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Filaggrin R501x and 2282del4 gene mutations and its tissue levels in patients with chronic plaque psoriasis

Abu el Ela, Mostafa M.a; Nagui, Noha A.a; EL-Komy, Mohamed H.M.a; Samir, Nesrina; Rashed, Lailab

Journal of the Egyptian Women's Dermatologic Society: January 2012 - Volume 9 - Issue 1 - p 32–37
doi: 10.1097/
Original articles

Background Psoriasis is a chronic inflammatory hyperproliferative disease. Psoriasis susceptibility locus 4 (PSORS4)-linked psoriasis to a region located at 1q21 chromosome, which contains the so-called epidermal differentiation complex, containing the filaggrin (FLG) gene.

Objective To detect the FLG R501x and 2282del4 gene mutations and whether such mutations alter tissue FLG expression and are involved in the pathogenesis of psoriasis.

Patients and methods Punch skin biopsies were taken from lesional, nonlesional skin of 30 patients with plaque psoriasis and normal skin of 20 healthy controls for FLG estimation by enzyme-linked immunosorbant assay. Five milliliter venous blood was withdrawn from patients and controls for the detection of FLG gene mutation by PCR.

Results FLG tissue levels were significantly lower in lesional skin compared with controls (P=0.0001) and nonlesional skin (P=0.0001). Both the R501x and 2282del4 FLG gene mutations were not statistically different between patients and controls (P=0.804 and P=0.236, respectively).

Conclusion The FLG R501X and 2282del4 mutations, in Egyptians, are not associated with a higher risk of psoriasis development. Although the cutaneous FLG level was reduced in patients, it is unlikely that this reduction is a consequence of the studied mutations. The presence of varied terminal differentiation, due to abnormal or reduced FLG, may lead to increased susceptibility to a change in the skin barrier, therefore inducing the onset of psoriasis.

aDepartments of Dermatology

bBiochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt

Correspondence to Noha A. Nagui, Department of Dermatology, Faculty of Medicine, Cairo University, Cairo 11562, Egypt Tel: +0 128 484 0346; fax: +0 20 2241174174; e-mail:

Received December 20, 2010

Accepted January 25, 2011

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Psoriasis is a chronic inflammatory skin condition affecting 2–3% of human population groups and, therefore, it is a considerable cause of morbidity worldwide. The disease presents as a variety of distinguishable subtypes and appears to be a classic multifactorial disorder where genetic predisposing factors combine with environmental stimuli to produce the disease 1.

Linkage studies have identified nine psoriasis susceptibility loci (PSORS1-PSORS9) to date, the most important of which is PSORS1 on chromosome 6p21. Other candidate loci identified by genetic linkage research include PSORS 2 (17q25), PSORS 3 (4q34), PSORS 4 (1q21), PSORS 5 (3q21), PSORS 6 (19p13), PSORS 7 (1p32), PSORS 8 (16q), and PSORS 9 (4q31) 2.

PSORS4-linked psoriasis to a region located at the 1q21 chromosome, which contains the so-called epidermal differentiation complex (EDC), a cluster of at least 70 genes expressed during epithelial differentiation, including filaggrin (FLG), loricrin, involucrin, trichohyalin, S100 proteins, and others. Several fine-mapping association studies have been performed to achieve a finer localization of PSORS4. However, the psoriasis susceptibility gene in this locus is still unknown 3.

FLG is initially synthesized as profilaggrin, an approximately 500-kD highly phosphorylated, histidine-rich polypeptide, which consists of an amino-terminal S100 calcium-binding domain, a downstream B-domain, and a carboxy-terminal domain, as well as a central region comprising a series of repeat units of FLG 4. The FLG gene comprises three exons and two introns 5. Smith et al.6 developed long-range PCR conditions to amplify the entire exon 3 and they identified two mutations in the first repeat of exon 3 in 14 families with ichthyosis vulgaris: R501X and 2282del4. Both mutations result in the formation of a premature stop codon and complete loss of FLG peptide production.

