摘要
寻常型鱼鳞病(Ichthyosis Vulgaris, IV, OMIM#146700)是一种常见的遗传性角化障碍性皮肤病,发病率在1：5300到1：250之间,通常在出生后一年内发病,好发于四肢伸侧及背部,以小腿最为明显。Ⅳ临床异质性较大,病情轻者仅表现为冬季皮肤干燥、粗糙,表面有细碎的糠样鳞屑；典型的皮损表现为灰褐色或深褐色菱形或多角形鳞屑,鳞屑中央固着,边缘游离,如鱼鳞状；其他临床特征还表现为掌跖线状裂、掌纹加深、遗传性过敏症和热耐受不良。
FLG失去功能的突变被公认为是Ⅳ的致病因素。到目前为止,在寻常型鱼鳞病患者中报道的FLG突变种类已接近30种。Filaggrin基因(OMIM#135940)位于1q21.3,由3个外显子组成,3号外显子长12.7-14.7kb,由10-12个几乎完全一样的重复区组成,编码几乎整个profilaggrin,是人类基因组外最大的外显子之一；Filaggrin蛋白由S100钙离子结合区、B结构域、2个FLG不完全重复区、10-12个FLG重复区和C-端组成。C-末端结构域是profilaggrin水解成filaggrin单体所必需的结构,FLG失去功能的突变使profilaggrin缺失C-末端结构域而无法正常水解,最终使表皮颗粒层filaggrin单体减少或缺失。
为了鉴定3个寻常型鱼鳞病家系的致病变异,本研究首先对家系的先证者开展了FLG突变研究,结果在家系1的先证者中鉴定了2个未见报道的变异(c.477-478insA, c.6218-6219delAA)和一个外来的已知致病变异c.3321delA。随后对家系1进行疾病共分离研究,发现c.477-478insA与家系1疾病共分离；c.6218-6219delAA是一个新发突变；c.3321delA与家系中外来的一支共分离。为了进一步验证上述结果,我们将变异c.477-478insA与家系进行了连锁分析,结果得到LOD值大于1的结果,支持该位点与疾病连锁；同时使用TA克隆测序方法对c.6218-6219delAA进行了验证,结果证实了该位点是家系1先证者新发的变异；这2个突变在200个正常对照中均未检测到,进一步证明了它们是致病变异。此外,在家系2和3中均鉴定到了已知致病变异c.3321delA。这些结果丰富了中国人群FLG突变谱。
第二部分中国人群寻常型银屑病Filaggrin突变研究
银屑病(Psoriasis, OMIM#177900),是一种以红斑、鳞屑为主要表现的慢性炎症性、免疫介导的皮肤疾病。临床可分为四种亚型：寻常型银屑病、关节型银屑病、脓疱型银屑病及红皮病型银屑病,其中寻常型银屑病为最常见的类型。因人种遗传背景不同该病的人群患病率为0.1%～3%,中国汉族人发病率为0.123%。
银屑病的具体发病机制尚未完全阐明,已有研究表明：环境、遗传因素和免疫炎症反应均在其发生和病理过程中起到十分重要的作用。通过全基因组扫描和连锁分析至少已鉴定了9个银屑病易感位点(PSORS1-9)。Filaggrin (FLG)是位于易感区间1q21的一个重要候选基因。FLG自发突变体小鼠(5303delA)皮损部位出现类似银屑病的炎性特征,其他研究小组在银屑病患者皮肤中检测到filaggrin表达量和表达模式都发生了显著变化,提示FLG可能与银屑病的发生相关。为了证明FLG与银屑病的相关性,研究小组分别在德国、爱尔兰和英国人群银屑病患者中开展的关联研究,结果显示FLG突变与银屑病的发生无关。到目前为止,还没有遗传学证据表明FLG与银屑病的发生有关。
本课题组许晓娟博士2009年采集到1个来自湖南岳阳的家系,这个家系的特点是银屑病与鱼鳞病患者共存：先证者表现为典型的银屑病症状,而先证者的外婆和姑姑为鱼鳞病患者。这个家系提示银屑病与鱼鳞病可能存在共同的发病机制。许晓娟随后对这个特殊的银屑病家系进行了FLG突变研究,发现先证者携带FLG p.K4022X纯合突变,而家系的鱼鳞病患者携带p.K4022X杂合突变,这个结果提示我们p.K4022X的纯合突变可能导致银屑病的发生。
本研究为了进一步明确FLG与银屑病易感性的关系,我们首先在441例患者和500个正常对照中针对p.K4022X进行了突变检测,结果检测到了2例患者携带p.K4022X的纯合改变,而在正常人中未发现纯合改变,提示纯合突变可能导致银屑病的发生。另外分别在29例患者(6.6%)和15个正常对照(3%)中检测到了p.K4022X的杂合改变。随后我们开展了p.K4022X病例-对照关联研究,结果显示p.K4022X在441例银屑病患者和500个对照样本间的基因型频率和等位基因频率比较的P值分别为0.011和0.002(p<0.05),说明差异有显著统计学意义。同时相对危险度(OR)大于1,且95%可信区间下限大于1(OR=2.552(95%CI=1.377-4.731)),提示p.K4022X是中国人群银屑病发生的危险因素。
其次,为了进一步研究FLG突变与银屑病的关系,我们分析了441例患者的整个FLG编码区序列,发现了5个无义或移码突变：一个未见报道的无义突变(p.W2583X)和4个在寻常型鱼鳞病或特异性皮炎中报道过的突变(p.R826X, c.3321delA, p.Q2417X, c.7945delA)。
此外,我们在银屑病患者中还鉴定了18个错义突变。其中p.E2652D在2个银屑病／鱼鳞病共存的家系中都鉴定到,2个家系中3个银屑病患者均携带该纯合突变,而2个鱼鳞病患者和3个表型正常的个体携带该杂合变异,提示p.E2652D的纯合突变可能导致银屑病的发生。
这些结果提示使FLG失去功能的纯合突变导致银屑病的可能性大。同时,纯合的错义突变也可能导致银屑病的发生。这是首次在遗传学上证明了FLG与银屑病的相关性,为中国人群银屑病发生机制的深入研究奠定了科学基础。
