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FLG Mutations (flg + mutation)

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Medical Sciences100%

Selected Abstracts

Filaggrin mutations in the onset of eczema, sensitization, asthma, hay fever and the interaction with cat exposure

ALLERGY, Issue 12 2009
M. L. A. Schuttelaar
Background:, Filaggrin gene (FLG) mutations contribute to the development of eczema and asthma, but their contribution to sensitization and hay fever remains unclear. Methods:,FLG mutations R501X, 2282del4 and R2447X were genotyped in the Prevention and Incidence of Asthma and Mite Allergy birth cohort (n = 934) to evaluate longitudinally, for up to 8 years, their association with eczema, sensitization, asthma, hay fever and their interaction with cat exposure. Results:, The combined FLG mutations were significantly associated with eczema at all ages when occurring in the first year of life (OR = 2.0; 95% CI: 1.4,2.8). Combined FLG mutations were associated with both atopic and nonatopic eczema, as well as asthma (OR = 3.7; 95% CI: 1.8,7.5). When the FLG 2282del4 mutation was analysed separately, it was significantly associated with the development of eczema during the first year, having eczema up to 8 years and sensitization at the age of 8 years, which was enhanced by early-life cat exposure (ORs being 8.2; 95% CI: 2.6,25.9, 6.0; 95% CI: 3.2,11.3 and 5.4; 95% CI: 1.2,23.6 respectively). FLG 2282del4 was significantly associated with hay fever from the age 5 years onwards (OR = 3.9; 95% CI: 1.5,10.5). Conclusions:,FLG mutations are associated both with atopic and nonatopic eczema starting in the first year of life. FLG mutations combined with eczema in the first year of life are associated with a later development of asthma and hay fever, a clear example of the atopic march. We confirm that cat exposure enhances the effect of a FLG mutation on the development of eczema and sensitization. [source]

Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema

ALLERGY, Issue 7 2010
J. M. Jungersted
To cite this article: Jungersted JM, Scheer H, Mempel M, Baurecht H, Cifuentes L, Høgh JK, Hellgren LI, Jemec GBE, Agner T, Weidinger S. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema. Allergy 2010; 65: 911,918. Abstract Background:, Prior to the discovery of filaggrin (FLG) mutations, evidence for an impaired skin barrier in atopic dermatitis (AD) has been documented, and changes in ceramide profile, altered skin pH and increased trans-epidermal water loss (TEWL) in patients with AD have been reported. Until now, no studies have analysed stratum corneum (SC) lipids combined with skin barrier parameters in subjects of known FLG genotype. Methods:, A cohort of 49 German individuals genotyped for the most common FLG mutations (R501X, 2282del4) had SC samples taken for lipid analysis by high-performance thin layer chromatography. In addition, TEWL, erythema, skin hydration and pH were measured. In 27 of the 49 individuals, a 24-h irritation patch test with sodium lauryl sulphate was performed. For the analysis, both the AD group and the control group were stratified by FLG mutation status (FLGmut/FLGwt). Results:, In the FLGmut AD group, significantly lower levels of ceramide 4 and significantly higher levels of ceramide 7 were observed when compared to both healthy control groups. However, ceramide 7 levels also significantly differed between FLGwt AD and FLGwt controls, as did ceramide 1 levels. No significant differences were observed for ceramide 2, 3, 5 and 6. FLGmut individuals had significantly higher skin pH values than individuals not carrying FLG mutations. Patients with AD with FLG mutations had significantly higher erythema compared to patients with AD without FLG mutations. Conclusion:, Our results confirm previous observations of altered ceramide levels in AD, which however appear to show no clear relationship with FLG mutations. [source]

Filaggrin mutations in the onset of eczema, sensitization, asthma, hay fever and the interaction with cat exposure

ALLERGY, Issue 12 2009
M. L. A. Schuttelaar
Background:, Filaggrin gene (FLG) mutations contribute to the development of eczema and asthma, but their contribution to sensitization and hay fever remains unclear. Methods:,FLG mutations R501X, 2282del4 and R2447X were genotyped in the Prevention and Incidence of Asthma and Mite Allergy birth cohort (n = 934) to evaluate longitudinally, for up to 8 years, their association with eczema, sensitization, asthma, hay fever and their interaction with cat exposure. Results:, The combined FLG mutations were significantly associated with eczema at all ages when occurring in the first year of life (OR = 2.0; 95% CI: 1.4,2.8). Combined FLG mutations were associated with both atopic and nonatopic eczema, as well as asthma (OR = 3.7; 95% CI: 1.8,7.5). When the FLG 2282del4 mutation was analysed separately, it was significantly associated with the development of eczema during the first year, having eczema up to 8 years and sensitization at the age of 8 years, which was enhanced by early-life cat exposure (ORs being 8.2; 95% CI: 2.6,25.9, 6.0; 95% CI: 3.2,11.3 and 5.4; 95% CI: 1.2,23.6 respectively). FLG 2282del4 was significantly associated with hay fever from the age 5 years onwards (OR = 3.9; 95% CI: 1.5,10.5). Conclusions:,FLG mutations are associated both with atopic and nonatopic eczema starting in the first year of life. FLG mutations combined with eczema in the first year of life are associated with a later development of asthma and hay fever, a clear example of the atopic march. We confirm that cat exposure enhances the effect of a FLG mutation on the development of eczema and sensitization. [source]