Profilaggrin is the main constituent of the electron-dense keratohyalin granules that are found within the granular layer of the epidermis. Profilaggrin itself has no keratin-binding activity but, in the later stages of epidermal terminal differentiation, during the posttranslational processing of profilaggrin, the individual FLG polypeptides, each approximately 35 kD, are proteolytically released. These are then dephosphorylated in a multistep process, a process that aids keratin filament aggregation and explains the origin of the name 'FLG' (filament aggregating protein). This process contributes to cellular compaction and allows extensive crosslinking of keratin intermediate filaments by transglutaminases to form a highly insoluble keratin matrix. This matrix acts as a protein scaffold for the attachment of cornified-envelope proteins and lipids that together form the stratum corneum. This is followed by conversion of basic arginine residues of FLG into citrulline residues by peptidylarginine deiminase(s). FLG is then hydrolyzed into free amino acids that are collectively referred to as the natural moisturizing factor, which contributes to skin hydration and possibly to ultraviolet protection 7.

It should be noted that when the granular cells differentiate and become transitional cells, the majority of the N-terminal domains are translocated from the keratohyalin granules to the nuclei. This nuclear translocation of the profilaggrin N-terminal domains suggests that these domains play a role in the nuclear disintegration that occurs before cornification, thus explaining the occurrence of parakeratosis in the absence of profilaggrin 8.

Sandilands et al.7 stated that loss of profilaggrin or FLG leads to a poorly formed stratum corneum and that FLG is, therefore, in the frontline of defense, protecting the body from the entry of foreign environmental substances that can otherwise trigger aberrant immune responses.

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Aim of this work

To estimate FLG quantitatively in lesional and nonlesional skin of psoriatic patients and to compare it with that of controls and to study two mutations of the FLG gene (R501X and 2282del4) in the blood of the psoriatic patients and compared it with that of healthy controls.

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Patients and methods


Thirty psoriasis vulgaris patients and 20 healthy control participants were included in this study. They were recruited from the Dermatology Outpatient Clinic, Kasr el Eini Hospital. All patients and controls were subjected to a full medical history and examination in addition to routine laboratory investigations. Participants with any systemic or other dermatologic diseases were excluded. The extent and the severity of the disease were assessed using the psoriasis area and severity index (PASI) score 9.

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Inclusion criteria

All the patients selected had psoriasis vulgaris. Patients with erythrodermic, pustular psoriasis, or psoriatic arthritis were excluded. The recruited patients had not received topical treatment for at least 3 weeks before enrollment in this study. None of the patients was on systemic therapy for at least 3 months before enrollment in this study. Both the patient and the control groups signed a written informed consent.

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Skin biopsy

Two 4–5 mm punch skin biopsies (lesional and nonlesional) were obtained from each patients back if affected or the least-exposed affected site if the back was free. Biopsies from lesional skin of psoriatic patients were obtained from the most recently developing lesions. Biopsy specimen from the lesional skin was divided into two parts. One part was stained with hematoxylin and eosin for histopathological confirmation of the diagnosis and the other part was processed for detection of FLG expression. Skin biopsy from controls was also obtained from the back. The specimens were frozen at −70°C and sent for FLG estimation using a solid-phase enzyme-linked immunosorbant assay (ELISA).

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Blood samples’ collection

Five milliliter venous blood was drawn from each patient and from the healthy controls. All blood samples were used for the detection of FLG gene mutations by PCR.

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Determination of the filaggrin genotype

Genotyping of R501X was performed using a TaqMan allelic discrimination assay. DNA extraction: DNA was isolated from the whole peripheral blood taken into EDTA tubes using the Qiagen DNA Isolation kit (Qiagen GmbH, Hilden, Germany).

