Filaggrin Research Articles

Whole-exome mutational landscape and molecular marker study in mucinous and clear cell ovarian cancer cell lines 3AO and ES2

BackgroundOvarian cancer is one of the most lethal cancers in women because it is often diagnosed at an advanced stage. The molecular markers investigated thus far have been unsatisfactory.MethodsWe performed whole-exome sequencing on the human ovarian cancer cell lines 3AO and ES2 and the normal ovarian epithelial cell line IOSE-80. Molecular markers of ovarian cancer were screened from shared mutation genes and copy number variation genes in the 6q21-qter region.ResultsWe found that missense mutations were the most common mutations in the gene (93%). The MUC12, FLG and MUC16 genes were highly mutated in 3AO and ES2 cells. Copy number amplification occurred mainly in 4p16.1 and 11q14.3, and copy number deletions occurred in 4q34.3 and 18p11.21. A total of 23 hub genes were screened, of which 16 were closely related to the survival of ovarian cancer patients. The three genes CCDC170, THBS2 and COL14A1 are most significantly correlated with the survival and prognosis of ovarian cancer. In particular, the overall survival of ovarian cancer patients with high CCDC170 gene expression was significantly prolonged (P < 0.001). The expression of CCDC170 in normal tissues was significantly higher than that in ovarian cancer tissues (P < 0.05), and its expression was significantly decreased in advanced ovarian cancer. Western blotting and immunofluorescence assays also showed that the expression of CCDC170 in ovarian cancer cells was significantly lower than that in normal cells (P < 0.001, P < 0.01).ConclusionsCCDC170 is expected to become a new diagnostic molecular target and prognostic indicator for ovarian cancer patients, which can provide new ideas for the design of antitumor drugs.

Relevance of Coding Variation in FLG And DOCK8 in Finnish Pediatric Patients with Early-Onset Moderate-To-Severe Atopic Dermatitis

Early-onset, persistent atopic dermatitis (AD) is proposed as a distinct subgroup that may have specific genotypic features. FLG gene loss-of-function variants are the best known genetic factors contributing to epidermal barrier impairment and eczema severity. In a cohort of 140 Finnish children with early-onset moderate-to-severe AD, we investigated the effect of coding variation in FLG and 13 other genes with epidermal barrier or immune function through the use of targeted amplicon sequencing and genotyping. A FLG loss-of-function variant (Arg501Ter, Ser761fs, Arg2447Ter, or Ser3247Ter) was identified in 20 of 140 patients showing higher transepidermal water loss values than patients without these variants. Total FLG loss-of-function variant frequency (7.14%) was significantly higher than in the general Finnish population (2.34%). When tested separately, only Arg2447Ter showed a significant association with AD (P= 0.003104). In addition, a modest association with moderate-to-severe pediatric AD was seen for rs12730241 and rs6587667 (FLG2:Gly137Glu). Loss-of-function variants, previously reported pathogenic variants, or statistically significant enrichment of nonsynonymous coding region variants were not found in the 13 candidate genes studied by amplicon sequencing. However, higher IgE and eosinophil counts were found in carriers of potentially pathogenic DOCK8 missense variants, suggesting that the role of DOCK8 variation in AD should be further investigated in larger cohorts.

Overview of Atopic Dermatitis in Different Ethnic Groups.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a high prevalence worldwide, including countries from Asia, Africa, and Latin America, and in different ethnic groups. In recent years, more attention has been placed on the heterogeneity of AD associated with multiple factors, including a patient's ethnic background, resulting in an increasing body of clinical, genetic, epidemiologic, and immune-phenotypic evidence that delineates differences in AD among racial groups. Filaggrin (FLG) mutations, the strongest genetic risk factor for the development of AD, are detected in up to 50% of European and 27% of Asian AD patients, but very rarely in Africans. Th2 hyperactivation is a common attribute of all ethnic groups, though the Asian endotype of AD is also characterized by an increased Th17-mediated signal, whereas African Americans show a strong Th2/Th22 signature and an absence of Th1/Th17 skewing. In addition, the ethnic heterogeneity of AD may hold important therapeutic implications as a patient's genetic predisposition may affect treatment response and, thereby, a tailored strategy that better targets the dominant immunologic pathways in each ethnic subgroup may be envisaged. Nevertheless, white patients with AD represent the largest ethnicity enrolled and tested in clinical trials and the most treated in a real-world setting, limiting investigations about safety and efficacy across different ethnicities. The purpose of this review is to describe the heterogeneity in the pathophysiology of AD across ethnicities and its potential therapeutic implications.