Ichthyosis vulgaris (IV, OMIM#146700) is a common genetic skin cornification disorder with a prevalence of one in250-1000. The onset of IV is usually within one year after birth. The patients manifest with white scaling on the extensor surfaces of the extremities and occasionally the trunk. Ichthyosis vulgaris, involves symmetric scaling of the skin, which ranges from minor roughness and dryness to the desquamation of large plates Their color varies from white to dirty gray to brown,which are usually small, irregular, and fine, with curled up edges that give the skin a rough feel. Clinical features also include hyperinearity of the palms and soles, atopy and heat intolerance or keratosis pilaris.
Loss-of-function mutations in FLG have been known to be a major predisposing factor for ichthyosis vulgaris, about30FLG variants have been identified in IV patients. The FLG gene (OMIM#135940), which encodes the protein filaggrin, is located on chromosome1q21.3, and consists of three exons,exon3(12-14kb) contains the N-terminal domain and10-12copies of a sequence about1kb in length, which encodes the proteolytically cleaved parts of filaggrin. Filaggrin plays a key role in facilitating epidermal differentiation, and in maintaining normal skin-barrier function and hydration.
To identify FLG mutations in three Chinese pedigrees with ichthyosis vulgaris, we first sequenced the entire coding region of FLG in the proband of each pedigree. We found two novel FLG null mutations (c.477-478insA and c.6218-6219delAA) and a known mutation (c.3321delA). Both novel mutations were identified in the proband of pedigree1; Then, we perfermed disease cosegregate study in pedegree1, the results suggesting c.477-478insA was cosegragate with IV while c.6218-6219delAA was a de novo mutation. To further confirm the above results, we performed linkage analysis with the site c.477-478insA in pedegree1, and we abtain a LOD greater than1which surport the above disease cosegragate study result; In addition, we used another sequencing methord--TA clone proved the mutation c.6218-6219delAA was a de novo one. Neither of these two mutations was found in200unrelated controls. These findings extend the spectrum of functional FLG variants possibly causing ichthyosis vulgaris.
Section2Mutation Analysis in Filaggrin Associated with Psorasis Vulgaris in Chinese Population
Psoriasis (OMIM#177900) is a chronic inflammatory immune-mediated skin disorder characterized by red lesions with silver white scales, affects approximately3%of Caucasian population and0.123%of the Chinese population. Psoriasis can be differentiated into four subgroups:psoriasis vulgaris, psoriaticarthritis, erythrodermic psoriasis, and annular pustular psoriasis. Of these, Psoriasis vulgaris is the most common one.
