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. Author manuscript; available in PMC: 2017 Jul 14.
Published in final edited form as: J Invest Dermatol. 2017 May;137(5):e67–e71. doi: 10.1016/j.jid.2016.04.039

The Molecular Revolution in Cutaneous Biology: Keratin Genes and their Associated Disease: Diversity, Opportunities, and Challenges

Pierre A Coulombe 1,2,3,4,5
PMCID: PMC5509967  NIHMSID: NIHMS878182  PMID: 28411849

Abstract

The abundance of keratin proteins and the filaments they form in surface epithelia has long been appreciated. This said, the remarkable diversity of keratin proteins and the notion that they are encoded by one of the largest gene families in the human genome has come to the fore relatively recently, coinciding with the sequencing of whole genomes. This complexity has generated some practical challenges, notably in terms of nomenclature and tractability. More importantly, however, studies of keratin have seeded the discovery of the genetic basis for a large number of genodermatoses and continue to provide a unique perspective on and insight into epithelial cells and tissues, whether normal or diseased.

Keratins are now understood by all to be intermediate filament-forming proteins encoded by two subgroupings of conserved genes, type I and type II, that are regulated in a pairwise-, differentiation-, and context-dependent fashion in all types of epithelial tissues (Schweizer et al., 2006). When coupled with their differentiation-dependent regulation, the diversity and differential immunogenicity of keratin proteins provides an unrivaled array of biomarkers with which to typify epithelial cells in healthy and diseased tissues. For instance, most of us are familiar with expression of the keratin (K) 5-K14 pair reflecting a progenitor state in stratified and pseudostratified epithelia, of the K1–K10 pair reflecting an early stage of terminal differentiation in the interfollicular epidermis, and of the K6–K16 pair reflecting a state of keratinocyte activation and/or alternative differentiation whenever a complex epithelium is under “duress” (Fuchs, 1995; Mansbridge et al., 1987; Sun et al., 1983). The discovery of keratin mutations as the underlying genetic defect in epidermolysis bullosa simplex (Bonifas et al., 1991; Coulombe et al., 1991), now 25 years old, has seeded an explosion of knowledge regarding the genetic etiology and pathophysiology of a very large number of diseases affecting skin and/or other tissues (Coulombe et al., 2009; Omary et al., 2004; Szeverenyi et al., 2008) (see Table 1 for a partial account of diseases arising from mutations in keratin genes). This contribution summarizes how we arrived at a tally of 54 functional keratin genes in the human genome and comments on the origins of the official nomenclature in use to designate these remarkable genes and proteins.

Table 1.

Examples of the variability in clinical presentation associated with mutations in the KRT5/KRT14, KRT1/KRT10, and KRT6/KRT16/KRT17 pairings1

