Other entities represented in this entry:
HGNC Approved Gene Symbol: FLG
SNOMEDCT: 254157005; ICD10CM: Q80.0;
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:152,302,165-152,325,239 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.3 | {Dermatitis, atopic, susceptibility to, 2} | 605803 | 3 | |
| Ichthyosis vulgaris | 146700 | Autosomal dominant; Autosomal recessive | 3 |
Profilaggrin is a major protein component of the keratohyalin granules of mammalian epidermis. It is initially expressed as a large polyprotein precursor which is subsequently proteolytically processed into individual functional filaggrin molecules. The filaggrins show wide species variations and their aberrant expression has been implicated in a number of keratinizing disorders (Baden et al., 1974; Holbrook et al., 1982; Sybert et al., 1985).
Deimination of FLG arginine residues by peptidylarginine deiminases (see PADI1, 607934) results in the dissociation of FLG from the matrix and promotes its degradation into free amino acids that are important for retaining water in the stratum corneum and for UV protection (summary by Hsu et al., 2011).
McKinley-Grant et al. (1989) isolated a cDNA clone encoding human filaggrin. They demonstrated that the human gene encodes a polyprotein precursor containing numerous tandem filaggrin repeats. This structure is similar to that of the mouse; however, the human filaggrin repeat is much longer (972 basepairs; 324 amino acids) and shows little sequence homology to the mouse protein. They found furthermore that the human filaggrin repeats show considerable sequence variations; such polymorphism is not found in the mouse. By peptide mapping, they defined a short linker sequence within the human filaggrin repeat that is excised by proteolysis to yield functional molecules. They showed by in situ hybridization that the expression of the gene for the human filaggrin precursor is tightly regulated at the transcriptional level in terminally differentiating epidermis.
Gan et al. (1990) isolated genomic DNA and cDNA clones encoding the 5-prime and 3-prime ends of the human gene and mRNA. They found evidence of likely CAT and TATA sequences, an intron in the 5-prime untranslated region, and several potential regulatory sequences. The gene is made up of repeats, all of the same length. Sequences showed considerable variation, most attributable to single-base changes. Thus, human filaggrin consists of a heterogeneous population of molecules of different sizes, charges, and sequences. Amino acid sequences encoding the amino and carboxyl termini were more conserved, as were the 5-prime and 3-prime DNA sequences flanking the coding portions of the gene. The presence of unique restriction enzyme sites in these conserved flanking sequences enabled Gan et al. (1990) to calculate the size of the full-length gene and the number of repeats in it; depending on the source of genomic DNA, the gene contains 10, 11, or 12 filaggrin repeats that segregate in families in a normal mendelian manner. Thus, the human profilaggrin gene is polymorphic with respect to size due to simple allelic differences between individuals.
Using RT-PCR, Wu et al. (2009) detected FLG expression in all normal tissues examined.
The FLG gene comprises 3 exons (Presland et al., 1992).
Using a cDNA clone as a probe in the study of a panel of mouse-human somatic cell hybrids retaining overlapping subsets of human chromosomal regions and for chromosomal in situ hybridization, McKinley-Grant et al. (1989) demonstrated that the human filaggrin gene maps to 1q21. Rothnagel et al. (1994) mapped the homologous gene to mouse chromosome 3 by PCR analyses of DNAs isolated from mouse/Chinese hamster somatic cell hybrids.
Genes of 3 protein families that are specifically expressed in the course of terminal differentiation of human epidermis have been mapped to 1q21. Volz et al. (1993) showed that these genes are physically linked within 2.05 Mb of DNA in the following order: calpactin I light chain (CAL1L; 114085), trichohyalin (THL; 190370), profilaggrin, involucrin (IVL; 147360), small proline-rich protein (SPRR1A; 182265), loricrin (LOR; 152445), and calcyclin (CACY; 114110).
