University of Groningen Epidermolysis bullosa simplex (original) (raw)

Chapter 9 fragility, whereas the, for EI characteristic, ichthyotic scaling and neonatal erythroderma were lacking. Of note, the clinical features resembled the phenotype of the patients with the one other, previously reported K1 L12 domain mutation. 8 With transfection studies we have shown that both the novel and the previously reported K1 L12 mutation cause keratin aggregations in vitro. This effect was aggravated upon application of a hypo-osmotic stress stimulus to the cells. In general, the functions of the linker domains of IFs are not well known. The results of the transfection studies performed in chapter 4 indicate that the L12 domain is involved in normal keratin assembly and stress resistance. The K1 L12 domain mutations cause mild phenotypes that might be missed because of the lack of resemblance to classical EI. The observation of unexplainable palmoplantar keratoderma in combination with mild skin fragility, blistering and/or peeling-skin like features should raise the suspicion of EI due to K1 linker domain mutations, especially when suprabasal epidermolysis and/or keratin aggregation is observed in ultrastructural analysis of patient's skin. Notably, in view of this mild blistering phenotype, EI could also be considered as a form of suprabasal EBS, although this was not acknowledged in the latest EB consensus, mainly because EI is generally thought of as an ichthyosiform, scaling disorder. Recently, we have discovered a novel, dominantly inherited missense mutation in the K10 L12 domain in a family with an even milder, more acral-peeling-skin-syndrome-like phenotype (unpublished). In general, mutations in the type II keratin K1 are associated with more severe phenotypes than mutations in K10 (type I). Moreover, recessive loss-of-protein expression mutations have been reported for K10, but not for K1. Similarly, in basal keratins only recessive loss-of-protein mutations have been observed for the type I keratin K14, but not for the type II K5. Furthermore, K5-knockout mice show a more severe and earlier lethal phenotype then the K14-knockout mice. 9 All these findings most likely reflect the functional redundancy of keratins. K14 loss can be (partly) compensated for by another basal keratin, K15, and upregulation of the wound-repair keratin K16. Furthermore, K10 mutations can be (partly) compensated for by expression of an additional type I keratin (K9) in palmoplantar skin. 10 On the other hand, patients with K9 mutations have palmoplantar keratoderma, so apparently K10 cannot compensate for K9 mutations. The type I keratins K5 and K1 have no alternative heterodimer partners, and therefore alterations in these proteins may cause more severe phenotypes. Alternatively, functional properties of type I and type II proteins differ. Of note, the phenomenon of functional redundancy of keratins is interesting in the light of therapeutic options for hereditary keratin disorders, as upregulation of other keratins may reduce the detrimental effect of the mutated keratin. Additional transfection studies will reveal whether the novel K10 L12 domain mutation has the same detrimental effect on the keratin cytoskeleton as the K1 L12 mutations in vitro, or perhaps has no notable effect and therefore causes such a mild phenotype. It would be interesting to perform transfections studies with the both the K1 and K10 linker domain mutations, and with helix boundary motif-affecting mutations as well.