Keratin Genes Disease Inheritance OMIM #2 Comments
KRT5 or KRT14 EBS Dowling Meara (severe) AD 131760 Classical EBS presentations dominated by trauma-induced bullous skin blisters, reflecting the fragility of basal layer keratinocytes. The most severe subtype (Dowling-Meara) is typified by clustered arrangement of lesions and presence of insoluble keratin aggregates in basal keratinocytes.
EBS–generalized AD 131900
EBS–localized (relatively mild) AD 131800
ESB recessive AR 601001
KRT5 EBS–mottled pigmentation AD 131960 Skin blistering is accompanied by mottled pigmentation of the trunk and limbs and is strongly associated with a specific mutation in KRT5, Pro25-Leu.
KRT5 Dowling-Degos disease AD 179850 Typified by disfiguring reticulate hyperpigmentation and dark hyperkeratotic papules in skin flexural region, due to KRT5 haploinsufficiency.
KRT5 EBS with migratory circinate erythema AD 609352 Skin blistering is accompanied by an unusual migratory and circular erythema, spreading “away” from blisters. Associated with frameshift mutations altering the tail domain of K5.
KRT14 Dermatopathia pigmentosa reticularis AD 125595 Similar syndromes showing reticular hyperpigmentation, hypohidrosis (reduced sweating), PPK-like lesions, and poor dermatoglyphics. Due to premature stop codon located very early in the KRT14 coding sequence.
KRT14 Naegali-Franceschetti-Jadassohn AD 161000
KRT1 or KRT10 Epidermolytic hyperkeratosis AD 113800 Related conditions typified by presence of erythroderma and flakiness, hyperkeratosis. Microscopy shows lysis (fragility) of keratinocytes in the suprabasal layers and hyperproliferation in the basal layer of epidermis.
Cyclic ichthyosis with EHK AD 607602
Ichthyosis hystrix (Curth Macklin) AD 146590
KRT1 Palmoplantar keratoderma (PPK) AD 144200 600962 607654 Applies to three clinically distinct subtypes of PPK (in which, as implied by the name, lesions preferentially occur on palm and sole skin): Epidermolytic, nonepidermolytic, and striate.
KRT10 Congenital reticular ichthyosiform erythroderma (also known as ichthyosis with confetti) AD 609165 Typified by slowly enlarging islands of normal skin surrounded by erythematous ichthyotic patches in a reticulated pattern. Accompanied by peculiar ultrastructural changes and caused by a frameshift mutation in KRT10.
KRT6A or KRT16 Pachyonychia congenita, type 1 (PC-1) AD 167200 Presentation dominated by nail dystrophy, severe PPK, oral leukoplakia. Follicular keratosis, hoarseness.
KRT6B or KRT17 Pachyonychia congenita, type 2 (PC-2) AD 167210 Similar to PC-1, but additionally typified by natal teeth, pili torti (twisted hair), and steatocystic skin lesions (steatocystoma multiplex).
KRT6C See comment AD 167200 600962 KRT6 is a relatively poorly expressed KRT6 paralog. Disease presentation related to that of PC-1 and/or NEPPK.
KRT16 Palmoplantar keratoderma, nonepidermolytic (NEPPK, focal) AD 600962 See description for relevant KRT1 entry.
KRT17 Steatocystoma multiplex AD 184500 Related to PC-2, but without much nail involvement. Dominated by steatocystic lesions that originate from sebaceous glands all over the body.
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Abbreviations: AD, autosomal dominant; AR, autosomal recessive; EBS, epidermolysis bullosa simplex; K, keratin.

1

The table does not include all of the diseases that have been attributed to mutations in these keratin genes to date. Figure 2 relates the chromosomal location of these keratin genes.

2

OMIM # refers to the numbering in the Online Mendelian Inheritance in Man catalog of human gene and genetic disorders. The information related in this table originates in the OMIM catalog (http://omim.org; see McKusick, 1998) and in the Human Intermediate Filament Mutation Database maintained at the Institute of Medical Biology in Singapore (http://www.interfil.org/index.php; see Szeverenyi et al., 2008).

Intermediate filaments (IFs) were discovered by Holtzer and colleagues, in developing skeletal muscle, in the late 1960s (Ishikawa et al., 1968). Although it took nearly 10 years for researchers to fully uncover the status of the then well-known keratin filaments as epithelial-specific IFs (Osborn et al., 1977; Sun and Green, 1978a), the late 1970s and early 1980s proved to be an incredibly fertile period of discovery in keratin-related research. In a span of 5–6 years, we learned that purified native epidermal keratins could self-assemble into 10-nm filaments as obligate heteropolymers in vitro (Aebi et al., 1983; Steinert et al., 1976), that keratin proteins were structurally diverse and very abundant elements in keratinocytes in primary culture as well as in epidermis in situ (Fuchs and Green, 1978; Sun and Green, 1978b), and that they are encoded by two distinct types of mRNAs (corresponding to “acidic” and “basic” keratins) regulated in a pairwise- and differentiation-related fashion in epidermis (Fuchs and Green, 1979; 1980; Fuchs et al., 1981; Woodcock-Mitchell et al., 1982). In the early 1980s, K14 was the first of many IFs to be completely sequenced at both the cDNA and genomic (gene) levels (Hanukoglu and Fuchs, 1982; Marchuk et al., 1985). Such gene and cDNA cloning efforts made it considerably easier to relate individual members to one another in the emerging family of IF sequences, including the affirmation of multiple subtypes of IF sequences, the recognition of hair keratins as bona fide IFs (Powell et al., 1983), the notion of a conserved substructure of subclasses of IF genes and of their corresponding protein products, and the beginnings of evolutionary insight (Fuchs et al., 1981). The remarkable arrangement of keratin genes into large and compact clusters was first uncovered in the chick genome (Molloy et al., 1982) and later confirmed in the human (Romano et al., 1988). All of these elements, however impressive, are a partial account of all the important realizations that were made in a short period of progress spanning the late 1970s to the early 1980s. It is also worth mentioning that the study of hair keratins in sheep by Australian scientists, at the gene and proteins levels, has contributed greatly to progress in the field before and during that period (Dowling and Sparrow, 1991; Rogers and Powell, 1993).

