Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris

Abstract

Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of approximately 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.

Filaggrin Genotype in Ichthyosis Vulgaris Predicts Abnormalities in Epidermal Structure and Function

“…FLG variants R501X, 2282del4, and R2447X were screened by restriction enzyme digestion of PCR products, FLG variants 3702delG and 6867delAG by sizing of fluorescently labeled PCR products as described previously. 9,12 For 2282del4 screening, we used an allele-specific PCR, amplifying a short fragment of 158 bp with high genotype completion rates. Genomic DNA was amplified by using Promega PCR buffer (Promega, Madison, WI), Promega Taq polymerase mix, and allele-specific primers: 5=-AGAAGACT-CAGACACACATTG-3= (forward), 5=-GGGAGGACTCA-GACTGTTT-3= (reverse).…”

Clinical polymorphism of atopic dermatitis and ichthyosis vulgaris upon mutations in the filaggrin gene

“…Геномную ДНК выделяли из венозной крови методом фенол-хлороформной экстракции [5]. Генотипирование на наличие мутаций 2282del4 и R501X выполняли по опубликованным методикам [15]. Мутация R501X у 11 человек реализовалась в виде АтД, а у 3 -как ВИ.…”

Ichthyosis: guide to recognition and current treatment options

“…1 Ichthyosis vulgaris usually becomes apparent during the first year of life and, in the vast majority, by the age of five years. The extent of scaling increases until puberty and subsequently decreases with age.…”