This report describes a fly model of epidermolysis bullosa simplex (EBS) using two human keratin genes that are implicated in most forms of EBS (KRT5, MIM:148040 and KRT14, MIM:148066). Keratins are a family of structurally related proteins that form intermediate filaments in epithelial cells; the basal cells of human epidermis express 2 keratin subunits, acidic keratin 14 (KRT14) and basic keratin 5 (KRT5). There are no genes orthologous to KRT5 or KRT14 in Drosophila, since keratins are not found in arthropods (chitin serves some similar functions).
Multiple UAS constructs of Hsap\KRT5 and Hsap\KRT14 have been introduced into flies, including wild-type and a variant form of KRT14 implicated in EBS; a second variant postulated to be associated with the disease has also been assessed. Since the formation of keratin heterodimers is necessary to form a keratin intermediate filament network, both genes must be expressed. Ubiquitous co-expression of both human wild-type genes results in the formation of extensive keratin networks in epithelial and non-epithelial tissues, but causes no overt phenotype. As is observed in mammalian cells, treatment of dissected larval trachea of transgenic animals with phosphatase inhibitors causes keratin network collapse.
Co-expression of KRT5 and a KRT14 variant that causes the most severe form of EBS (see FBhh0000857) results in widespread formation of EBS-like cytoplasmic keratin aggregates in epithelial and non-epithelial fly tissues, causing semi-lethality; adult survivors develop wing blisters and are flightless due to a lack of intercellular adhesion during wing development. Variant(s) implicated in human disease tested (as transgenic human gene, KRT14): the R125C and R125P variant forms have been introduced into flies.
[updated Sep. 2019 by FlyBase; FBrf0222196]
Epidermolysis bullosa simplex is a clinically and genetically heterogeneous skin disorder characterized by blistering of the skin following minor physical trauma as a result of cytolysis within the basal epidermal cells. The disease is categorized into different forms based on severity and mode of inheritance. [from MIM:131800; 2018.07.23]
Most forms of epidermolysis bullosa simplex show autosomal dominant inheritance. All 3 major forms of EBS (localized, generalized, and generalized severe) can be caused by mutation in the KRT5 or the KRT14 gene. [from MIM:131800; 2018.07.23]
Autosomal recessive forms of EBS have also been described, see MIM:601001 for a recessive form caused by homozygous or compound heterozygous mutation in either the KRT14 or the KRT5 gene. [from MIM:601001; 2018.07.23]
In the most severe forms of EBS, large cytoplasmic clumps of tonofilaments that can be labeled with antibodies against the basal epidermal keratins are observed. Progressive truncation of KRT14 results in a correspondingly progressive disruption of filament structure and accumulation of the truncated protein into cytoplasmic aggregates. [from MIM:148066; 2018.07.23]
Keratins are a family of structurally related proteins that form intermediate filaments in epithelial cells. Keratins can be divided into 2 subfamilies: acidic (type I) and basic (type II). The basal cells of human epidermis express 2 keratin subunits, acidic keratin 14 (KRT14) and basic keratin 5 (KRT5). [from MIM:148030; 2018.07.23]
There is no gene orthologous to KRT14 in Drosophila.
There is no gene orthologous to KRT5 in Drosophila.