FLG mutation p.Lys4021X in the C-terminal imperfect filaggrin repeat in Japanese patients with atopic eczema

BRITISH JOURNAL OF DERMATOLOGY, Issue 6 2009
I. Nemoto-Hasebe
Summary Background, Mutations in the gene encoding filaggrin (FLG) have been shown to predispose to atopic eczema (AE). Objectives, Further to establish population genetics of FLG mutations in the Japanese population and to elucidate effects of FLG mutations to filaggrin biosynthesis in skin of patients with AE. Methods, We searched for FLG mutations in 19 newly recruited Japanese patients with AE. We then screened 137 Japanese patients with AE and 134 Japanese control individuals for a novel mutation identified in the present study. In addition, we evaluated FLG mRNA expression by real-time reverse transcription,polymerase chain reaction and profilaggrin/filaggrin protein expression by immunohistochemical staining in the epidermis of the patients carrying the novel mutation. Results, We identified a novel FLG nonsense mutation c.12069A>T (p.Lys4021X) in one patient with AE. Upon further screening, p.Lys4021X was identified in four patients with AE (2·9% of all the patients with AE). In total, there are at least eight FLG variants in the Japanese population. Here we show that about 27% of patients in our Japanese AE case series carry one or more of these eight FLG mutations and these variants are also carried by 3·7% of Japanese general control individuals. There is a significant statistical association between the eight FLG mutations and AE (,2P = 6·50 × 10,8). Interestingly, the present nonsense mutation is in the C-terminal incomplete filaggrin repeat and is the mutation nearest the C-terminal among previously reported FLG mutations. Immunohistochemical staining for filaggrin revealed that this nonsense mutation leads to remarkable reduction of filaggrin protein expression in the patients' epidermis. Conclusions, We clearly demonstrated that FLG mutations are significantly associated with AE in the Japanese population. The present results further support the hypothesis that the C-terminal region is essential for proper processing of profilaggrin to filaggrin. [source]

Ichthyosis vulgaris: novel FLG mutations in the German population and high presence of CD1a+ cells in the epidermis of the atopic subgroup

BRITISH JOURNAL OF DERMATOLOGY, Issue 4 2009
V. Oji
Summary Background, Ichthyosis vulgaris (IV) is a genetic disorder with a prevalence of 1 : 250,1000 caused by filaggrin (FLG) mutations, which also predispose to atopic diseases. Objectives, To study the genotype/phenotype relationship in IV and to analyse whether the suggested skin barrier defect is associated with differences of epidermal dendritic cells. Patients/methods, We evaluated a cohort of 26 German patients with IV, established an IV severity score and analysed epidermal ultrastructure, histology, filaggrin and CD1a antigens. Mutations were screened by restriction enzyme analysis. Particular sequencing techniques allowed the complete FLG analysis to reveal novel mutations. Results, The combined null allele frequency of R501X and 2282del4 was 67·3%. Patients also showed the mutations S3247X and R2447X as well as five novel FLG mutations: 424del17 and 621del4 (profilaggrin S100 domain), 2974delGA (repeat 2), R3766X (repeat 101) and E4265X (repeat 102). Their combined allele frequency in controls was < 0·7%. No mutation was found in one IV patient, all in all ,27% were heterozygous, and the majority (,69%) showed two null alleles. The IV severity score and ultrastructure showed a significant correlation with genotypes. Interestingly, CD1a cell counts showed a significant difference between nonatopic and atopic IV patients both with eczema and without eczema. Conclusions, We confirm that the mutations R501X and 2282del4 represent the most frequent genetic cause in German IV patients. The novel mutations are probably population and family specific. The observed differences of CD1a cells support the hypothesis that there is a barrier defect that predisposes to atopic manifestations, possibly independent of atopic eczema. [source]