The pathogenesis of psoriasis involves both genetic and environmental risk factors. At least nine susceptibility loci for psoriasis have been identified through classic genome-wide linkage, which are called psoriasis susceptibility1through9(PSORS1-9). FLG, encoding a keratin filament associated protein (filaggrin), has been reported to be major causative genes for two skin diseases, ichthyosis vulgaris and atopic dermatitis. FLG spontaneous mutated mouse (5303de1A) showed a phenotype of inflammatory infiltration in skin lesions similarity to psoriasis, and Huffineier et al. showed that the filaggrin expression altered markedly in psoriatic skins, all these suggest a relation between psoriasis and FLG. However, another two groups failed to identify the association between psoriasis and mutations of FLG in German, Irish and United Kingdom population.
Our aim is to identify FLG causative mutations in Chinese Psoriasis patients. Our previous study collected a Chinese psoriasis/IV coexisting family. And through mutation analysis on FLG with this family, our laboratory colleagues Xu Xiaojuan identified a non-sense mutation of FLG (p.K4022X) in this psoriasis/Ⅳ coexisting family. The homozygous p.K4022X mutation was detected in a psoriasis patient, whereas the heterozygous p.K4022X mutation was identified in two IV patients and four apparently normal family members, It is the first time reported FLG mutation in psoriasis patients.
This study aims to confirm the association between FLG and psoriasis, we first genotyped p.K4022X variant in441sporadic Chinese psoriasis patients and found homozygous mutation in two patients(0.45%), while no homozygous variant was found in500control individuals (0%). Moreover, p.K4022X heterozygous mutation was identified in29psoriasis patients (6.6%) and15control individuals (3%), respectively. Mutation p.K4022X showed a significant association with psoriasis. The P values of genotypic frequency and allelic frequency for p.K4022X in case-control analysis were0.011and0.002, respectively. The odds ratio (OR) for the dominant model (T vs. A) was2.552(95%CI,1.377-4.731; P=0.002). Thus our data implied an association of p.K4022X variant in FLG gene with the psoriasis in Chinese population.
Second, in order to further investigate FLG mutations in psoriasis patients, we sequenced the entire coding region of FLG in441psoriasis patients, and identified another five mutations, including one novel mutation (p.W2583X) and four mutations (p.R826X, c.3321delA, p.Q2417X and c.7945de1A) that have been reported in IV or AD patients.
Additionally, we identified18missense mutations.One of the missense mutation p.E2652D was identified in two psoriasis/Ichthyosis co-exiting pedigrees.Interestingly, three psoriasis patients of the two pedigree carry the homozygous p.E2652D while two IV patients carry heterozygous one, suggesting that the homozygous variant of p.E2652D may lead to psoriasis.
These results suggest that loss-of-function homozygous mutations of FLG much more likely lead to psoriasis. As well, the homozygous missense mutation may lead to psoriasis. This is the first time revealed the relation between FLG and psoriasis, and it will provide evidence for further understanding the pathogenisis of psoriasis.
引文
[1]Barankin B,Freiman A.(2005)Misnomers in dermatology J Cutan Med Surg,9: 284-288.
[2]Wells R S,Kerr C B.(1966)Clinical features of autosomal dominant and sex-linked ichthyosis in an English population.Br Med J,1:947-950.
[3]Liu P,Yang Q,Wang X, et al.(2008)Identification of a genetic locus for ichthyosis vulgaris on chromosome 10q22.3-q24.2.J Invest Dermatol,128: 1418-1422.
[4]Sybert V P,Dale B A,Holbrook K A.(1985)Ichthyosis vulgaris:identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules.J Invest Dermatol,84:191-194.
[5]Compton J G,DiGiovanna J J,Johnston K A, et al.(2002)Mapping of the associated phenotype of an absent granular layer in ichthyosis vulgaris to the epidermal differentiation complex on chromosome 1.Exp Dermatol,11: 518-526.
[6]Zhong W,Cui B,Zhang Y, et al.(2003)Linkage analysis suggests a locus of ichthyosis vulgaris on 1q22.J Hum Genet,48:390-392.
[7]Smith F J,Irvine A D,Terron-Kwiatkowski A, et al.(2006)Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.Nat Genet, 38:337-342.
[8]Sandilands A,O'Regan G M,Liao H, et al.(2006)Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis.J Invest Dermatol,126:1770-1775.
[9]Gruber R,Janecke A R,Fauth C, et al.(2007)Filaggrin mutations p.R501X and c.2282del4 in ichthyosis vulgaris.Eur J Hum Genet,15:179-184.
[10]Nomura T,Sandilands A,Akiyama M, et al.(2007)Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis.J Allergy Clin Immunol,119:434-440.
