The genetic basis of epidermolysis bullosa simplex with mottled pigmentation.

Abstract

Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant skin diseases characterized by blistering, due to mechanical stress-induced degeneration of basal epidermal cells. It is now well-established that the three major subtypes of EBS are genetic disorders of the basal epidermal keratins, keratin 5 (K5) and keratin 14 (K14). Here we show that a rare subtype, referred to as EBS with mottled pigmentation (MP), is also a disorder of these keratins.Affected members of two seemingly unrelated families with EBS-MP had a C to T point mutation in the second base position of codon 24 of one of two KS alleles, leading to a Pro:Leu mutation. This mutation was not present in unaffected members nor in 100 alleles from normal individuals.Linkage analyses mapped the defect to this type H keratin gene (peak logarithm of odds score at 4) = 0 of 3.9), which is located on chromosome 12q11-q13. This provides strong evidence that this mutation is responsible for the EBS-MP phenotype. Only conserved between K5 and K6, and not among any of the other type H keratins, Pro-24 is in the nonhelical head domain of K5, and only mildly perturbs the length of 10-nm keratin filaments assembled in vitro. However, this part of the K5 head domain is likely to protrude on the filament surface, perhaps leading to additional aberrations in intermediate filament architecture and/or in melanosome distribution that are seen ultrastructurally in patients with the mutation.Epidermolysis bullosa simplex (EBS) has been subdivided into three major types (1-3). (i) EBS Dowling-Meara (EBS-DM) is the most severe type, typified by blistering over whole body regions and keratin filament clumping and cytolysis in basal cells. (ii) EBS Kobner (EBS-K) is also characterized by generalized blistering and basal cell cytolysis, but with fewer abnormalities in basal cell keratin networks. (iii) EBS WeberCockayne (EBS-WC) is the mildest form, with blistering concentrated primarily in palmar and plantar regions, and very minor keratin filament perturbations. An unusual and rare form of EBS with generalized blistering and hyper-and hypopigmented spots over the body surface was first reported by Fischer and Gedde-Dahl (4). The unifying feature of all of these EBS subtypes is basal cell cytolysis, with a largely normal differentiation process in the suprabasal layers.

Defining the Properties of the Nonhelical Tail Domain in Type II Keratin 5: Insight from a Bullous Disease-causing Mutation

“…In this latter case, a mutation resulting in a Pro 24 3 Leu substitution in the N-terminal head domain of K5 causes EBS with mottled pigmentation (Uttam et al, 1996;Irvine et al, 1997). In addition, a single nucleotide deletion within exon 9 of K5 (1649delG) that results in the frameshift-induced lengthening of K5's Cterminal tail domain was discovered in two independent instances of a form of EBS showing annular migratory circinate erythema (EBS-MCE).…”

“…In recent years, the genetic basis of rarer forms of EBS was found to involve a distinct group of target genes, including plectin, integrin ␤4, and BP180 (Chavanas et al, 1996;Pulkkinen et al, 1996;Smith et al, 1996;Huber et al, 2002;Jonkman et al, 2002;Fontao et al, 2004), or a different type of mutation in the K5 gene. In this latter case, a mutation resulting in a Pro 24 3 Leu substitution in the N-terminal head domain of K5 causes EBS with mottled pigmentation (Uttam et al, 1996;Irvine et al, 1997). In addition, a single nucleotide deletion within exon 9 of K5 (1649delG) that results in the frameshift-induced lengthening of K5's Cterminal tail domain was discovered in two independent instances of a form of EBS showing annular migratory circinate erythema (EBS-MCE).…”

Donor splice site mutation in keratin 5 causes in-frame removal of 22 amino acids of H1 and 1A rod domains in Dowling-Meara epidermolysis bullosa simplex

“…12,[21][22][23][24][25][26] Recently, a missense mutation in the non-helical V1 head domain of K5 was identified in patients with EBS with mottled pigmentation. 27,28 We investigated a multigenerational family dominantly affected with EBS-DM for mutations in K5 cDNA. We describe abnormal splicing of the last 66 nucleotides in exon 1 caused by a genomic mutation at the consensus donor splice site of intron 1.…”

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 /

“…L'histologie de la peau montre une teneur accrue en mélanine dans les mélanophages (Fischer and Gedde-Dahl, 1979) et l'analyse ultra-structurale des zones pigmentées a révélé une présence abondante des mélanosomes dans les kératinocytes basaux (Uttam et al, 1996). L'EBS-MP est souvent liée à une mutation faux-sens P25L…”