The yin and the yang of keratin amino acid substitutions and epidermolysis bullosa simplex.

Mutations that change the same amino acid can result in different clinical phenotypes. Through in silico modeling and keratin filament assessment of genetically engineered HaCaT cells, Natsuga et al., as reported in this issue, have demonstrated how changes in charge and structure of a replacement amino acid in keratin 14 can cause disease (KRT14pA413P, EB simplex) or no clinical effect (KRT14pA413T, polymorphism).

Suspected epidermolysis bullosa simplex in a 5-week-old Nigerian: a case report.

BACKGROUND: Epidermolysis bullosa is a rare non scaring autosomal dominant disorder characterized by recurrent blistering of the skin and mucous membrane. The skin is fragile and minor rubbing may cause blistering. It's epidemiology in our environment is unknown probably because of paucity of information on the clinical presentation and management with resultant mortality within the first few months of life. METHOD: A case report of a 5-week-old female who presented with generalized blistering and denudation of the skin first noticed on the left foot at birth and a review of the literature on the subject using Medline and online search was used. She was treated at various traditional medicine homes and clinics before referral to the teaching hospital. She was managed initially for bullous pemphigus with antibiotics for proven septicaemia, and the wound infection ignorantly managed with daily sofratulle dressing alternating with closed dressings before a definitive clinical diagnosis of was made. RESULT: The patient was referred late to the tertiary centre. She was initially treated for bullous pemphigus and sepsis with antibiotics and wound dressings with poor response before the diagnosis of epidermlysis bullosa was made. The patient died from severe foot bleeding before blood could be transfused. CONCLUSION: Delay in making the right diagnosis hence the appropriate treatment even in a tertiary health is being highlighted.

Defining the properties of the nonhelical tail domain in type II keratin 5: insight from a bullous disease-causing mutation.

Inherited mutations in the intermediate filament (IF) proteins keratin 5 (K5) or keratin 14 (K14) cause epidermolysis bullosa simplex (EBS), in which basal layer keratinocytes rupture upon trauma to the epidermis. Most mutations are missense alleles affecting amino acids located in the central alpha-helical rod domain of K5 and K14. Here, we study the properties of an unusual EBS-causing mutation in which a nucleotide deletion (1649delG) alters the last 41 amino acids and adds 35 residues to the C terminus of K5. Relative to wild type, filaments coassembled in vitro from purified K5-1649delG and K14 proteins are shorter and exhibit weak viscoelastic properties when placed under strain. Loss of the C-terminal 41 residues contributes to these alterations. When transfected in cultured epithelial cells, K5-1649delG incorporates into preexisting keratin IFs and also forms multiple small aggregates that often colocalize with hsp70 in the cytoplasm. Aggregation is purely a function of the K5-1649delG tail domain; in contrast, the cloned 109 residue-long tail domain from wild type K5 is distributed throughout the cytoplasm and colocalizes partly with keratin IFs. These data provide a mechanistic basis for the cell fragility seen in individuals bearing the K5-1649delG allele, and point to the role of the C-terminal 41 residues in determining K5's assembly properties.