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Primers and PCR

Genotyping of the R501X of FLG gene was determined by PCR and sequencing analysis. PCR was performed in a total volume of 25 μl containing 50 ng genomic DNA, 2–6 pmol of each primer F: 5 _ -GCA CTGGAG GAA GAC AAG GAT-3 _ ; primer R: 5 _ -CTC TTG GGA CGCTGA ATG C; probe 1: 5 _ -CTG TCT CGT GCC TGC-3 _ ; probe 2:5 _ -CTG TCT CAT GCC TGC-3 _, X Taq polymerase buffer (1.5 mmol/l MgCl2), and 0.25 U of Amplitaq DNA polymerase (Perkin Elmer, Foster City, California, USA). PCR amplification was performed in a programmable thermal cycler gradient PCR system (Eppendorf AG, Hamburg, Germany).The PCR amplification was performed for 35 cycles (denaturation at 94°C for 1 min, annealing at 55 C for 1 min, extension at 72°C for 1 min, and a final extension for 10 min at 72°C). The PCR product was analyzed by 1.5% agarose gel electrophoresis, followed by ethidium bromide staining and ultraviolet visualization, and then sequenced with a Taq-Dye deoxy-terminator cycle sequencing kit by Applied BioSystems (Carlsbad, California, USA) using an automated ABI 3770 sequencer (Applied BioSystems).

Also, the deletion of four base pairs (2282del4) was carried out as size-based analysis of PCR fragments on an Applied Biosystems 3100 sequencer as described by Palmer et al. 10, both the genotyping methods were conducted.

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Measurement of filaggrin level in skin biopsy specimens

Tissue homogenization: a portion of the skin tissue (lesional and nonlesional) was homogenized for testing of the FLG level by ELISA. Homogenization was performed after the tissue samples had been diluted in 5 vol of homogenate buffer [10 mmol/l 4-(2-Hydroxyethyl)-piperazine-1-ethanesulfonic acid (pH 7.9), 10 mmol/l KCL, 0.1 mmol/l ethylene glycol tetraacetic acid, 1 mmol/l dithiothreitol, and 0.5 mmol/l phenylmethanesulfonyl fluoride] using a vertishear tissue homogenizer (Tekmar Tissuemizer, Teledyne Tekmar, Mason, Ohio, USA). Skin homogenates were centrifuged at 3000 g for 15 min at 4°C. The supernatants were subsequently stored at −80°C until the ELISA could be performed. FLG concentrations were measured in previously prepared skin tissue (supernatant) by an enzyme immunoassay using the human FLG ELISA kits supplied by Uscn Life Science Inc., (Zhuanyang Avenue, Economic & Technological Development Zone, Wuhan, P.R.China) according to the manufacturer's instructions.

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Statistical analysis

Data were statistically described in terms of range, mean±SD, frequencies (number of cases), and percentages when appropriate. Comparison of quantitative variables between the study groups was performed using the Mann–Whitney U-test for independent samples when not normally distributed. For comparing categorical data, the χ2-test was performed. An exact test was used when the expected frequency was less than 5. Correlation between various variables was assessed using the Spearman’s rank correlation equation for nonnormally distributed variables. A probability value (P-value) less than 0.05 was considered statistically significant. All statistical calculations were performed using computer programs Microsoft Excel 2003 (Microsoft Corporation, New York, New York, USA) and Statistical Package for the Social Science; SPSS Inc., Chicago, Illinois, USA version 15 for Microsoft Windows.

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The study included 30 patients with plaque-type psoriasis (15 men and 15 women) and 20 healthy age-matched and sex-matched healthy controls (nine men and 11 women). The age of the patients ranged from 16 to 68 years, with a mean age of 46±13.7 years. The control participants’ ages ranged from 33 to 65 years, with a mean of age 45.9±9.7 years. The patients’ duration of illness ranged from 0.25 to 45 years, with a mean of 10.67±10.8 years. PASI score ranged from 1.6 to 36, with a mean of 13.8±8.6.

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Filaggrin tissue levels

The mean levels of FLG in lesional, nonlesional skin of patients, and skin of controls were 3.8±1.9, 7.7±2.3, and 14.9±3.1 pg/mg, respectively. The mean FLG levels were significantly higher in control skin than in both lesional (P=0.0001) and nonlesional skin of patients (P=0.0001).

The mean FLG levels were significantly higher in nonlesional skin in comparison with lesional skin of patients (P-value 0.0001) (Table 1).

Table 1

Table 1

On studying the genotyping of the two FLG gene variants R501X and 2282de14 in the blood of patients and controls, the following genotypes were detected:

  • Wild-type AA (which occurs most commonly in the general population) (normal).
  • Variant heterozygous Aa (reduced expression of the FLG) (mutant).
  • Variant homozygous aa (poor or no expression of the FLG) (mutant).