Filaggrin gene polymorphisms in Indian children with atopic dermatitis: A cross-sectional multicentre study.

Background Filaggrin (FLG) gene encoding the protein filaggrin plays an important role in barrier function of the skin and its alteration is a predisposing factor for atopic dermatitis. FLG gene variants result in absent or decreased filaggrin protein. Worldwide, the prevalence of FLG variants ranges from 14 to 56%. FLG null variants are distinct in each population. Objectives To study the FLG gene polymorphisms in Indian children and attempt a genotype-phenotype correlation in atopic dermatitis. Methods This was a cross-sectional, multicentre study conducted on 75 Indian children. Demographic details, clinical features and identified FLG null variants were recorded. We performed a whole gene sequencing of the entire FLG coding region using next-generation sequencing technology. Results The prevalence of FLG null variants was 34.7%. A total of 20 different FLG loss of function variants in 26 children were documented. Sixteen (80%) variants were novel and four (20%) were previously reported in Asian and European populations. We found a statistically significant association between FLG variants with early age of onset of atopic dermatitis (P = 0.016) and elevated serum IgE levels (P = 0.051). There was no significant difference between atopic dermatitis phenotypes in children having one variant as compared to children harbouring two or more null variants. Limitation Small sample size. Conclusion Our study reports a unique set of FLG variants different from Asian and European populations, with these variants being significantly associated with an early age of onset of atopic dermatitis and elevated serum IgE levels.

Altered expression of S100 fused-type proteins in an atopic dermatitis skin model.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder with elevated interleukin (IL)-4 and IL-13 signatures and extensive barrier dysfunction, which is correlated with the downregulation of filaggrin (FLG). FLG is a member of the S100 fused-type protein family and this family also includes cornulin (CRNN), filaggrin-2 (FLG2), hornerin (HRNR) repetin (RPTN), trichohyalin (TCHH) and trichohyalin-like 1 (TCHHL1). The present study aimed to examine the effects of IL-4 and IL-13 and the downregulation of FLG on the expression of S100 fused-type proteins using a three-dimensional (3D) AD skin model by immunohistochemical study and quantitative polymerase chain reaction. In the 3D AD skin model, which was generated by a stimulation of recombinant IL-4 and IL-13, the expression of FLG, FLG2, HRNR and TCHH was decreased, while that of RPTN was increased in comparison to the 3D control skin. In the FLG knockdown (KD) 3D skin model, which was generated using FLG siRNA, the expression of HRNR was increased. The expression of the other proteins did not differ to a statistically significant extent. The expression of fused-S100 type protein family members may differ in AD skin. This suggests that these proteins play different roles in the pathogenesis of AD.

Skin Barrier Function and Its Relationship With IL-17, IL-33, and Filaggrin in Malar Melasma.