Smith et al. (2006) reviewed the function of filaggrin, also known as filament-aggregating protein, in the formation of the stratum corneum. Keratohyalin granules in the granular layer of interfollicular epidermis are predominantly composed of the 400-kD protein profilaggrin. Following a short, unique N-terminal domain, most of the profilaggrin molecule consists of 10 to 12 repeats of the 324-residue filaggrin sequence (Gan et al., 1990). Upon terminal differentiation of granular cells, profilaggrin is proteolytically cleaved into filaggrin peptides of approximately 37 kD and the N-terminal domain containing an S100-like calcium-binding domain. Filaggrin rapidly aggregates the keratin cytoskeleton, causing collapse of the granular cells into flattened anuclear squames. This condensed cytoskeleton is crosslinked by transglutaminases during formation of the cornified cell envelope (CCE). The CCE is the outermost barrier layer of the skin which not only prevents water loss but also impedes the entry of allergens and infectious agents. Filaggrin is therefore a key protein in facilitating epidermal differentiation and maintaining barrier function.
Using RT-PCR, Wu et al. (2009) found that expression of both FLG and FLG2 (616284) increased 200-fold in cultured human foreskin keratinocytes following calcium-induced differentiation.
In 15 kindreds with ichthyosis vulgaris (146700), Smith et al. (2006) identified homozygous or compound heterozygous mutations R501X (135940.0001) and 2282del4 (135940.0002) in the FLG gene in individuals with a moderate or severe phenotype. They concluded that these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations showed 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 crosslinked to form a major component of the cornified cell envelope. Smith et al. (2006) found that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.
Twin and family studies have indicated a highly heritable predisposition to atopic disease, including atopic dermatitis (see 603165), allergy, and asthma (see 600807). Although genetic studies have focused on immunologic mechanisms of atopic dermatitis, a primary epithelial barrier defect has been anticipated (Cookson and Moffatt, 2002). Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Palmer et al. (2006) showed that 2 independent loss-of-function genetic variants, R501X (135940.0001) and 2282del4 (135940.0002), in the FLG gene are very strong predisposing factors for atopic dermatitis (605803). These mutations had been shown to be the cause of ichthyosis vulgaris in 15 families and isolated cases (Smith et al., 2006). The R501X and 2282del4 variants, carried by approximately 9% of people of European origin, also showed highly significant association with asthma occurring in the context of atopic dermatitis. This work established a key role for impaired skin barrier function in the development of atopic disease.
Sandilands et al. (2007) showed that the 2 common filaggrin-null mutations reported by Smith et al. (2006) and Palmer et al. (2006) are ancestral European variants carried on conserved haplotypes. To facilitate comprehensive analysis in other populations, they reported a strategy for full sequencing of this large, highly repetitive gene, and described 15 variants, including 7 that are prevalent. All the variants were either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the 5 most common European mutations showed a strong association with moderate to severe childhood eczema. They found 3 additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.
Using the transmission-disequilibrium test in 476 German parent-offspring trios with atopic dermatitis, Weidinger et al. (2006) found a significant association between the loss-of-function mutations R501X and 2282del4 in the FLG gene and extrinsic atopic dermatitis, allergic sensitization, total IgE level, asthma, and palmar hyperlinearity; there was no significant association with intrinsic atopic dermatitis.
Marenholz et al. (2006) genotyped 1092 children with eczema (atopic dermatitis) from 2 large European populations for the R501X and 2282del4 mutations in the FLG gene and confirmed a highly significant association between the null mutations and eczema and concomitant asthma. Moreover, the authors found that these mutations predisposed to asthma, allergic rhinitis, and allergic sensitization only in the presence of eczema, highlighting the importance of the epidermal barrier in the pathogenesis of these disorders (the so-called 'atopic march').
Nomura et al. (2007) sequenced the entire FLG gene in 7 Japanese patients with ichthyosis vulgaris from 4 unrelated families who were negative for the R501X and 2282del4 mutations, and identified heterozygosity for 2 novel mutations, S2554X (135940.0003) and 3321delA (135940.0004), respectively. The authors then screened 143 Japanese patients with atopic dermatitis from 140 unrelated families for the novel null mutations and identified S2554X in 6 patients and 3321delA in 2 patients; they were not found in 156 unrelated Japanese nonatopic and nonichthyotic controls, yielding a chi-square p value of 0.0015. Noting that the R501X and 2282del4 mutations were absent from a total of 253 Japanese individuals, including their patients with ichthyosis vulgaris and atopic dermatitis, Nomura et al. (2007) concluded that FLG mutations in Japan are different from those found in European-origin populations.
