Genomic Characterization of the Human Type I Cuticular Hair Keratin hHa2 and Identification of an Adjacent Novel Type I Hair Keratin Gene hHa5

Hair keratins, a subset of the keratin multigene family expressed in hard keratinizing structures, previously have been thought to comprise four members of each subfamily, designated Ha1-4 (type I) and Hb1-4 (type II), which are differentially expressed in the cuticle and cortex of the hair follicle. This report describes the genomic cloning and sequencing of the human type I cuticular hair keratin hHa2, as well as the identification of a previously unknown human type I hair keratin gene. The 12.5-kilobase pair genomic clone ghkI2.12, obtained by hybridization of a human genomic deoxyribonucleic acid library with a 3'–complementary deoxyribonucleic acid probe of hHa2, as well as the partially overlapping 14.4-kilobase pair genornic clone ghk12.17, isolated using a 5'-fragment of clone ghk12.12, allowed the characterization of the entire hHa2 genes The gene displays the same exon/intron structure as two previously characterized type I mouse and sheep hair/wool keratin genes with strict positional conservation of the six introns in the region coding for the central α-helix, At the 5'-extremity of clone ghk12.17, approximately 8.0 kilobase pairs upstream of the hHa2 gene and oriented in the same transcriptional direction, lies the gene for a hitherto unknown human type I hair keratin, Clone ghkl2.17 contains partial sequence information for this gene beginning with introit 5 and extending to the end of the gene. Screening of a human scalp complementary deoxyribonucleic acid library with a 3'-fragment of the gene yielded a full length complementary deoxyribonucleic acid clone of the new hair keratin, which in continuation of the current nomenclature for hair keratins was termed hHa5. Remarkably, the hHa5 gene, which contains an additional 7th intron in its 3'-noncoding region, is expressed mainly in supramatricial cells and lowermost cortical cells of the hair bulb and thus constitutes a very early component of hair morphogenesis. Our results confirm the type specific clustering of keratin genes and indicate that the human type I hair keratin subfamily contains more members than previously assume

Characterization of a Novel Human Type II Epithelial Keratin K1b, Specifically Expressed in Eccrine Sweat Glands

In this study, we show that a novel human type II epithelial keratin, K1b, is exclusively expressed in luminal duct cells of eccrine sweat glands. Taking this luminal K1b expression as a reference, we have used antibodies against a plethora of epithelial keratins to systematically investigate their expression in the secretory globule and the two-layered sweat duct, which was divided into the intraglandular, intradermal, and intraepidermal (acrosyringium) segments, the latter being further subdivided into the sweat duct ridge and upper intraepidermal duct. We show that (i) each of the eccrine sweat gland tissue compartments expresses their own keratin patterns, (ii) the peripheral and luminal duct layers exhibit a sequential keratin expression, with both representing self-renewing cell layers, (iii) the intradermal duct and the sweat duct ridge display hitherto unknown length variations, and (iv) out of all cell layers, the luminal cell layer is the most robust layer and expresses the highest number of keratins, these being concentrated at the apical side of the cells to form the cuticle. We provide evidence that the cellular and intercellular properties of the peripheral and the luminal layers reflect adaptations to different functions

Integrin-linked kinase is required for epidermal and hair follicle morphogenesis

Integrin-linked kinase (ILK) links integrins to the actin cytoskeleton and is believed to phosphorylate several target proteins. We report that a keratinocyte-restricted deletion of the ILK gene leads to epidermal defects and hair loss. ILK-deficient epidermal keratinocytes exhibited a pronounced integrin-mediated adhesion defect leading to epidermal detachment and blister formation, disruption of the epidermal–dermal basement membrane, and the translocation of proliferating, integrin-expressing keratinocytes to suprabasal epidermal cell layers

Disturbed Epidermal Structure in Mice with Temporally Controlled Fatp4 Deficiency

