BACKGROUND: Since publication in 2000 of the Second International Consensus Report on Diagnosis and Classification of Epidermolysis Bullosa, many advances have been made to our understanding of this group of diseases, both clinically and molecularly. At the same time, new epidermolysis bullosa (EB) subtypes have been described and similarities with some other diseases have been identified. OBJECTIVE: We sought to arrive at a new consensus of the classification of EB subtypes. RESULTS: We now present a revised classification system that takes into account the new advances, as well as encompassing other inherited diseases that should also be included within the EB spectrum, based on the presence of blistering and mechanical fragility. Current recommendations are made on the use of specific diagnostic tests, with updates on the findings known to occur within each of the major EB subtypes. Electronic links are also provided to informational and laboratory resources of particular benefit to clinicians and their patients. LIMITATIONS: As more becomes known about this disease, future modifications may be needed. The classification system has been designed with sufficient flexibility for these modifications. CONCLUSION: This revised classification system should assist clinicians in accurately diagnosing and subclassifying patients with EB.

The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB.

Integrins are transmembrane cell-adhesion molecules that carry signals from the outside to the inside of the cell and vice versa. Like other cell surface receptors, integrins signal in response to ligand binding; however, events within the cell can also regulate the affinity of integrins for ligands. This feature is important in physiological situations such as those in blood, in which cells are always in close proximity to their ligands, yet cell-ligand interactions occur only after integrin activation in response to specific external cues. This review focuses on the mechanisms whereby two key proteins, talin and the kindlins, regulate integrin activation by binding the tails of integrin-beta subunits.

https://science.sciencemag.org/content/sci/324/5929/895.full.pdf

The Tail of Integrins, Talin, and Kindlins

The ternary complex of integrin-linked kinase (ILK), PINCH and parvin functions as a signalling platform for integrins by interfacing with the actin cytoskeleton and many diverse signalling pathways. All these proteins have synergistic functions at focal adhesions, but recent work has indicated that these proteins might also have separate roles within a cell. They function as regulators of gene transcription or cell-cell adhesion.

/pdf/ilk-pinch-and-parvin-the-tipp-of-integrin-signalling-34u61z98wa.pdf

ILK, PINCH and parvin: the tIPP of integrin signalling.

The adhesive interactions of cells with their environment through the integrin family of transmembrane receptors have key roles in regulating multiple aspects of cellular physiology, including cell proliferation, viability, differentiation and migration. Consequently, failure to establish functional cell adhesions, and thus the assembly of associated cytoplasmic scaffolding and signalling networks, can have severe pathological effects. The roles of specific constituents of integrin-mediated adhesions, which are collectively known as the 'integrin adhesome', in diverse pathological states are becoming clear. Indeed, the prominence of mutations in specific adhesome molecules in various human diseases is now appreciated, and experimental as well as in silico approaches provide insights into the molecular mechanisms underlying these pathological conditions.

The integrin adhesome: from genes and proteins to human disease.

Integrin receptors provide a dynamic, tightly-regulated link between the extracellular matrix (or cellular counter-receptors) and intracellular cytoskeletal and signalling networks, enabling cells to sense and respond to their chemical and physical environment. Talins and kindlins, two families of FERM-domain proteins, bind the cytoplasmic tail of integrins, recruit cytoskeletal and signalling proteins involved in mechanotransduction and synergize to activate integrin binding to extracellular ligands. New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation and show that RIAM recruits talin to the plasma membrane, whereas vinculin stabilizes talin in cell-matrix junctions. How kindlins act is less well-defined, but disease-causing mutations show that kindlins are also essential for integrin activation, adhesion, cell spreading and signalling.

/pdf/talins-and-kindlins-partners-in-integrin-mediated-adhesion-4tbmjkvk0j.pdf

Talins and kindlins: partners in integrin-mediated adhesion

Kindler syndrome is an autosomal recessive disorder characterized by neonatal blistering, sun sensitivity, atrophy, abnormal pigmentation, and fragility of the skin. Linkage and homozygosity analysis in an isolated Panamanian cohort and in additional inbred families mapped the gene to 20p12.3. Loss-of-function mutations were identified in the FLJ20116 gene (renamed “KIND1” [encoding kindlin-1]). Kindlin-1 is a human homolog of the Caenorhabditis elegans protein UNC-112, a membrane-associated structural/signaling protein that has been implicated in linking the actin cytoskeleton to the extracellular matrix (ECM). Thus, Kindler syndrome is, to our knowledge, the first skin fragility disorder caused by a defect in actin-ECM linkage, rather than keratin-ECM linkage.

https://www.cell.com/ajhg/pdf/S0002-9297(07)63903-2.pdf

Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome

There is no single immunoelectron microscopical method for invariably effective localization of both intracellular and extracellular antigens. We describe a simple and practicable immunogold technique that can be used to localize various skin basement membrane zone antigens at the ultrastructural level. Small pieces of skin were incubated with primary antibodies recognizing epitopes on a range of basement membrane zone-related antigens (two different lamina lucida-associated antigens, laminin, type VII collagen, fibrillin and keratin 14). This was followed by incubation with 1-nm colloidal gold-conjugated secondary antibody and subsequent silver intensification. The specimens were then processed for transmission electron microscopy. Precise immunolocalization with good ultrastructural preservation was achieved for all basement membrane zone antibodies tested. The results of basal cell keratin immunostaining showed that this microscopic approach could also be applied to some extent in the characterization of intracellular antigens. This immunoelectron microscopy technique provides a useful approach to the study of macromolecules at the basement membrane zone.

Immunoelectron microscopy of skin basement membrane zone antigens: a pre-embedding method using 1-nm immunogold with silver enhancement.

Iconography : Inherited epidermolysis bullosa: Updated recommendations on diagnosis and classification

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Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome

Immunoelectron microscopy of skin basement membrane zone antigens: a pre-embedding method using 1-nm immunogold with silver enhancement.

Iconography : Inherited epidermolysis bullosa: Updated recommendations on diagnosis and classification