The pathogenesis of melasma remains unclear. Interleukin (IL)-17, a proinflammatory mediator, disturbs barrier function. Filaggrin (FLG) is a protein involved in epidermal barrier homeostasis and may be affected by IL-17 and IL-33. To evaluate epidermal barrier function in malar melasma and its association with the expression of FLG, IL-17, and IL-33. Twenty patients with malar melasma were included in this study. Colorimetric and transepidermal water loss (TEWL) was measured in lesional and adjacent unaffected skin at baseline and 30 minutes after barrier disruption using the tape-stripping test. Biopsies from melasma and perilesional skin were performed to evaluate the presence of FLG by immunohistochemistry, and profilaggrin, IL-17, and IL-33 expression were analyzed by reverse transcription-qualitative polymerase chain reaction. After the stripping test, the erythema and TEWL values were higher in the melasma than in the unaffected skin ( P = 0.01). Thirty minutes later, TEWL diminished, but it remained higher than in the perilesional skin. Profilaggrin increased as TEWL gradually decreased (R = -0.68, P = 0.04). FLG and IL-17 were higher in the melasma than in the perilesional skin ( P = 0.003). IL-17 and profilaggrin expression were positively associated (R = 0.60, P = 0.04). IL-33 expression was higher in the adjacent normal skin than in the melasma ( P = 0.01). This study found subclinical inflammation in the skin adjacent to the melasma, dysfunction of the epidermal barrier in lesions associated with chronic inflammation, and an abnormal differentiation process promoting an increase in FLG. These findings highlight the need to preserve the integrity of the facial stratum corneum in these patients.

Effects of donkey milk on UVB-induced skin barrier damage and melanin pigmentation: A network pharmacology and experimental validation study.

Dairy products have long been regarded as a controversial nutrient for the skin. However, a clear demonstration of donkey milk (DM) on skincare is required. In this study, spectrum and chemical component analyses were applied to DM. Then, the effects of DM on UVB-induced skin barrier damage and melanin pigmentation were first evaluated in vitro and in vivo. Cell survival, animal models, and expression of filaggrin (FLG) were determined to confirm the effect of DM on UVB-induced skin barrier damage. Melanogenesis and tyrosinase (TYR) activity were assessed after UVB irradiation to clarify the effect of DM on whitening activities. Further, a network pharmacology method was applied to study the interaction between DM ingredients and UVB-induced skin injury. Meanwhile, an analysis of the melanogenesis molecular target network was developed and validated to predict the melanogenesis regulators in DM. DM was rich in cholesterols, fatty acids, vitamins and amino acids. The results of evaluation of whitening activities in vitro and in vivo indicated that DM had a potent inhibitory effect on melanin synthesis. The results of effects of DM on UVB‑induced skin barrier damage indicated that DM inhibited UVB-induced injury and restored skin barrier function via up-regulation expression of FLG (filaggrin). The pharmacological network of DM showed that DM regulated steroid biosynthesis and fatty acid metabolism in keratinocytes and 64 melanin targets which the main contributing role of DM might target melanogenesis, cell adhesion molecules (CAMs), and Tumor necrosis factor (TNF) pathway. These results highlight the potential use of DM as a promising agent for whitening and anti-photoaging applications.

Investigations into the FLG Null Phenotype: Showcasing the Methodology for CRISPR/Cas9 Editing of Human Keratinocytes

Ever since the association between filaggrin (FLG) loss-of-function mutations and ichthyosis vulgaris and atopic dermatitis disease onset was identified, filaggrins function has been under investigation. Intra-individual genomic predisposition, immunological confounders, and environmental interactions complicate the comparison between FLG genotypes and related causal effects. Using CRISPR/Cas9, we generated human FLG knockout (ΔFLG) N/TERT-2G keratinocytes. Filaggrin deficiency was demonstrated by immunohistochemistry of human epidermal equivalent (HEE) cultures. Next to (partial) loss of structural proteins (IVL, HRNR, KRT2, and TGM1), the stratum corneum was more dense and lacked the typical basket weave appearance. In addition, electrical impedance spectroscopy and transepidermal water loss analyses highlighted a compromised epidermal barrier in ΔFLG-HEEs. Correction of FLG reinstated the presence of keratohyalin granules in the stratum granulosum, filaggrin protein expression, and expression of aforementioned proteins. The beneficial effects on stratum corneum formation were reflected by normalization of EIS and TEWL. This study demonstrates the causal phenotypical and functional consequences of filaggrin deficiency, indicating filaggrin is not only central in epidermal barrier function but also vital for epidermal differentiation by orchestrating the expression of other important epidermal proteins. These observations pave the way to fundamental investigations into the exact role of filaggrin in skin biology and disease.

Deep palmar phenotyping in atopic eczema: patterns associated with Filaggrin variants, disease severity and barrier function in a South Asian population.