In a landmark article, Moll et al. (1982) proposed a nomenclature that could accommodate and name the array of 19 so-called “cytokeratins” that had been inventoried, at the time, on the basis of a combination of immunological, molecular, and biochemical criteria; remarkably, this effort preceded the availability of keratin cDNA or gene sequences. These researchers, in particular, had accumulated a wealth of information from a systematic characterization of the keratin-rich insoluble protein fraction prepared from several human tissues and cell lines (normal and diseased) and from their analysis via two-dimensional PAGE, in which proteins are first resolved by charge in a first “dimension” and then by mass in a second “dimension.” Moll et al. (1982) had the clever idea of representing all 19 cytokeratins in a virtual two-dimensional PAGE (Figure 1), enabling them to name individual cytokeratins according to their position in the gel, with the so-called type II basic-neutral keratin subgrouping named K1–K8 reflecting their decreasing mass, and the so-called type I acidic keratins named K9–K19 according to the same principle. As a result of this proposed nomenclature, for instance, the type II/type I keratin pairing that was commonly designated as 50-/58-kD (see Nelson and Sun, 1983) became K5–K14 (Figure 1). The “Moll catalog” was subsequently validated to near perfection by gene-cloning efforts (excepting K11, which proved to be an erroneous assignment) and could accommodate known hair-specific keratins, the type II Hb1–4 and type I Ha1–4. The Moll catalog article has been cited more than 5,000 times according to Google Scholar, making it one of the most highly cited papers in this field.

Figure 1. The origin of the Moll catalog for human keratin proteins.

Figure 1

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Cytoskeletal proteins from various human epithelia, carcinomas and cultured epithelial cells were separated by two-dimensional gel electrophoresis. Cytokeratin polypeptides detected and identified by antibody binding in immunoblot experiments, and in most cases also by peptide mapping, are arranged according to their mobilities in these gel electrophoretic systems. X axis: isoelectric pH values for molecules denatured in 9.5 mol/L urea (data combined from isoelectric focusing and nonequilibrium pH gradient electrophoresis). Y axis: relative molecular weight, as determined by SDS-PAGE. Cytokeratin polypeptides are designated by Arabic numerals. Horizontal series of spots indicate different isoelectric variants of the same polypeptide. Large dots indicate the specific major variant, usually the most basic, nonphosphorylated one. Small dots indicate minor variants. Open circles indicate variants of the specific polypeptide not always found in analyses from various cell types. A, rabbit actin; BSA, bovine serum albumin; Mr, molecular mass; PGK, 3-phosphoglycerokinase; V, human vimentin. Figure and legend reproduced from (Moll et al., 1982) with permission.