[11]Sandilands A,Terron-Kwiatkowski A,Hull P R, et al.(2007)Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.Nat Genet,39:650-654.
[12]Hamada T,Sandilands A,Fukuda S, et al.(2007)De Novo Occurrence of the Filaggrin Mutation p.R501X with Prevalent Mutation c.3321delA in a Japanese Family with Ichthyosis Vulgaris Complicated by Atopic Dermatitis.J Invest Dermatol,128(5):1323-1325.
[13]Oji V,Seller N,Sandilands A, et al.(2009)Ichthyosis vulgaris:novel FLG mutations in the German population and high presence of CD1a+ cells in the epidermis of the atopic subgroup.Br J Dermatol,160:771-781.
[14]Samdani A J,Naz N,Ahmed N.(2010)Molecular studies of ichthyosis vulgaris in Pakistani families.J Coll Physicians Surg Pak,20:644-648.
[15]Hsu C K,Akiyama M,Nemoto-Hasebe I, et al.(2009)Analysis of Taiwanese ichthyosis vulgaris families further demonstrates differences in FLG mutations between European and Asian populations.Br J Dermatol,161:448-451.
[16]李彩云,梁羽,王威等.(2010)中国寻常型鱼鳞病患者FLG基因变异的研究.中国现代医学杂志,20:5.
[17]Chen H,Ho J C,Sandilands A, et al.(2008)Unique and recurrent mutations in the filaggrin gene in Singaporean Chinese patients with ichthyosis vulgaris.J Invest Dermatol,128:1669-1675.
[18]Manabe M,Sanchez M,Sun T T, et al.(1991)Interaction of filaggrin with keratin filaments during advanced stages of normal human epidermal differentiation and in ichthyosis vulgris.Differentiation,48:43-50.
[19]Dale B A,Presland R B,Lewis S P, et al.(1997)Transient expression of epidermal filaggrin in cultured cells causes collapse of intermediate filament networks with alteration of cell shape and nuclear integrity.J Invest Dermatol,108:179-187.
[20]Haydock P V,Blomquist C,Brumbaugh S, et al.(1993)Antisense profilaggrin RNA delays and decreases profilaggrin expression and alters in vitro differentiation of rat epidermal keratinocytes.J Invest Dermatol,101:118-126.
[21]Presland RB,Boggess D,Lewis SP, et al.(2000)Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice:an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris. J Invest Dermatol,115:1072-1081.
[22]Nirunsuksiri W,Presland RB,Brumbaugh SG, et al.(1995)Decreased profilaggrin expression in ichthyosis vulgaris is a result of selectively impaired posttranscriptional control.J Biol Chem,270:871-876.
[23]Li C, Luo Q, Li X, et al.(2010)FiIaggrin Mutations are associated with Ichthyosis VuIgarisin the Southern Chinese PopuIation.Health:4.
[24]孙澍彬,李雪梅,张锡宝等.(2011)寻常型鱼鳞病一家系FiIaggrin基因突变分析.右江医学,39：3.
[25]Kang T W,Lee J S,Oh S W, et al.(2009)Filaggrin mutation c.3321delA in a Korean patient with ichthyosis vulgaris and atopic dermatitis. Dermatology, 218:186-187.
[26]Griffiths C E,Barker J N.(2007)Pathogenesis and clinical features of psoriasis. Lancet,370:263-271.
[27]Schafer T.(2006)Epidemiology of psoriasis. Review and the German perspective.Dermatology,212:327-337.
[28]Fan X,Yang S,Huang W, et al.(2008)Fine mapping of the psoriasis susceptibility locus PSORS1 supports HLA-C as the susceptibility gene in the Han Chinese population.PLoS Genet,4:e1000038.
[29]Wuepper K D,Coulter S N,Haberman A.(1990)Psoriasis vulgaris:a genetic approach. J Invest Dermatol,95:2S-4S.
[30]Duffy D L,Spelman L S,Martin N G.(1993)Psoriasis in Australian twins.J Am Acad Dermatol,29:428-434.
[31]Chandran V,Raychaudhuri SP.(2009)Geoepidemiology and environmental factors of psoriasis and psoriatic arthritis.J Autoimmun,
[32]Asumalahti K,Ameen M,Suomela S, et al.(2003)Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis.J Invest Dermatol, 120:627-632.
[33]Tazi Ahnini R,Camp NJ,Cork MJ, et al.(1999)Novel genetic association between the corneodesmosin (MHC S) gene and susceptibility to psoriasis. Hum Mol Genet,8:1135-1140.
