowded environment inside the cell. Multiple chaperone systems are required to fold proteins correctly. In addition, degradation pathways participate by destroying improperly folded proteins. The intricacy of this multisystem process provides many opportunities for error. Furthermore, mutations cause misfolded, nonfunctional forms of proteins to accumulate. As a result, many pathological conditions are fundamentally rooted in the protein-folding problem that all cells must solve to maintain their function and integrity. Here, to illustrate the breadth of this phenomenon, we describe five examples of protein-misfolding events that can lead to disease: improper degradation, mislocalization, dominant-negative mutations, structural alterations that establish novel toxic functions, and amyloid accumulation. In each case, we will highlight current therapeutic options for battling such diseases.
    Disease Models and Mechanisms 01/2014; 7(1):9-14. DOI:10.1242/dmm.013474 · 5.54 Impact Factor
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    • "K16 is a marker for differentiated keratinocytes, which is strongly induced during wound healing (Leigh et al., 1995). Besides providing mechanical integrity, networks of keratin filaments are also involved in cellular functions like apoptosis and stress response (Chamcheu et al., 2011). Therefore, we asked whether additional structural components were dif­ ferentially regulated and performed expression analysis by RNA­seq of epidermal sheets. "
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    ABSTRACT: Cells of the epidermis renew constantly from germinal layer stem cells. Although epithelial cell differentiation has been studied in great detail and the role of Wnt signaling in this process is well described, the contribution of epidermal Wnt secretion in epithelial cell homeostasis remains poorly understood. To analyze the role of Wnt proteins in this process, we created a conditional knockout allele of the Wnt cargo receptor Evi/Gpr177/Wntless and studied mice that lacked Evi expression in the epidermis. We found that K14-Cre, Evi-LOF mice lost their hair during the first hair cycle, showing a reddish skin with impaired skin barrier function. Expression profiling of mutant and wild-type skin revealed up-regulation of inflammation-associated genes. Furthermore, we found that Evi expression in psoriatic skin biopsies is down-regulated, suggesting that Evi-deficient mice developed skin lesions that resemble human psoriasis. Immune cell infiltration was detected in Evi-LOF skin. Interestingly, an age-dependent depletion of dendritic epidermal T cells (DETCs) and an infiltration of γδ(low) T cells in Evi mutant epidermis was observed. Collectively, the described inflammatory skin phenotype in Evi-deficient mice revealed an essential role of Wnt secretion in maintaining normal skin homeostasis by enabling a balanced epidermal-dermal cross talk, which affects immune cell recruitment and DETC survival.
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    • "In the current study, the EPPK patients exhibited typical diffuse palmar and plantar hyperkeratosis, due to the c.C487T missense mutation of KRT9. Keratins usually play an important role in the cellular resilience of epithelia, and have highly tissue-specific expression patterns , sharing a common structure with other intermediate filament proteins that comprise a central a-helical rod domain of about 300 amino acids (1A, 1B, 2A, and 2B segments) flanked by three flexible nonhelical linkers (L1, L2, and L12) (Reis et al., 1994; Goldman et al., 2008; Chamcheu et al., 2011; McLean and Moore, 2011). The start and end regions of the rod domain, the helix initiation motif (HIM) of 1A and the helix termination motif (HTM) of 2B, are known to be critical for keratin heterodimerization. "
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    ABSTRACT: Epidermolytic palmoplantar keratoderma (EPPK) is generally associated with dominant-negative mutations of the Keratin 9 gene (KRT9), and rarely with the Keratin 1 gene (KRT1). To date, a myriad of mutations has been reported with a high frequency of codon 163 mutations within the first exon of KRT9 in different populations. Notably, a distinct phenotypic heterogeneity, digital mutilation, was found recently in a 58-year-old female Japanese EPPK patient with p.R163W. Here, we report the most common mutation, c.C487T (p.R163W) of KRT9, in two large EPPK pedigrees from southeast China. The arginine residue in peptide position 163 remains almost constant in at least 47 intermediate filament proteins ranging from snail to human. A substitution in arginine alters both the charge and shape of the 1A rod domain and disrupts the function of the helix initiation motif of keratins, finally compromising the integrity of filaments and weakening their stability in the epidermis of palms and soles. We summarize the clinical symptoms of EPPK in Chinese and show that knuckle pads are associated with KRT9 mutations. We suggest that the frequency of p.R163W in Chinese EPPK patients (31.03%) is consistent with that in the general population (29.33%), and that codon 163 is truly a hotspot mutational site of KRT9.
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