Hu et al. (2012) found association between a nonsense variant in the FLG gene (K4022X; 135940.0005) and the psoriasis/ichthyosis vulgaris phenotype in the Chinese population. Hu et al. (2012) noted that Nemoto-Hasebe et al. (2009) reported heterozygosity for the same variant, which they designated K4021X, in Japanese patients with atopic dermatitis.
Netherton syndrome (256500), an autosomal recessive multisystem disorder characterized by congenital ichthyosiform erythroderma, hair shaft defects and atopy, is caused by mutation in the SPINK5 gene (605010). Hewett et al. (2005) created mice with an R820X mutation in the Spink5 gene. Newborn homozygotes developed a severe ichthyosis with a loss of skin barrier function and dehydration, resulting in death within a few hours. Biochemical analysis of skin revealed a substantial increase in the proteolytic processing of profilaggrin into its constituent filaggrin monomers. The authors suggested that in the absence of SPINK5 there is an abnormal increase in the processing of profilaggrin, and that this may play a direct role in the observed deficit in the adhesion of the stratum corneum and the severely compromised epidermal barrier function.
Fallon et al. (2009) reported a 1-bp deletion mutation, 5303delA, analogous to common human FLG mutations, within the murine Flg gene in the spontaneous mouse mutant 'flaky tail' (ft). Fallon et al. (2009) demonstrated that topical application of allergen to mice homozygous for this mutation resulted in cutaneous inflammatory infiltrates and enhanced cutaneous allergen priming with development of allergen-specific antibody responses. These data validated flaky tail as a useful model of filaggrin deficiency and provided experimental evidence for the hypothesis that antigen transfer through a defective epidermal barrier is a key mechanism underlying elevated IgE sensitization and initiation of cutaneous inflammation in humans with filaggrin-related atopic disease.
In 7 unrelated ichthyosis vulgaris (146700) families and 8 additional 'sporadic' cases from Ireland, Scotland, and the U.S., Smith et al. (2006) found that ichthyosis vulgaris was associated with an arg501-to-stop (R501X) mutation arising from a 1501C-to-T transition near the start of repeat 1 in exon 3 of the FLG gene. In 3 families, ichthyosis vulgaris patients with a very pronounced phenotype were homozygous for R501X. In other families and isolated cases, they found individuals with the marked ichthyosis vulgaris phenotype to be compound heterozygous for R501X and a second mutation, 2282del4, in exon 3 (135940.0002). The 2282del4 mutation leads to a premature termination codon 107 bp downstream and, like R501X, stops protein translation within the first filaggrin repeat.
Ichthyosis vulgaris is semidominant: that is, heterozygotes had either no discernible phenotype or milder ichthyosis, whereas homozygotes or compound heterozygotes had marked ichthyosis and an overt histologic skin barrier defect. In an extension of the work of Smith et al. (2006), Palmer et al. (2006) noted that in their families with ichthyosis vulgaris, many individuals null or heterozygous for filaggrin also had atopic dermatitis (605803) (eczema) and, in a few cases, also had asthma (see 600807). Specifically, atopic dermatitis was prevalent in the individuals with mild ichthyosis vulgaris, all of whom were heterozygous for either the R501X or 2282del4 FLG-null allele (13/29; 44%). Atopic dermatitis was particularly common in individuals with severe ichthyosis vulgaris, all of whom were homozygous or compound heterozygous for FLG-null alleles (16/21; 76%). None of the individuals in these families who lacked an FLG-null allele had atopic dermatitis (n = 13). Thus, atopic dermatitis is inherited as a semidominant trait in these families, with high penetrance in FLG-null homozygotes or compound heterozygotes and reduced penetrance in heterozygotes.
