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Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis 总被引:21,自引:0,他引:21
Palmer CN Irvine AD Terron-Kwiatkowski A Zhao Y Liao H Lee SP Goudie DR Sandilands A Campbell LE Smith FJ O'Regan GM Watson RM Cecil JE Bale SJ Compton JG DiGiovanna JJ Fleckman P Lewis-Jones S Arseculeratne G Sergeant A Munro CS El Houate B McElreavey K Halkjaer LB Bisgaard H Mukhopadhyay S McLean WH 《Nature genetics》2006,38(4):441-446
Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. 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. 相似文献
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Concentrations of serum alpha-2-macroglobulin in twins 总被引:6,自引:0,他引:6
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Goudie DR D'Alessandro M Merriman B Lee H Szeverényi I Avery S O'Connor BD Nelson SF Coats SE Stewart A Christie L Pichert G Friedel J Hayes I Burrows N Whittaker S Gerdes AM Broesby-Olsen S Ferguson-Smith MA Verma C Lunny DP Reversade B Lane EB 《Nature genetics》2011,43(4):365-369
Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma-like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars. High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome-related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer. 相似文献
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Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris 总被引:21,自引:0,他引:21
Smith FJ Irvine AD Terron-Kwiatkowski A Sandilands A Campbell LE Zhao Y Liao H Evans AT Goudie DR Lewis-Jones S Arseculeratne G Munro CS Sergeant A O'Regan G Bale SJ Compton JG DiGiovanna JJ Presland RB Fleckman P McLean WH 《Nature genetics》2006,38(3):337-342
Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show 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 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. 相似文献
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DR.J.P.Semwal 《天津科技大学学报》2004,19(Z1)
INTRODUCTION
India is among one of the ten most industrialized nations in the world. Increase in population has raised the urbar industrial, transport and agriculture demands which are major reasons for the degradation of the environmel condition. For India besides land and soil degradation, deforestation, low accessibility of water, ,industrial pollution and urban congestion are the major environmental issues of priority. The industries that generate huge quantities of waste are thermal power station, Iron and Steel Plants, Sugar, Paper and Fertilizer Industries. 相似文献
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