W H Irwin McLean

..Our study confirms the presence of population-specific as well as recurrent FLG mutations in Singapore...

....

..5 (rs7927894) and a single nucleotide polymorphism (rs877776) within the gene encoding hornerin on chromosome 1q21...

..Along with the recent discovery of prevalent null mutations in the gene encoding filaggrin, a protein essential for stratum corneum formation, these data point to an innate epidermal-barrier defect in atopy...

....

..This could herald the dawn of a new era in translational medical research applied to genetics...

..i. = 20-1,136)). We found three 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...

..Interestingly, the phenotypes of individuals homozygous for R501X, 2282del4, or compound heterozygous for R501X and 3702delG, were comparable, suggesting that mutations located centrally in the filaggrin repeats are also pathogenic...

....

..Owing to the high population frequency of FLG mutations, filaggrin is a possible genetic modifier in other genodermatoses...

..These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease...

..CNV within FLG makes a significant, dose-dependent contribution to atopic dermatitis risk, and therefore treatments to increase filaggrin expression may have therapeutic utility...

..Here, we review the genotype-phenotype trends emerging from the spectrum of mutations in these genes and apply these correlations to make predictions about PC phenotypes based on the site of mutation and keratin pair involved...

..Filaggrin is a key protein involved in skin barrier function. Filaggrin (FLG) null mutations are important genetic predisposing factors for atopic disease...

..KRT6C was shown to be expressed in the plantar epidermis using reverse transcription-PCR, consistent with the phenotype observed in this tissue. These data expand the genetic testing repertoire for the PPKs...

..S148fsX30. These data confirm that haploinsufficiency for K5 causes DDD and points to a prominent role for the keratin intermediate filament cytoskeleton within basal keratinocytes in epidermal pigment biology...

..These data suggest that FLG mutations are unlikely to be involved in genetic susceptibility to psoriasis and implies that there may be within-locus heterogeneity in chromosomal regions involved in both AD and psoriasis...

..Multiple steatocystomas that develop during puberty are a useful feature distinguishing PC-2 from PC-1. At the molecular level it has been shown that mutations in keratin K6a or K16 cause PC-1 whereas those in K6b or K17 lead to PC-2...

..We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and cellular proliferation...

..The recent publication of a strategy to sequence this difficult gene identifies a spectrum of both prevalent and rare mutations that collectively have a significant impact on susceptibility to atopic disease...

..Keratinocytes exhibiting specific knockdown of LaNt alpha3 displayed impaired adhesion, stress resistance, and reduced ability to close scratch wounds in vitro...

..This is the first report of a genetic defect in this domain of K1. The unusual gain-of-function mutation points to a subtle role of the 1B domain in mediating filament-filament interactions with regular periodicity...

..Understanding the genetic basis of these disorders allows better counseling for patients and paves the way for therapy development...

..The most promising allele-specific siRNA, siR163Q-13, was tested in a mouse model and was confirmed to preferentially inhibit mutant allele expression in vivo...

..At present no treatment exists which addresses the underlying pathology of corneal dystrophy. The aim of this study was to design and assess the efficacy and potency of an allele-specific siRNA approach as a future treatment for MECD...

..The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization...

..This study, together with previously reported mutations, identifies mutation hotspot codons that may be useful in the development of personalized medicine for PC...

..Filaggrin is therefore in the frontline of defence, and protects the body from the entry of foreign environmental substances that can otherwise trigger aberrant immune responses...

..In a cell-based model system, the lead inhibitors were able to significantly reverse the cytoskeletal aggregation phenotype. Overall, this approach shows promise for the treatment of EBS and paves the way for future clinical trials...

....

..This review aims to highlight the key milestones in filaggrin research over the past 25 years, to discuss the mechanistic, clinical, and therapeutic implications, and to consider possible future directions for ongoing investigation...

..The second mutation was only present in DNA derived from keratinocytes and was absent from lymphocyte DNA. This case represents a novel mechanism of revertant mosaicism and is an example of "natural gene therapy"...

..Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy...

..Using expression studies we show that the V2 domain is essential for normal function of keratin intermediate filaments...

....

..Study of these diseases has shed new light on the vital structural role of keratins in maintaining the integrity of epithelial cells...

..These data suggest that siRNAs can specifically and very potently target mutated genes in the skin and support development of these inhibitors as potential therapeutics...

..These data set the scene for further unraveling signaling pathways that control the K6a promoter, as well as facilitating clinical trials for statins in PC patients...

..Defolliculated may be a useful model for determining further functions of the sebaceous gland, and for understanding the regulation of catagen and hair follicle immunology...

..These mutations appear to have a less damaging effect than previously reported mis-sense mutations sited in the helix boundary motifs. This report extends the range of phenotypes associated with mutations in KRT1...

..The mutation was detected in genomic DNA, confirmed in reverse transcription polymerase chain reaction products, and was excluded from 100 ethnically matched control individuals by restriction enzyme analysis...

..Kindler syndrome is therefore the first skin fragility syndrome due to disruption of the actin-extracellular matrix system...

..57, 95% CI 2.84-23.03). These data emphasize that skin-barrier impairment due to reduced filaggrin expression plays an important role in the pathogenesis of AD and sheds further light on the genetic architecture of atopy in Japan...

....

..These results demonstrate a prominent role for the epidermal barrier in atopic disease and have important implications for the study of complex traits...

..One of the characteristic features of AD and causative factor for the disease is an impaired epidermal skin barrier based on a primary defect of epidermal differentiation...

..Possible pathogenic mechanisms are discussed with respect to the clinicopathologic and genetic correlations observed...

..These studies suggest that siRNAs can discriminate single nucleotide mutations and further suggest that "designer siRNAs" may allow effective treatment of a host of genetic disorders including PC...

....

..These results suggest that efficient delivery of these "designer siRNAs" may allow effective treatment of numerous genetic disorders including PC...

..This study helps to further define the nature of the AD phenotype associated with FLG null alleles...

..Recently, mutations in the filaggrin gene, FLG, were identified in European families with ichthyosis vulgaris (IV) and shown to be an important predisposing factor for atopic dermatitis (AD)...

..Thus, Kindler syndrome is, to our knowledge, the first skin fragility disorder caused by a defect in actin-ECM linkage, rather than keratin-ECM linkage...

..Null mutations within the filaggrin gene (FLG) are associated with moderate-to-severe atopic eczema; their role in mild-to-moderate eczema in the general population is unknown...

..Atopic disease is a major health problem. Mutations in the filaggrin gene (FLG) confer major susceptibility to eczema and related asthma...

..However, their role in the development of other atopic diseases such as asthma and rhinitis has not yet been clarified in large population-based studies...

..If clinical efficacy is ultimately demonstrated, this "first-in-skin" siRNA may herald a paradigm shift in the treatment of dominant-negative genetic disorders...

..It is anticipated that the Human Intermediate Filament Database (HIFD) will provide a useful resource to study human genome variations for basic scientists, clinicians, and students alike...

..This unexpected finding expands the Clouston syndrome phenotype and suggests that some patients diagnosed with pachyonychia may in fact be suffering from Clouston syndrome...

..Delineation of these recurrent mutations is also relevant to optimizing mutation detection strategies in Kindler syndrome patients from particular ethnic backgrounds...

..These genes encode proteins thought to be involved in the regulation of posttranslation processing of filaggrin (FLG), the strongest identified genetic risk factor for eczema to date...