Hyperlinear palms are described as a feature of loss-of-function (LoF) variants in Filaggrin (FLG). To explore the phenotype of participants (age <31 years) with atopic eczema of Bangladeshi ancestry from East London and investigate which factors best associate with LoF FLG variants. A cross-sectional study with participants recruited between May 2018 and March 2020. Patterns of palmar linearity were categorised and modelled with Eczema Area and Severity Index (EASI), transepidermal water loss (TEWL), skin hydration (SH) and LoF FLG variants. Five hundred and six complete cases were available. Five palm patterns were noted. The 'prominent diamond' pattern associated best with EASI (marginal effects [ME], 2.53, 95% CI 1.74-3.67), TEWL (ME 1.32, 95% CI 1.11-1.62) and SH (ME 0.85, 95% CI 0.78-0.96). Using five palm patterns had some ability to discriminate LoF FLG variants (area under the receiver operator characteristic [AUROC] 76.07; 95% CI 71.58-80.57), improving in subgroup analysis with only fine perpendicular/prominent diamond patterns and SH (AUROC 89.11%; 95% CI 84.02-94.19). Single centre study design with humans classifying clinical patterns. Stability of temperature and humidity not guaranteed across TEWL and SH measurements despite using a climate controlled room. Palm patterns associate with EASI and TEWL. The fine perpendicular/prominent diamond patterns are markers to detect absence/presence of LoF FLG variants respectively.

Biallelic mutations in FLG, TGM1, and STS genes segregated with different types of ichthyoses in eight families of Pakistani origin.

Congenital ichthyosis is a diverse group of keratinization disorders associated with generalized scaling of skin of varying severity. The non-syndromic forms of congenital ichthyosis are further grouped into common ichthyosis (ichthyosis vulgaris and X-linked ichthyosis), autosomal recessive congenital ichthyosis, and keratopathic ichthyosis. To identify sequence variants involved in different forms of hereditary ichthyoses. We studied eight families with different types of ichthyosis including four families with autosomal recessive congenital ichthyosis and four families with common ichthyosis. Whole exome sequencing and PCR based genotyping was carried out to find out the molecular basis of disease. In one family, a novel duplication sequence variant NM_002016.2:c.2767dupT; NP_002007.1:p.Ser923PhefsTer2 was identified in FLG gene; in four families a previously reported nonsense sequence variant NM_000359.3:c.232C>T; NP_002007.1:p.Arg78Ter was identified in TGM1 gene, while, in three families of X-linked recessive ichthyosis, the whole STS gene (NM_001320752.2; NP_001307681.2) regions were deleted. Gene expression studies have not been performed that would have strengthened the findings of computational analysis. This study highlights the significance of the c.232C>T variant in the TGM1 gene as a possible founder mutation, complete STS gene deletion as reported previously in Pakistani population, while novel sequence variant in the FLG gene expands the spectrum of variations in this gene. These findings may be used for genetic counseling of the studied families.

Epigenome alterations in food allergy: A systematic review of candidate gene and epigenome-wide association studies.

The aim of this study was to systematically review the evidence across studies that assessed DNA methylome variations in association with food allergy (FA). A systematic review of the literature and meta-analysis were carried out within several databases. However, the risk of bias in the included articles was not evaluated. PubMed, Cochrane Database of Systematic Reviews,and Web of Science were used to search up to July 2022. We included targeted and epigenome-wide association studies (EWASs) that assessed DNA methylome alterations in association with FA in adult or paediatric populations. Among 366 publications, only 16 were retained, which were mainly focused on FA in children. Seven candidate gene-targeted studies found associations in Th1/Th2 imbalance (IL4, IL5, IL10, INFG, IL2 and IL12B genes), regulatory T cell function (FOXP3 gene), Toll-like receptors pathway (TLR2, CD14 genes) and digestive barrier integrity (FLG gene). Nine EWAS assessed the association with peanut allergy (n=3), cow's milk allergy (n=2) or various food allergens (n=4). They highlighted 11 differentially methylated loci in at least two studies (RPS6KA2, CAMTA1, CTBP2, RYR2, TRAPPC9, DOCK1, GALNTL4, HDAC4, UMODL1, ZAK and TNS3 genes). Among them, CAMTA1 and RPS6KA2, and CTBP2 are involved in regulatory T cell function and Th2 cell differentiation, respectively. Gene-functional analysis revealed two enriched gene clusters involved in immune responses and protein phosphorylation. ChIP-X Enrichment Analysis 3 showed eight significant transcription factors (RXRA, ZBTB7A, ESR1, TCF3, MYOD1, CTCF, GATA3 and CBX2). Ingenuity Pathway Analysis identified canonical pathways involved, among other, in B cell development, pathogen-induced cytokine storm signalling pathway and dendritic cell maturation. This review highlights the involvement of epigenomic alterations of loci in Th1/Th2 and regulatory T cell differentiation in both candidate gene studies and EWAS. These alterations provide a better insight into the mechanistic aspects in FA pathogenesis and may guide the development of epigenome-based biomarkers for FA.

Laser Treatment of Hypertrophic Scar in a Porcine Model Induces Change to Epidermal Histoarchitecture That Correlates to Improved Epidermal Barrier Function.

Mechanisms and timing of hypertrophic scar (HTS) improvement with laser therapy are incompletely understood. Epidermal keratinocytes influence HTS through paracrine signaling, yet they are understudied compared to fibroblasts. It was hypothesized that fractional ablative CO2 laser scar revision (FLSR) would change the fibrotic histoarchitecture of the epidermis in HTS. Duroc pigs (n = 4 FLSR and n = 4 controls) were injured and allowed to form HTS. HTS and normal skin (NS) were assessed weekly by noninvasive skin probes measuring trans-epidermal water loss (TEWL) and biopsy collection. There were 4 weekly FLSR treatments. Immediate laser treatment began on day 49 postinjury (just after re-epithelialization), and early treatment began on day 77 postinjury. Punch biopsies from NS and HTS were processed and stained with H&E. Epidermal thickness and rete ridge ratios (RRR) were measured. Gene and protein expression of involucrin (IVL) and filaggrin (FIL) were examined through qRT-PCR and immunofluorescent (IF) staining. After treatment, peeling sheets of stratum corneum were apparent which were not present in the controls. TEWL was increased in HTS vs NS at day 49, indicating decreased barrier function (P = .05). In the immediate group, TEWL was significantly decreased at week 4 (P < .05). The early group was not significantly different from NS at the prelaser timepoint. After four sessions, the epidermal thickness was significantly increased in treated scars in both FLSR groups (immediate: P < .01 and early: P < .001, n = 8 scars). Early intervention significantly increased RRR (P < .05), and immediate treatment trended toward an increase. There was no increase in either epidermal thickness or RRR in the controls. In the immediate intervention group, there was increased IVL gene expression in HTS vs NS that decreased after FLSR. Eight scars had upregulated gene expression of IVL vs NS levels pretreatment (fold change [FC] > 1.5) compared to four scars at week 4. This was confirmed by IF where IVL staining decreased after FLSR. FIL gene expression trended towards a decrease in both interventions after treatment. Changes in epidermal HTS histoarchitecture and expression levels of epidermal differentiation markers were induced by FLSR. The timing of laser intervention contributed to differences in TEWL, epidermal thickness, and RRR. These data shed light on the putative mechanisms of improvement seen after FLSR treatment. Resolution of timing must be further explored to enhance efficacy. An increased understanding of the difference between the natural history of HTS improvement over time and interventional-induced changes will be critical to justifying the continued approved usage of this treatment.

