Keratins, the major structural protein of all epithelia provide structural support to keratinocytes and maintain the integrity of the skin. 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. 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.
COBISS.SI-ID: 27780057
Four decades have passed since the first recombinant protein, somatostatin, was produced in Escherichia coli. To date, more than 160 biopharmaceuticals gained medical approval. For a long time IB formation represented a problem in protein production. Recent studies reveal that friendlier bacterial cultivation leads to production of non-classical IBs (ncIBs), composed of properly folded and biologically active proteins. Such active ncIBs can be used either for protein isolation (production) or as active nanoparticles, a further development of the use of active IBs is expected.
COBISS.SI-ID: 27780569
In K5 and K14 mutant (EBS) keratinocytes we found many genes associated with the cytoskeleton having altered expression levels; in particular cell junction components are down-regulated. That this is due to the expression of the mutant keratins, and not to other genetic variables, is supported by experiments on isogenic cells we generated from wild type keratinocytes transfected with the same K5 and 14 mutations. These findings help explain other aspects of EBS-associated pathology. The weakened cell junctions may be also contributing to the reported increased risk of BCC in EBS patients.
COBISS.SI-ID: 25777881
A novel missense mutation (p.Thr198Ser) in the 1A helix of keratin 5 (K5) has been identified in a four-generation family with a history of the localized variant of epidermolysis bullosa simplex (EBS-loc), a genetic skin fragility disorder caused by K5 or K14 mutations. K5 p.Thr198Ser lies at the C-terminal end of the 1A helical domain and is considered to be outside of the main mutation hotspot region. This is the first reported mutation to affect position 30 of the 1A helix (1A:T30S) in any of the 54 known keratins.
COBISS.SI-ID: 4058138
Epidermolysis bullosa simplex (EBS) is a blistering skin disease caused by mutations in keratin genes (KRT5 or KRT14), with no existing therapies. Aggregates of misfolded mutant keratins are seen in cultured keratinocytes from severe EBS patients. In other protein-folding disorders, involvement of molecular chaperones and the ubiquitin-proteasome system may modify disease severity. In this study, the effects of heat stress on keratin aggregation in immortalized cells from two patients with EBS (KRT5) and a healthy control were examined with and without addition of various test compounds. Heat-induced (43 °C, 30 minutes) aggregates were observed in all cell lines, the amount of which correlated with the donor phenotype. In EBS cells pre-exposed to proteasome inhibitor, MG132, and p38-mitogen-activated protein kinase (MAPK) inhibitor, SB203580, the proportion of aggregate-positive cells increased, suggesting a role of proteasomes and phosphorylation in removing mutated keratin. In contrast, aggregates were reduced by pretreatment with twochemical chaperones, trimethylamine N-oxide (TMAO) and 4-phenylbutyrate (4-PBA). TMAO also modulated stress-induced p38/c-jun N-terminal kinase (JNK) activation and expression of heat shock protein (HSPA1A), the latter of which colocalized with phosphorylated keratin 5 in EBS cells. Taken together, our findings suggest therapeutic targets for EBS and other keratinopathies.
COBISS.SI-ID: 28273369