On comparing the presence of the R501X gene mutation in the blood of patients and controls, we did not find any statistically significant difference between both groups (P=0.804). Similarly, no statistically significant difference was found between both groups regarding the 2282de14 gene mutation (P=0.236) (Table 2). Although the variant homozygous was found in two patients for R501X and none of the controls, this was still statistically insignificant.

Table 2

Table 2

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Effect of R501X or 2282de14 gene mutation on the mean tissue level of filaggrin in both patients and controls

No statistically significant difference was detected in the lesional tissue level of FLG between patients with either R501X or 2282de14 gene mutations and those with no detectable mutations (P=0.226 and P=0.351, respectively). Also, no statistically significant difference was detected in the nonlesional tissue level of FLG between patients with either R501X or 2282de14 gene mutations and those with no detectable mutations (P=0.311 and P=0.604, respectively).

No statistically significant difference was detected in the tissue level of FLG of the skin of controls with either R501X or 2282de14 gene mutations and those with no detectable mutations (P=0.967) and (P=0.074), respectively (Table 3). There was also no statistically significant relation between R501X and 2282del4 mutants and wild variants with a PASI score P=0.567 and P=0.756, respectively.

Table 3

Table 3

No statistically significant correlation was found between the tissue level of FLG in lesional skin and either patients’ age (r=0.056, P=0.769) or disease duration (r=−0.042, P=0.824), or PASI score (r=0.109, P=0.568).

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The results of this study showed that FLG expression was significantly reduced in psoriatic skin (both lesional and nonlesional) in comparison with healthy controls. This was not, however, accompanied by a significant increase in the rate of the R501X or 2282del4 FLG gene mutations as this mutation between patients and controls did not reveal any statistically significant difference.

In the current work, Egyptian psoriatic patients had a significantly reduced lesional expression of FLG than controls (P=0.0001) and nonlesional skin (P=0.0001). However, nonlesional FLG levels were still significantly lower than those in controls (P=0.0001). Indeed, the FLG expression pattern has been reported to be altered in the psoriatic epidermis 11. Watanabe et al.12 showed that FLG expression was lost from the granular layer in psoriatic lesions, although it was present in nonlesional epidermis. Similarly, other previous studies have shown that FLG expression in the stratum corneum and stratum granulosum was discontinuous or absent in psoriatic lesions 13–15.

Weichenthal et al.16 suggested that although FLG expression might be diminished in the psoriatic plaque in parallel to the loss of the granular layer, it is normally expressed in the uninvolved skin and becomes reconstituted during healing of the psoriatic plaque. This suggests that the basic FLG function as far as it is genetically determined might be undisturbed, and lesional loss of FLG expression may rather be a reactive process due to loss of the granular layer. Unlike the previous authors, in this study, we found decreased FLG tissue levels in noninvolved psoriatic skin in comparison with controls rather than a normal expression. The uninvolved skin of psoriatic patients may be considered as a prepsoriatic skin, which might explain the lower expression of FLG detected in the patients of this study in comparison with the controls. It is, however, important to investigate the degree of thinning of the granular layer in noninvolved skin of psoriatic patient to verify the present findings.

Comparison of the presence of the R501X mutation in the blood of patients and controls did not show any statistically significant difference (P=0.804). Similarly, comparison of the presence of the 2282del4 mutation between patients and controls did not reveal any statistically significant difference (P=0.236). In particular, the rate for homozygous null carriers was not significantly enhanced in either FLG gene variants. Moreover, there was no correlation between the R501X and the 2282del4 mutant and wild variants with the PASI score, which suggests that these mutations are possibly not involved in the pathogenesis of psoriasis.

Quite similar to the present findings, Zhao et al.17, on comparing the variants frequencies in an Irish population between the psoriasis cohort and the controls, showed a nonsignificant difference, where the P-values for the R501X and 2282del4 variants were 0.075 and 0.932, respectively. Also, English patients with psoriasis were compared with healthy controls; the R501X allele again showed a weak association that failed to reach significance, P=0.075, and also the 2282del4 allele, which showed no significant association, P=0.366 17.

