title: Filaggrin mutations p.R501X and c.2282del4 in ichthyosis vulgaris.
abstract: Ichthyosis vulgaris (IV) is the most common hereditary disorder of cornification in humans, characterized by generalized fine scaling of the skin, palmar hyperlinearity with or without keratosis pilaris and atopy. Recently, the molecular basis of IV was ascribed to loss-of-function mutations in the gene encoding filaggrin (FLG), namely p.R501X and c.2282del4. Homozygotes and compound heterozygotes were severely affected whereas heterozygotes showed mild disease or were asymptomatic, suggesting semidominant inheritance with incomplete penetrance in heterozygotes. We report the presence of FLG mutations in 15 out of 21 IV patients with a marked generalized scaling phenotype, including eight affected members of a four-generation family. In this group of patients not only homozygous and compound heterozygous, but also heterozygous patients for p.R501X and c.2282del4 display a pronounced phenotype, whereas in none of six individuals these two mutations were detectable despite decreased filaggrin expression on immunohistochemistry in two patients, indicating that other mutations in FLG and/or in other genes remain to be identified. In contrast, two additional p.R501X heterozygotes from the extended family are asymptomatic. In a control population from west-Austria a combined p.R501X and c.2282del4 carrier frequency of 6/110 (5.45%) was observed. We confirm that these FLG variants are common, but our results point to the existence of additional modifiers.
authors.affiliation: Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Gruber
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.forename: Christine
authors.initials: C
authors.lastname: Fauth
authors.forename: Gerd
authors.initials: G
authors.lastname: Utermann
authors.forename: Peter O
authors.initials: PO
authors.lastname: Fritsch
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmuth
mesh_terms: D001317:Austria; D005260:Female; D000091344:Filaggrin Proteins; D005787:Gene Frequency; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016112:Ichthyosis Vulgaris / Q000235:genetics* / Q000473:pathology; D007381:Intermediate Filament Proteins / Q000032:analysis / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012867:Skin / Q000737:chemistry / Q000473:pathology
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins