Missense, silent, non-sense and frame-shift mutations in exon 3 of the filaggrin gene in patients with bronchial asthma, atopic dermatitis, allergic rhinitis and mixed atopy

Salama, Ragaa H. M.; Rasheed, Zafar; Ahmed, Ahmed A.; Saif, Ghada A. Bin; Elkholy, Maha; Elmoniem, Alaa E. Abd; Zedan, Khaled; Robaee, Ahmad A. Al; Alzolibani, Abdullateef A.

doi:10.1080/15257770.2021.1880009

Cited by 7 publications

(4 citation statements)

References 27 publications

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“…Within the next 5 years, an extensive mutation map was generated that showed significant differences between European and Asian populations (Figure 5). A recent analysis of 126 patients with atopic dermatologic disorders in Saudi Arabia detected 227 variants, including missense, silent, nonsense, frameshift and noncoding mutations in exon 3 of the profilaggrin gene [67]. Within the decade following the publication by McLean's team in 2006, a nearly a five-fold increase in the number of research articles related to filaggrin appeared in the literature (Figure 6).…”

Section: Mutations That Cause Loss Of Filaggrinmentioning

confidence: 99%

The Discovery and Function of Filaggrin

Hoober

Eggink

2022

IJMS

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Keratohyalin granules were discovered in the mid-19th century in cells that terminally differentiate to form the outer, cornified layer of the epidermis. The first indications of the composition of these structures emerged in the 1960s from a histochemical stain for histidine, followed by radioautographic evidence of a high incidence of histidine incorporation into newly synthesized proteins in cells containing the granules. Research during the next three decades revealed the structure and function of a major protein in these granules, which was initially called the ‘histidine-rich protein’. Steinert and Dale named the protein ‘filaggrin’ in 1981 because of its ability to aggregate keratin intermediate filaments. The human gene for the precursor, ‘profilaggrin,’ was reported in 1991 to encode 10, 11 or 12 nearly identical repeats. Remarkably, the mouse and rat genes encode up to 20 repeats. The lifetime of filaggrin is the time required for keratinocytes in the granular layer to move into the inner cornified layer. During this transition, filaggrin facilitates the collapse of corneocytes into ‘building blocks’ that become an impermeable surface barrier. The subsequent degradation of filaggrin is as remarkable as its synthesis, and the end-products aid in maintaining moisture in the cornified layer. It was apparent that ichthyosis vulgaris and atopic dermatitis were associated with the absence of this protein. McLean’s team in 2006 identified the cause of these diseases by discovering loss-of-function mutations in the profilaggrin gene, which led to dysfunction of the surface barrier. This story illustrates the complexity in maintaining a healthy, functional epidermis.

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Section: Mutations That Cause Loss Of Filaggrinmentioning

confidence: 99%

The Discovery and Function of Filaggrin

Hoober

Eggink

2022

IJMS

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“…This may be related to the fact that about 9% of gastric cancers harbor EBV infection. The deletion mutations of the FLG gene are also prevalent in Asian populations, so making related genetic research valuable ( Salama et al, 2021 ). However, the precise mechanisms underlying its development are still unclear as little is known about the role of the FLG gene.…”

Section: Introductionmentioning

confidence: 99%

Association of FLG mutation with tumor mutation load and clinical outcomes in patients with gastric cancer

Liu

Tian

et al. 2022

Front. Genet.

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Background: Stomach adenocarcinoma (STAD) is one of the most frequently diagnosed cancers in the world with a poor prognosis due to genetic heterogeneity. The present study aimed to explore potential prognostic predictors and therapeutic targets that can be used for STAD treatment.Methods: We collected relevant data of STAD patients from the Cancer Genome Atlas (TCGA), including somatic mutation, transcriptome, and survival data. We performed a series of analyses such as tumor mutational burden (TMB), immune infiltration, and copy number variation (CNV) analysis to evaluate the potential mechanism of filaggrin (FLG) mutation in gastric cancer. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were performed for annotation of differentially expressed genes (DEGs). The STRING online database was used to construct the protein–protein interaction (PPI) and ceRNA network and hub genes were identified. Univariate and multivariate Cox regression analyses were used to determine the effect of selected DEGs on tumor prognosis.Results: The FLG-mutant group (FLG-MT) showed a higher mutation load and immunogenicity in gastric cancer. GO and KEGG analyses identified and ranked unique biologic processes and immune-related pathway maps that correlated with the FLG-mutant target. GSEA analysis showed that several tumorigenesis and metastasis-related pathways were indeed enriched in FLG-mutant tumor tissue. Both cell cycle–related pathways and the DNA damage and repair associated pathways were also enriched in the FLG-MT group. The FLG mutations resulted in increased gastric cancer sensitivity to 24 chemotherapeutic drugs. The ceRNA network was established using Cytoscape and the PPI network was established in the STRING database. The results of the prognostic information further demonstrated that the OS and DFS were significantly higher in FLG mutation carriers, and the FLG gene mutation might be a protective factor.Conclusion: The multiple molecular mechanisms of the FLG gene in STAD are worthy of further investigation and may reveal novel therapeutic targets and biomarkers for STAD treatment.

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“…Thus, association of KP with AD seems to be infrequent in Finnish patients which may be explained by the fact that the tested FLG LoF mutations are overall much rarer in the Finnish population compared for example, with central Europe or Asia 4 . Mutations in other locations of the FLG gene or other genes of the epidermal barrier may play a more important role in Finnish patients and need further research 15 …”

Section: Discussionmentioning

confidence: 99%

“…Prick positivity was defined as positive result to any of the following: Birch, timothy, mug wort, cat, dog, horse, house dust mite and Cladosporium herbarum. AD, Atopic dermatitis; FDR, first-degree relative; FLG, filaggrin, LoF, loss-of-function mutations are overall much rarer in the Finnish population compared for example, with central Europe or Asia.4 Mutations in other locations of the FLG gene or other genes of the epidermal barrier may play a more important role in Finnish patients and need further research 15.…”

mentioning

confidence: 99%

Keratosis pilaris and filaggrin loss‐of‐function mutations in patients with atopic dermatitis – Results of a Finnish cross‐sectional study

Salava

Salo

Remitz

2022

The Journal of Dermatology

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Keratosis pilaris (KP) associates with epidermal barrier defects in atopic dermatitis (AD) but its role in disease severity and concomitant atopic diseases seems to vary between populations. We performed a cross‐sectional observational study with 502 randomly selected AD patients of a Finnish tertiary health care center. At a single clinical examination, disease severity (Rajka Langeland severity score and EASI), clinical signs and patient history were evaluated and total IgE levels and frequent filaggrin (FLG) loss‐of‐function mutations were investigated. There was no link with disease severity (p = 0.649, 95% CI 0.569–0.654), asthma (p = 0.230, 95% CI 0.206–0.281) or atopic sensitization (p = 0.351, 95% CI 0.309–0.392). Keratosis pilaris was significantly associated with palmar hyperlinearity (p < 0.000, 95% CI 0.000–0.006, OR 4.664, 95% CI 2.072–10.496) and the filaggrin loss‐of‐function mutation 2282del4 (p < 0.000, 95% CI 0.000–0.009, OR 4.917, 95%CI 1.961–12.330). The prevalence of KP in the cohort was generally low and KP seems to be infrequent in Finnish AD patients. This may be explained by the fact that the tested FLG loss‐of‐function mutations are rarer in the Finnish population compared for example, with central Europe or Asia. Mutations in other locations of the FLG gene or other genes of the epidermal barrier may play a more important role.

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Missense, silent, non-sense and frame-shift mutations in exon 3 of the filaggrin gene in patients with bronchial asthma, atopic dermatitis, allergic rhinitis and mixed atopy

Cited by 7 publications

References 27 publications

The Discovery and Function of Filaggrin

The Discovery and Function of Filaggrin

Association of FLG mutation with tumor mutation load and clinical outcomes in patients with gastric cancer

Keratosis pilaris and filaggrin loss‐of‐function mutations in patients with atopic dermatitis – Results of a Finnish cross‐sectional study

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