Genetic polymorphism (rs6587666) in FLG protects from eczema in admixed Brazilian children population with high African ancestry

Genetic variants in filaggrin (FLG) are key in eczema and are less common in Africans than in Europeans and Asians. Here we examined the association between FLG Single Nucleotide Polymorphisms (SNPs) and eczema in a population of admixed Brazilian children and whether African ancestry modifies this association. We included 1010 controls and 137 cases and ran logistic regressions between SNPs in FLG and eczema in the studied population and also stratified the analyses according to the degree of African ancestry. In addition, we tested the replication of the findings on an independent set of individuals, as well as, we verified the impact on FLG expression according to each SNP genotype. The T allele of SNP rs6587666 was negatively associated with eczema in additive model (OR: 0.66, 95% CI: 0.47–0.93, P: 0.017). Moreover, African ancestry modifies the association between rs6587666 and eczema. The effect of the T allele was higher among individuals with higher African ancestry and the association with eczema was lost in individuals with lower African ancestry. In our analyses the expression of FLG in skin was slightly downregulated by the presence of the T allele of rs6587666. In our population, the T allele of rs6587666 in FLG was associated with protection to eczema and the degree of African ancestry was able to modify the observed association.

Infants with loss of function filaggrin mutations show augmented response to early life, short term skin barrier protection compared to filaggrin wild type infants; results from the STOP-AD trial.

Loss-of-function (LoF) filaggrin (FLG)-mutations are the strongest genetic risk factor for atopic dermatitis (AD). The STOP-AD study showed early initiation of daily specialized emollient, used only until 2 months, reduces the incidence of AD in the first year of life in high-risk infants.

A New Algorithm Identifying Association of Staphylococcus aureus Strains with Low Expression of Filaggrin in Atopic Dermatitis

Skin colonization with Staphylococcus aureus (S. aureus; Sa) contributes to the development of atopic dermatitis (AD). AD is associated with low filaggrin (FLG) expression in the skin due to genetic mutations and inflammation. We hypothesized that in the context of low FLG, colonizing Sa strains may have distinct gene patterns.

Optimization of long-range PCR protocol to prepare filaggrin exon 3 libraries for PacBio long-read sequencing

BackgroundThe filaggrin (FLG) protein, encoded by the FLG gene, is an intermediate filament-associated protein that plays a crucial role in the terminal stages of human epidermal differentiation. Loss-of-function mutations in the FLG exon 3 have been associated with skin diseases. The identification of causative mutations is challenging, due to the high sequence homology within its exon 3 (12,753 bp), which includes 10 to 12 filaggrin tandem repeats. With this study we aimed to obtain the whole FLG exon 3 sequence through PacBio technology, once 13-kb amplicons have been generated.Methods and resultsFor the preparation of SMRTbell libraries to be sequenced using PacBio technology, we focused on optimizing a 2-step long-range PCR protocol to generate 13-kb amplicons covering the whole FLG exon 3 sequence. The performance of three long-range DNA polymerases was assessed in an attempt to improve the PCR conditions required for the enzymes to function properly. We focused on optimization of the input template DNA concentration and thermocycling parameters to correctly amplify the entire FLG exon 3 sequence, minimizing non-specific amplification.ConclusionsTaken together, our findings suggested that the PrimeSTAR protocol is suitable for producing the amplicons of the 13-kb FLG whole exon 3 to prepare SMRTbell libraries. We suggest that sequencing the generated amplicons may be useful for identifying LoF variants that are causative of the patients’ disorders.

Baricitinib Blocks Cytokine-Mediated Downregulation of PAD1 in Human Keratinocytes: A Possible Molecular Link to the Effects of JAK Inhibitors in Atopic Dermatitis

Atopic Dermatitis (AD) is one of the most common chronic inflammatory skin conditions in the developed world. It has a complex aetiology with genetic, immunological and environmental factors causing skin barrier disruption and immune dysregulation (Elias and Steinhoff, 2008). Available immune modulating treatments for AD have proven the importance of Th2 immune activation/dysregulation in AD pathogenesis. In contrast, loss-of-function mutations in the gene encoding filaggrin (FLG) is the strongest genetic pre-disposing factor for development of AD, emphasizing the involvement of skin barrier dysregulation in AD pathogenesis.

Filaggrin Gene Mutation in Pediatric Patients with Atopic Dermatitis: A Look into Indian Gene Pool, a Pilot Study.