Using the transmission-disequilibrium test in 476 German parent-offspring trios with atopic dermatitis, Weidinger et al. (2006) found a significant association between the loss-of-function mutations R501X and 2282del4 in the FLG gene and extrinsic atopic dermatitis, allergic sensitization, total IgE level, asthma, and palmar hyperlinearity; there was no significant association with intrinsic atopic dermatitis.
Marenholz et al. (2006) genotyped 1092 children with eczema (atopic dermatitis) from 2 large European populations for the R501X and 2282del4 mutations in the FLG gene and replicated the highly significant association between the null mutations and eczema and concomitant asthma. Moreover, the authors found that these mutations predisposed to asthma, allergic rhinitis, and allergic sensitization only in the presence of eczema, and that the mutations predisposed equally to atopic (intrinsic) and nonatopic (extrinsic) forms of eczema. They demonstrated that the presence of 2 null alleles is an independent risk factor for asthma in children with eczema (OR, 11.76, p = 0.0085). Together, the 2 mutations accounted for approximately 11% of eczema cases in the German population.
For discussion of the 4-bp deletion in the FLG gene (2282del4) that was found in compound heterozygous state in patients with ichthyosis vulgaris (146700) by Smith et al. (2006), see 135940.0001.
For discussion of the 2282del4 deletion in the FLG gene that was found in compound heterozygous state in patients with atopic dermatitis (605803) by Palmer et al. (2006), see 135940.0001.
Weidinger et al. (2006) found a significant association between atopic dermatitis, in particular the extrinsic type, and the R501X and 2282del4 mutations; Marenholz et al. (2006) replicated the association and also found that the presence of 2 null alleles was an independent risk factor for asthma in children with eczema. See 135940.0001.
In affected members of 2 unrelated Japanese families with ichthyosis vulgaris (146700) who were negative for previously identified null mutations in the FLG gene, Nomura et al. (2007) identified heterozygosity for a 7661C-G transversion in exon 3 of the FLG gene, resulting in a ser2554-to-ter (S2554X) substitution, predicted to cause premature termination of profilaggrin translation in the filaggrin repeat domain 7. The older sister of 1 proband, who had a severe presentation of the disease, was found to be homozygous for S2554X. The authors then screened 143 Japanese patients with atopic dermatitis (605803) from 140 unrelated families for this null mutation and identified S2554X in 6 patients. The mutation was not found in 156 unrelated nonatopic and nonichthyotic Japanese controls.
In 2 probands from 2 unrelated Japanese families with ichthyosis vulgaris (146700), who were negative for previously identified null mutations in the FLG gene, Nomura et al. (2007) identified heterozygosity for a 1-bp deletion (3321delA) in exon 3 of the FLG gene, resulting in a premature termination of profilaggrin translation in filaggrin repeat domain 2. The authors then screened 143 Japanese patients with atopic dermatitis (605803) from 140 unrelated families for this deletion and identified 3321delA in 2 patients. The deletion was not found in 156 unrelated nonatopic and nonichthyotic Japanese controls.
This variant is classified as a variant of unknown significance because its contribution to a cutaneous phenotype has not been confirmed.
In a Chinese male patient with psoriasis (603935), whose paternal aunt and grandmother had been diagnosed with ichthyosis vulgaris (146700), Hu et al. (2012) analyzed the entire coding region of the FLG gene and identified homozygosity for a nonsense mutation, K4022X. The variant was found in heterozygosity in his aunt and grandmother with ichthyosis vulgaris as well as in 4 unaffected family members, including his father and mother. Hu et al. (2012) noted that Nemoto-Hasebe et al. (2009) reported heterozygosity for the same variant, which they designated LYS4022TER (K4021X), in Japanese patients with atopic dermatitis (605803). Screening for K4022X in 441 unrelated Chinese psoriasis cases revealed another 2 patients who were homozygous; the variant was also found in heterozygosity in 29 (6.6%) of the patients and in 15 (3%) of 500 controls who were not screened for the absence of psoriasis. The odds ratio for the dominant model was 2.552 (p = 0.002), suggesting an association of the K4022X variant with the psoriasis/ichthyosis vulgaris phenotype in the Chinese population, and case-control analysis yielded significant association with psoriasis (p = 0.01).
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