Molecular confirmation of the unique phenotype of epidermolysis bullosa simplex with mottled pigmentation

Abstract

SummaryBackground A distinctive subtype of epidermolysis bullosa simplex, with the additional feature of mottled pigmentation (EBS±MP), was initially characterized in a Swedish family in 1979, and seven further families have been reported. Features of EBS±MP that are observed in most affected patients include acral blistering early in childhood, mottled pigmentation distributed in a number of sites, focal punctate hyperkeratoses of the palms and soles, and dystrophic, thickened nails. The genetic basis of EBS±MP has been ascribed in five unrelated families to a heterozygous point mutation, P25L, in the non-helical V1 domain of K5. Objectives We report a clinical, ultrastructural and molecular study of two of the earliest families to be clinically characterized as EBS±MP. Methods The P25L mutation was identified in all affected members of each of these families, bringing the total number of EBS±MP families with this mutation to seven. Results This unusual recurrent mutation may uniquely cause EBS±MP. Conclusions While the exact molecular mechanisms by which this mutation causes epidermolysis, palmoplantar keratoderma and pigmentation remain elusive, we suggest possible molecular mechanisms through which the P25L substitution could cause this unusual phenotype.

Acromelanosis Albo-Punctata: A Distinct Inherited Dermatosis with Acral Spotty Dyspigmentation without Systemic Involvement

“…Histologically, skin cleavage within the basal epidermal layer and basal layer keratinocyte degeneration are similar to other basal EBS subtypes. Ultrastructural analysis of the area of pigmentation demonstrates dense packing of compound melanosomes around the keratinocyte nucleus [39]. …”

Impact de l'interféron gamma sur la production de la kératine 15 dans les kératinocytes isolés de la peau de patients atteints d'épidermolyse bulleuse simplex /

“…Ces taches ont environ 2 à 5 millimètres de diamètre (Irvine et al, 2001). Une étude a rapporté que ces troubles de la pigmentation disparaissent avec l'âge (Tay and Weston, 1996) mais parfois restent toute la vie (Fischer and Gedde-Dahl, 1979).…”

“…(substitution de la proline en leucine) sur le domaine VI non-hélicoïdal de la K5 (Irvine et al, 2001). Il a été également rapporté que des mutations au niveau du gène codant pour la K14 pouvaient être responsables de ce type d'EBS (Browning and Mohr, 2012).…”

Diseases of epidermal keratins and their linker proteins

“…This mutation has been consistently detected in each of the unrelated families with EBS-MP tested to date. Preliminary investigations of this mutation has revealed that the keratin 5 head domain may directly bind to a cytoplasmic dynein cargo complex transporting melanosomes, thus unraveling the basis for abnormal pigment distribution in this rare disorder [23].…”

“…This mutation has been consistently detected in each of the unrelated families with EBS-MP tested to date. Preliminary investigations of this mutation has revealed that the keratin 5 head domain may directly bind to a cytoplasmic dynein cargo complex transporting melanosomes, thus unraveling the basis for abnormal pigment distribution in this rare disorder [23].Epidermolytic Hyperkeratosis (EHK; OMIM 113800) -Mutations in the KRT1 and KRT10 Genes EHK, also known as bullous congenital ichthyosiform erythroderma (BCIE), is a relatively rare, autosomal dominant keratinization disorder which presents at birth with generalized erythema, blistering, erosions and peeling of the skin. Later on, hyperkeratotic areas with verrucous scales, mainly involving flexural and intertriginous areas develop, and in the majority of patients palmoplantar hyperkeratosis is present.…”