Huffmeier et al.18 demonstrated that the FLG null variants R501X and 2282del4 were not associated with increased susceptibility to psoriasis in German patients. In another study in the same population, Weichenthal et al.16 detected no association for any of the FLG mutations with psoriasis, where P=0.84 for R501X, P=1 for 2282del4. These rates also compared well with the figures reported for an Italian population 19.

Notably, there were huge differences in allele frequencies across Europe, depending on the countries in which the participants lived and their ethnicity; still, no association with psoriasis could be detected. It has to be noted, however, that although R501X and 2282del4 are common in populations of European ancestry, they are absent in Asian populations, in which a different spectrum of FLG variants has been identified 20. Chang et al.21 studied a group of 200 Asians with psoriasis who were screened for the presence of FLG R501X and 2282del4 gene mutations, but none of these individuals carried either of these mutations. In this study on Egyptian patients of North-East Africans – near Eastern genetic lineage 22,23, patients and controls, both R501X and 2282del4 mutations were detected. The variant homozygous was found only in two patients for R501X and was absent in controls and this was statistically insignificant.

As confirmed both biochemically and histologically, individuals who carry the R501X and 2282del4 FLG mutations either as homozygotes or as compound heterozygotes (heterozygous for both polymorphisms) fail to express any detectable FLG protein within their epidermis, whereas heterozygotes of an FLG null allele were found to have reduced amounts of FLG in their epidermis compared with participants with the wild-type genotype 6. However, in the current results, on comparing the mean FLG levels in lesional skin of patients with either R501X or 2282del4 mutations and patients with no detectable mutation, no statistically significant difference was detected (P=0.226 and P=0.351, respectively). This was also observed when the same comparisons were performed on nonlesional skin of patients and normal skin of controls. Moreover, in the two patients with variant homozygous for the R501X mutation, the FLG expression could still be detected in lesional and nonlesional skin.

It should be noted that the methods we used for measuring FLG do not allow differentiation between FLG with less repeats (because of the presence of the mutation) and normal-functioning FLG. On the basis of previous reports, we assume that our patients with evidence of R501X or 2282del4 mutations express an abnormal nonfunctioning epidermal FLG.

FLG with loss-of-function mutations has been implicated convincingly in the pathogenesis of ichthyosis vulgaris and atopic dermatitis, and there is strong evidence that EDC variation might also play a role in psoriasis 24. Zhao et al.17 concluded that FLG can be excluded as an EDC gene for psoriasis in European populations, although it is clearly very important in atopic dermatitis, suggesting that, in the 1q21 locus at least, the shared genetic susceptibility observed for these inflammatory skin conditions may be due to the clustering of genes with similar but nonidentical functions rather than distinct clinical conditions arising from the same causative polymorphisms. However, an association of a variant that is not analyzed in any functional study shows only an arguable relation to a disease. Independent association studies and functional data confirming these results are necessary to draw any conclusions 21. As FLG functionality was not determined in this work, we suggest that this point needs to be addressed in further studies.

On the basis of the prevailing concept that common variants contribute to genetic risk for common diseases (common disease–common variant hypothesis), Chang et al.21, hypothesized that an unknown functional mutation may be present at or adjacent to the FLG gene, giving rise to the interindividual variation of FLG function or expression, and thereby contributing to the risk of psoriasis. So far, 22 loss-of-function mutations in the FLG gene have been reported. As new FLG variant mutations are being determined, it remains possible that a different variant not yet discovered might play a role in psoriasis. In addition, the EDC might still harbor a major gene for psoriasis as the PSORS4 locus has been repeatedly confirmed in independent patient cohorts 25–27.

In conclusion, from the present study, it seems that the FLG R501X and 2282del4 gene mutations, in Egyptians (like Europeans), are not associated with a higher risk for psoriasis development. Although the cutaneous FLG level was reduced in patients, it is unlikely that this reduction is a consequence of the studied mutations. Abnormalities in the granular layer may account for the aberrant or the reduced FLG level resulting in a varied terminal differentiation that may subsequently lead to increased susceptibility to a change in the skin barrier, therefore inducing the onset of psoriasis.

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Conflicts of interest

There are no conflicts of interest.

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epidermal differentiation complex; filaggrin; gene; mutation; psoriasis; susceptibility locus

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