So far, little is known about the physiological role of fatty acid transport protein 4 (Fatp4, Slc27a4). Mice with a targeted disruption of the Fatp4 gene display features of a human neonatally lethal restrictive dermopathy with a hyperproliferative hyperkeratosis, a disturbed epidermal barrier, a flat dermal–epidermal junction, a reduced number of pilo-sebaceous structures, and a compact dermis, demonstrating that Fatp4 is necessary for the formation of the epidermal barrier. Because Fatp4 is widely expressed, it is unclear whether intrinsic Fatp4 deficiency in the epidermis alone can cause changes in the epidermal structure or whether the abnormalities observed are secondary to the loss of Fatp4 in other organs. To evaluate the functional role of Fatp4 in the skin, we generated a mouse line with Fatp4 deficiency inducible in the epidermis. Mice with epidermal keratinocyte-specific Fatp4 deficiency developed a hyperproliferative hyperkeratosis with a disturbed epidermal barrier. These changes resemble the histological abnormalities in the epidermis of newborn mice with total Fatp4 deficiency. We conclude that Fatp4 in epidermal keratinocytes is essential for the maintenance of a normal epidermal structure

New consensus nomenclature for mammalian keratins

Keratins are intermediate filament–forming proteins that provide mechanical support and fulfill a variety of additional functions in epithelial cells. In 1982, a nomenclature was devised to name the keratin proteins that were known at that point. The systematic sequencing of the human genome in recent years uncovered the existence of several novel keratin genes and their encoded proteins. Their naming could not be adequately handled in the context of the original system. We propose a new consensus nomenclature for keratin genes and proteins that relies upon and extends the 1982 system and adheres to the guidelines issued by the Human and Mouse Genome Nomenclature Committees. This revised nomenclature accommodates functional genes and pseudogenes, and although designed specifically for the full complement of human keratins, it offers the flexibility needed to incorporate additional keratins from other mammalian species

Mice with targeted disruption of the fatty acid transport protein 4 (Fatp 4, Slc27a4) gene show features of lethal restrictive dermopathy

The fatty acid transport protein family is a group of evolutionarily conserved proteins that are involved in the cellular uptake and metabolism of long and very long chain fatty acids. However, little is known about their respective physiological roles. To analyze the functional significance of fatty acid transport protein 4 (Fatp4, Slc27a4), we generated mice with a targeted disruption of the Fatp4 gene. Fatp4-null mice displayed features of a neonatally lethal restrictive dermopathy. Their skin was characterized by hyperproliferative hyperkeratosis with a disturbed epidermal barrier, a flat dermal–epidermal junction, a reduced number of pilo-sebaceous structures, and a compact dermis. The rigid skin consistency resulted in an altered body shape with facial dysmorphia, generalized joint flexion contractures, and impaired movement including suckling and breathing deficiencies. Lipid analysis demonstrated a disturbed fatty acid composition of epidermal ceramides, in particular a decrease in the C26:0 and C26:0-OH fatty acid substitutes. These findings reveal a previously unknown, essential function of Fatp4 in the formation of the epidermal barrier

The human keratins: biology and pathology

The keratins are the typical intermediate filament proteins of epithelia, showing an outstanding degree of molecular diversity. Heteropolymeric filaments are formed by pairing of type I and type II molecules. In humans 54 functional keratin genes exist. They are expressed in highly specific patterns related to the epithelial type and stage of cellular differentiation. About half of all keratins—including numerous keratins characterized only recently—are restricted to the various compartments of hair follicles. As part of the epithelial cytoskeleton, keratins are important for the mechanical stability and integrity of epithelial cells and tissues. Moreover, some keratins also have regulatory functions and are involved in intracellular signaling pathways, e.g. protection from stress, wound healing, and apoptosis. Applying the new consensus nomenclature, this article summarizes, for all human keratins, their cell type and tissue distribution and their functional significance in relation to transgenic mouse models and human hereditary keratin diseases. Furthermore, since keratins also exhibit characteristic expression patterns in human tumors, several of them (notably K5, K7, K8/K18, K19, and K20) have great importance in immunohistochemical tumor diagnosis of carcinomas, in particular of unclear metastases and in precise classification and subtyping. Future research might open further fields of clinical application for this remarkable protein family