Mutations in the filaggrin (FLG) gene has been reported to be an indicator of poor prognosis of atopic dermatitis (AD). It has been reported that there is a considerable variation in the mutations detected in the FLG gene in different ethnicities. To detect the presence of mutations in the FLG gene in pediatric subjects with atopic dermatitis (AD) and to compare the detected mutations with those already reported from different ethnicities. Genomic DNA extracted using standard procedure from peripheral venous blood of 30 patient and 15 control samples. Sequence analysis of the FLG gene carried out and detected changes was then cross referenced with those mutations already reported to check for novelty of detected changes. Amino acid changes were detected in 28 of the patient samples and in none of the control samples indicating that changes in the FLG gene were more common in the patient group than the control group (Fishers exact test, P < 0.0001). The most commonly reported mutations R501X and 2282del4 were not detected. Only 5 of the detected 22 amino acid changes H2507Q, L2481S, K2444E, E2398Q, and S2366T have been previously reported and are not clinically significant; however, in one patient a stop codon was detected (S2366STOP). P2238N, R2239W, and V2243L detected in 70% of the samples and S2231E detected in 67% of the patient samples have not been reported so far and their clinical significance is yet to be analyzed. Analyses of mutations already reported showed that the changes detected from this study are novel to Indian traits. While this adds on to the minimal data available from the Indian subcontinent further analyses has to be carried out to analyze the pathogenicity of these detected changes on larger samples sizes. To detect the presence of mutations in the FLG gene in pediatric subjects with atopic dermatitis (AD) and to compare the detected mutations with those already reported from different ethnicities.

Skin Barrier Function and Infant Tidal Flow-Volume Loops-A Population-Based Observational Study.

The relationship between the skin barrier- and lung function in infancy is largely unexplored. We aimed to explore if reduced skin barrier function by high transepidermal water loss (TEWL), or manifestations of eczema or Filaggrin (FLG) mutations, were associated with lower lung function in three-month-old infants. From the population-based PreventADALL cohort, 899 infants with lung function measurements and information on either TEWL, eczema at three months of age and/or FLG mutations were included. Lower lung function by tidal flow-volume loops was defined as a ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE) &lt;0.25 and a tPTEF &lt;0.17 s (&lt;25th percentile). A high TEWL &gt;8.83 g/m2/h (&gt;75th percentile) denoted reduced skin barrier function, and DNA was genotyped for FLG mutations (R501X, 2282del4 and R2447X). Neither a high TEWL, nor eczema or FLG mutations, were associated with a lower tPTEF/tE. While a high TEWL was associated with a lower tPTEF; adjusted OR (95% CI) 1.61 (1.08, 2.42), the presence of eczema or FLG mutations were not. Overall, a high TEWL, eczema or FLG mutations were not associated with lower lung function in healthy three-month-old infants. However, an inverse association between high TEWL and tPTEF was observed, indicating a possible link between the skin barrier- and lung function in early infancy.

Genetic variations of filaggrin encoding gene \(\textit{(FLG)}\) in the Vietnamese population revealed from whole-exome sequencing

Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and maintains skin barrier function. Mutations in the gene encoding filaggrin (FLG) have been identified to cause ichthyosis vulgaris, increase the risk of atopic dermatitis and other skin diseases. In this study, we established the database of FLG gene obtained by whole-exome sequencing (WES) of 244 Vietnamese. We also estimated allele and genotype frequencies of the FLG gene in this Vietnamese population and predicted the impact of novel variants on protein function using in silico analysis tools. The detected variants included 126 nonsynonymous, six nonsense mutations, six frameshift insertions/deletions, and one non-frameshift deletion, mostly located in exon 3. Of which, there were 11 novel variants have been identified and four of them were predicted as detrimental for encoding protein. Remarkable pathogenic variants were mostly nonsense variants, showing the main genetic factor underlying the pathology of diseases caused by FLG. The results obtained in this study would provide essential information about the genetic characteristics of FLG in the Vietnamese population and the risk of occurrence of diseases related to this gene, which facilitates the development of new specific and accurate diagnosis, treatment, and prevention options for FLG-related diseases, particularly in Vietnamese.