Disease relevance of Flg

• Finally, since the dual abnormalities in the lamellar body secretory system and filaggrin processing resemble two key features of human Harlequin ichthyosis, Pig-a null mice could provide an appropriate analog for further studies of this disease [1].
• Defective interaction between keratin and filaggrin is seen in epidermolytic hyperkeratosis [2].
• Filaggrin immunofluorescence in invasive carcinomas was negative or only slightly positive [3].
• Exuberant papillomas showed a pleomorphic distribution of filaggrin with alternating positive and negative areas of immunofluorescence [3].
• Comparisons of amino acid sequences indicated significant similarities of MBP with filaggrin, a protein that is deiminated in another autoimmune disease, rheumatoid arthritis, suggesting that comparable epitopes could be targeted in both pathologies [4].

High impact information on Flg

• Further, these antibodies demonstrated specific binding to citrullinated filaggrin in rat esophagus by indirect immunofluorescence and citrullinated fibrinogen by Western blot [5].
• Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1 [6].
• Profilaggrin is a large epidermal polyprotein that is proteolytically processed during keratinocyte differentiation to release multiple filaggrin monomer units as well as a calcium-binding regulatory NH2-terminal filaggrin S-100 protein [6].
• The basal cells of affected mice ceased to proliferate, and expressed the profilaggrin and loricrin genes which are normally transcribed only in the latest stages of epidermal differentiation [7].
• However, only a small fraction of the cells express the markers K1, K10, CE, or filaggrin in the higher Ca2+ medium [8].

Biological context of Flg

• Genetic linkage analysis has shown that mouse loricin and profilaggrin lie within 1.5 +/- 1.1 centimorgans of each other [9].
• In contrast to the dramatic repression of mRNAs typical for spinous cell differentiation, activation of PKC concurrently enhances expression of mRNAs and proteins for the granular cell markers loricrin and filaggrin [10].
• Studies with phosphorylated P1 suggest that PEP1 specificity may be partly regulated by profilaggrin phosphorylation [11].
• Total mouse genomic DNA and the filaggrin gene isolated from a cosmid library were found to contain a super-stoichiometric repeat of the same size [12].
• We report here that cosmid clone cFM6.1A2 contains 20 filaggrin repeats and 15,213 base pairs of coding sequences [13].

Anatomical context of Flg

• Loricrin is the major component of a specialized structure, termed the cornified cell envelope, that is formed beneath the plasma membrane of stratified squamous epithelial cells and is coexpressed with profilaggrin in terminally differentiating epidermal keratinocytes [9].
• Using PCR analyses of DNAs isolated from mouse x Chinese hamster somatic cell hybrids, we have mapped both the loricrin and the profilaggrin genes to chromosome 3 [9].
• Finally, consistent with results of earlier studies, keratins 1, 10, 13, and 15, and filaggrin, involucrin, and loricrin were not detected at any stage of mammary gland development [14].
• The filaggrin epitope is first detected in large, irregularly shaped, keratohyalin granules (F-granules) in the stratum granulosum, and then distributed throughout the cytoplasms of the innermost layers of stratum corneum cells [15].
• Expression of hornerin in stratified squamous epithelium in the mouse: a comparative analysis with profilaggrin [16].

Associations of Flg with chemical compounds

• Moreover, topical treatment of hairless mice with ciglitazone or troglitazone increases loricrin, involucrin, and filaggrin expression without altering epidermal morphology [17].
• The induction of filaggrin and loricrin by CS corresponds to a granular layer differentiation program, where PKC activation occurs and was blocked by the PKC inhibitor GF 109203X [18].
• These keratins and filaggrin were studied in a pulse-labelled cell cohort in hairless mouse epidermis stimulated to proliferate by TPA or the hyperplasiogen cantharidin [19].
• A major event in the keratinization of epidermis is the production of the histidine-rich protein filaggrin (26,000 mol wt) from its high molecular weight (greater than 350,000) phosphorylated precursor (profilaggrin) [20].
• Double-stain immunofluorescence for bromodeoxyuridine/beta-gal and filaggrin/beta-gal of mixtures grown in organotypic cultures for 7 days demonstrated that when increasing numbers of normal cells were added (12:1), II-4 ceased to proliferate and expressed filaggrin [21].

Other interactions of Flg

• We found that loricrin mRNA and protein were expressed by E16, following the expression of keratins K1 and K10 and preceding the expression of profilaggrin [22].
• In this study we examined the expression of hornerin compared with that of profilaggrin in various mouse tissues [16].
• Furthermore, the expression of both mRNA and protein for the calcium inducible keratinocyte differentiation markers, filaggrin and loricrin, were down-regulated in the epidermis of Casr(-/-) mice, whereas the number of proliferating cells were increased even though the calcium gradient within the epidermis was enhanced [23].
• The human hornerin gene was mapped between trichohyalin and filaggrin on chromosome 1q21.3, the region being completely syntenic with the counterpart of the mouse [24].
• Minor but significant differences are: in forestomach, striated material resembling lamellar granules is intercalated between the cornified squames; and in forestomach granular layer cells, loricrin-containing L-granules are more abundant, and filaggrin-containing F-granules less abundant than in epidermis [25].

Analytical, diagnostic and therapeutic context of Flg

• This animal model provides a tool for understanding the role of filaggrin in normal epidermal function and may provide insight into the molecular basis of the filaggrin-deficient human skin disorder ichthyosis vulgaris [26].
• Distribution of profilaggrin and its derivatives has also been revealed by immunoelectron microscopy [2].
• We refined mapping of the mouse gene and other markers on a radiation hybrid panel of Chr 3 and found the order cen, Acrb2, Lor, Iv1, Flg, tel [27].
• Furthermore, Western blot analysis of the mouse skin showed that the hornerin protein was cleaved during the process of epidermal differentiation, indicating possible posttranslational proteolytic processing as is observed in profilaggrin [28].
• In situ hybridization was used to show that the filaggrin precursor mRNA is located precisely over the granular layer of the epidermis, indicating that expression of this gene is regulated at the transcriptional level as for the differentiation-specific keratin 1 protein [12].

References