On the Role of the Epidermal Differentiation Complex in Ichthyosis Vulgaris, Atopic Dermatitis and Psoriasis

S. Hoffjan; S. Stemmler


The British Journal of Dermatology. 2007;157(3):441-449. 

In This Article

Role of the Epidermal Differentiation Complex in the Pathogenesis of Ichthyosis Vulgaris

Ichthyosis vulgaris is a common genetic skin disorder characterized by fine scaling that is most prominent over the lower abdomen, arms and legs and usually presents within the first few months of life.[2] Palmar hyperlinearity and keratosis pilaris are also common features of ichthyosis vulgaris.[2] Histologically, keratohyaline granules are reduced or absent in the epidermis of patients with ichthyosis vulgaris.[19] Based on a survey of 6051 healthy school children, the incidence of ichthyosis vulgaris is approximately 1 in 250 individuals,[20] with varying degrees of severity.

Twenty years ago, the first evidence emerged that the EDC protein filaggrin might play an important role in the pathogenesis of ichthyosis vulgaris. Immunohistochemical staining revealed that filaggrin was absent in the epidermis of severely affected individuals and reduced in intensity in the less severely affected family members compared with healthy controls and unaffected family members.[21] More recent studies showed that profilaggrin mRNA levels were significantly reduced in the epidermis in ichthyosis vulgaris, presumably due to a defect in post-transcriptional control.[22] Additional hints for an important role of filaggrin were gained from mouse models. A recessive mouse mutation named flaky tail (ft) exhibits symptoms similar to human ichthyosis vulgaris in the homozygous state. Affected homozygous mice (ft/ft) show dry, scaly skin, an annular tail and paw constrictions in the neonatal period.[23] It was demonstrated that ft/ft mice express an abnormal profilaggrin polypeptide that does not form normal keratohyaline granules and is not proteolytically processed to filaggrin.[23] The flaky tail phenotype is caused by a single autosomal recessive mutation that maps to mouse chromosome 3,[24] close to the genes encoding mouse loricrin and profilaggrin.[25] Linkage analysis in humans suggested linkage of ichthyosis vulgaris to chromosome 1q22 in two Chinese families.[26] Another study reported linkage of a clinical subtype of ichthyosis vulgaris with an absent granular epidermal layer to the chromosomal region containing the EDC.[27]

Thus, variation in the FLG gene has long been suspected as a major reason for ichthyosis vulgaris. Yet, the unusual and complex structure of the EDC in general and the human FLG gene in particular has long prevented the identification of causative mutations (Fig. 3). The FLG gene consists of three exons. Exon 1 (15 bp) encodes only untranslated sequence and exon 2 (159 bp) contains the translation initiation codon, while exon 3 (12-14 kb) contains the N-terminal domain and 10-12 copies of a 1-kb sequence that encode the proteolytically cleaved parts of filaggrin.[28] It has proved quite difficult to amplify the entire 12-14-kb sequence as well as to develop specific primers within the highly homologous structure of 10-12 identical repeats.

Nevertheless, Smith et al. recently managed to develop long-range polymerase chain reaction conditions to amplify the entire exon 3 and, although they were unable to sequence the fragment completely, they identified two mutations in the first repeat of exon 3 in 14 families with ichthyosis vulgaris: R501X and 2282del4.[29] Both mutations result in formation of a premature stop codon and complete loss of filaggrin peptide production.29 Analysis of the pedigrees indicated that these mutations are semidominant with individuals homozygous for either mutation or compound heterozygous being severely affected while heterozygotes were only mildly affected.[29] Two heterozygous individuals did not show any clinical symptoms, suggesting incomplete penetrance. The combined allele frequency of the two mutations was estimated as ∼4% in populations of European ancestry.[29] In a second report, six Irish families with ichthyosis vulgaris were screened for mutations in the FLG gene. In all six families, the severely affected index patients were homozygous or compound heterozygous for FLG mutations and the semidominant mode of inheritance was confirmed.[30] In one family, a third FLG mutation, 3702delG, was identified in the third repeat block that, in compound heterozygous state with R501X, produced an indistinguishable severe phenotype of ichthyosis vulgaris. Yet, in contrast to the previously reported mutations, the 3702delG mutation was found to be very rare (undetectable in about 400 population controls).[30] A third recent report found the R501X and 2282del4 mutations in 15 of 21 patients with a severe ichthyosis vulgaris phenotype.[31] Yet, in this group of patients not only homozygous or compound heterozygous individuals were severely affected but also heterozygous individuals, and six patients with a severe phenotype did not harbour either of these two mutations, raising the question of whether or not additional allelic or nonallelic mutations might be detectable in these patients.[31] Very recently, the first analysis of FLG loss-of-function mutations in a non-European cohort was published. Evaluation of the R501X and 2282del4 mutations in Japanese individuals showed that they were absent in both families with ichthyosis vulgaris and healthy controls. Subsequently, sequencing of the FLG gene in four Japanese families with ichthyosis vulgaris revealed two novel mutations (3321delA and S2554X).[32] Both mutations result in formation of a premature stop codon, and skin biopsies from affected family members demonstrated that keratohyaline granules were greatly reduced in quantity.[32]

In conclusion, it has been convincingly demonstrated that mutations in the FLG gene underlie ichthyosis vulgaris. Mutations appear to be unique between European and Oriental populations, although additional studies are warranted in order to confirm these results. For all reported mutations to date, the stop in translation occurs after the N-terminal fragment of filaggrin. It remains to be elucidated whether or not mutations within the N-terminal domain might result in separate phenotypes.

Figure 3.

Structure of the filaggrin (FLG) gene. The FLG gene comprises three exons. Exon 1 (15 bp) consists only of 5' untranslated (UTR)sequence, exon 2 (159 bp) contains the translation initiation codon and exon 3 (12-14 kb) consists of the N-terminal domain and 10-12 copiesof a 1-kb sequence that encode the proteolytically cleaved parts of filaggrin. The localization of the two common loss-of-function mutationsR501X and 2282del4 and the rare mutation 3702delG identified in European populations as well as of the two mutations found in Japanesecohorts (3321delA and S2554X) is shown.


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