Is filaggrin really a filament-aggregating protein in vivo?

Filaggrin, a basic protein of the stratum corneum, was named as such because of its capability to aggregate keratin intermediate filaments in vitro. To investigate its filament-aggregating capability in vivo, we performed immunoelectron microscopy in three autosomal dominant genodermatoses serving as in vivo models of abnormalities of keratin filament aggregation. In bullous congenital ichthyosiform erythroderma Brocq and epidermolytic palmoplantar keratoderma Voerner suprabasal clumping of keratin filaments prevents the normal spreading of keratohyalin between keratin filaments. Keratohyalin granules, either isolated or attached to clumped keratins, were specifically labelled by the anti-filaggrin antibody, whereas tonofilament clumps did not show any reaction. In epidermolysis bullosa herpetiformis Dowling-Meara the abnormal filament aggregation occurred in basal cell keratins where no reaction of the anti-filaggrin antibody was detected. In high level keratinocytes with normal distribution of tonofilaments, normal stellate keratohyalin reacted specifically. In all instances keratin filament clumping occurred independently of, and spatially separated from, the first signs of profilaggrin synthesis and keratohyalin granule formation. Thus, in these disorders, filaggrin is not involved in filament aggregation.