Another wave of rapid progress occurred in the 1980s and 1990s by using conventional cloning strategies to clone and sequence known and novel keratin genes, indicating that there were significantly more than the 19 recognized in Moll et al.’s 1982 catalog. This said, the full extent of keratin diversity remained underappreciated until the release of drafts for the human and mouse genomes near the turn of the millennium (Hesse et al., 2001, 2004). Currently, we are aware of 28 type I keratin genes and 26 type II keratin genes that are clustered, respectively, on the long arms of chromosomes 17 and 12 in the human genome (Figure 2) and are conserved to a high degree (including genomic organization) in mice and other mammals (Schweizer et al., 2006). The dramatic increase in the number of keratin genes and their attributes could not be accommodated in a straightforward fashion in the Moll catalog system. As an offshoot of the 2004 Gordon Research Conference on Intermediate Filaments held in Oxford, UK, a broad coalition of leaders in keratin IF-related research teamed up with the Human Genome and the Mouse Genome Nomenclature Committees to devise a new nomenclature for keratin genes and their proteins. After consideration of several scenarios, the decision was made to have the new nomenclature extend the original Moll 1982 system, thus preserving the naming system that had been used for more than 25 years across the world and adhering to internationally agreed-on rules for naming genes and proteins in the literature (Schweizer et al., 2006).

Figure 2. Human keratin phylogenic tree, postgenomics.

Figure 2

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(a) Comparison of the primary structure of human keratins using publicly available ClustalW and TreeView softwares. Sequence relatedness is inversely correlated with the length of the lines connecting the various sequences as well as the number and position of branch points. This comparison makes use of the sequences from the head and central rod domain for each keratin. Two major branches are seen in this tree, corresponding exactly to the known partitioning of keratin genes into type I and type II sequences. Beyond this dichotomy, each subtype is further segregated into major subgroupings. (b) Location and organization of type I and type II keratin genes in the human genome. All functional type I keratin genes, except KRT18 are clustered on the long arm of human chromosome 17, and all functional type II keratin genes are located on the long arm of chromosome 12. KRT18, a type I gene, is located at the telomeric boundary of the type II gene cluster. The suffix P identifies keratin pseudogenes. As highlighted by the color code used in frames a and b, individual type I and type II keratin genes belonging to the same subgroup, on the basis of the primary structure of their protein products, tend to be clustered in the genome. Moreover, highly homologous keratin proteins (e.g., K5 and K6 paralogs; also K14, K16, and K17) are often encoded by neighboring genes, pointing to the key role of gene duplication in generating keratin diversity. These features are virtually identical in mice (not shown). This figure is adapted from Coulombe et al., 2013 with permission.

The diversity of clinical presentations triggered by mutations in specific keratin genes represents yet another manifestation of the sheer complexity of keratin genes and the roles fulfilled by their protein products. Examples of the compelling phenotypic diversity associated with mutations in either member of the K5-K14, K1–K10, and K6/K16/K17 keratin pairings are conveyed in Table 1. In most instances, additional efforts are required to foster a better understanding of phenotype-genotype correlations in such keratin gene disorders, both at the level of the gene and the specific mutation involved.

We are still searching for satisfying answers regarding the significance of many of the basic attributes of keratin genes and proteins that were discovered by the pioneers of this field in the late 1970s and early 1980s. Why, for instance, are keratin filaments strict heteropolymers of type I and the II IF sequences, a very old evolutionary attribute? Why and how are so many type I and II keratin genes tightly regulated, at least transcriptionally, as specific pairs (e.g., K5/K14, K6/K16, etc.) but organized into two separate, large clusters in metazoan genomes? What other functional elements (e.g., mRNAs, long noncoding RNAs, locus control elements) might be contained within or proximal to the keratin gene clusters? What is the significance of the exquisitely context-dependent regulation of keratin genes? While searching for answers to these core issues, researchers are uncovering many unexpected, noncanonical, and exciting new roles for keratin proteins including, as an example, their participation in the regulation of gene expression in tumor keratinocytes, a role that entails their presence inside the nucleus (Chung et al., 2015; Hobbs et al., 2015; Hobbs et al., 2016). Unsolved puzzles and great opportunities lie ahead!

Acknowledgments

The author would like to dedicate this contribution to several pioneers in the keratin field, notably Henry Sun, Elaine Fuchs, Werner Franke, Roland Moll, Klaus Weber, Peter Steinert, Jürgen Schweizer, and Ueli Aebi. Research in the author’s laboratory is supported by grants AR042047, AR044232, and CA160255 from the National Institutes of Health.

Abbreviations

IF

intermediate filaments

K

keratin

Footnotes

CONFLICT OF INTEREST

The author states no conflict of interest.

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