[34]Asumalahti K,Laitinen T,Itkonen-Vatjus R, et al.(2000)A candidate gene for psoriasis near HLA-C, HCR (Pg8), is highly polymorphic with a disease-associated susceptibility allele.Hum Mol Genet,9:1533-1542.
[35]Enlund F,Samuelsson L,Enerback C, et al.(1999)Analysis of three suggested psoriasis susceptibility loci in a large Swedish set of families:confirmation of linkage to chromosome 6p (HLA region), and to 17q, but not to 4q.Hum Hered,49:2-8.
[36]Capon F,Helms C,Veal CD, et al.(2004)Genetic analysis of PSORS2 markers in a UK dataset supports the association between RAPTOR SNPs and familial psoriasis.J Med Genet,41:459-460.
[37]Matthews D,Fry L,Powles A, et al.(1996)Evidence that a locus for familial psoriasis maps to chromosome 4q.Nat Genet,14:231-233.
[38]Capon F,Semprini S,Dallapiccola B, et al.(1999)Evidence for interaction between psoriasis-susceptibility loci on chromosomes 6p21 and 1q21.Am J Hum Genet,65:1798-1800.
[39]Capon F,Semprini S,Chimenti S, et al.(2001)Fine mapping of the PSORS4 psoriasis susceptibility region on chromosome 1q21.J Invest Dermatol,116: 728-730.
[40]Zhang X J,Huang W,Yang S, et al.(2009)Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.Nat Genet,41:205-210.
[41]Giardina E,Capon F,De Rosa M C, et al.(2004)Characterization of the loricrin (LOR) gene as a positional candidate for the PSORS4 psoriasis susceptibility locusAnn Hum Genet,68:639-645.
[42]Enlund F,Samuelsson L,Enerback C, et al.(1999)Psoriasis susceptibility locus in chromosome region 3q21 identified in patients from southwest Sweden.r J Hum Genet,7:783-790.
[43]Lee YA,Ruschendorf F,Windemuth C, et al.(2000)Genomewide scan in german families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13 Am JHum Genet,67:1020-1024.
[44]Huffmeier U,Lascorz J,Bohm B, et al.(2009)Genetic variants of the IL-23R pathway:association with psoriatic arthritis and psoriasis vulgaris, but no specific risk factor for arthritis J Invest Dermatol,129:355-358.
[45]Nair RP,Duffin KC,Helms C, et al.(2009)Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.Nat Genet,41: 199-204.
[46]Nair RP,Henseler T,Jenisch S, et al.(1997)Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet,6:1349-1356.
[47]Zhang XJ,He P P,Wang ZX, et al.(2002)Evidence for a major psoriasis susceptibility locus at 6p21(PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese hans.J Invest Dmrmatol,119:1361-1366.
[48]Asumalahti K,Laitinen T,Lahermo P, et al.(2003)Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1.JInvest Dermatol,121:735-740.
[49]Capon F,Di Meglio P,Szaub J, et al.(2007)Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.Hum Genet,122:201-206.
[50]Capon F,Bijlmakers M J,Wolf N, et al.(2008)Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene.Hum Mol Genet,17: 1938-1945.
[51]Capon F HC, Veal CD, Tillman D, et al.(2004)Genetic analysis of PSORS2 markers in a UK dataset supports the association between RAPTOR SNPs and familial psoriasis.J Med Genet,41(6):60.
[52]Matthews D F L, Powles A, Weber J, et al. (1998) Evidence that a locus for familial psoriasis maps to chromosome 4q.Nat Genet,14(2):3.
[53]Capon F,Novelli G,Semprini S, et al.(1999)Searching for psoriasis susceptibility genes in Italy:genome scan and evidence for a new locus on chromosome 1.J Invest Dermatol,112:32-35.
[54]Parham C C M, Timans J, Vaisberg E, et al. (2002)A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbetal and a novel cytokine receptor subunit, IL-23R.J Immunol,168(11):10.
[55]Zhang XJ, Wang ZX, Zhang J, et al. (2002)Evidence for a major psoriasis susceptibility locus at 6p21(PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese hans J Invest Dermatol.,119(6):6.
[56]Asumalahti K, Laitinen T, Lahermo P, et al. (2003)Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1.J. Invest. Derm,121:6.
[57]Cargill M, Schrodi S J, Chang M, et al. (2007)A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.Am. J. Hum. Genet,80:117.
[58]Capon F, Wolf N, Quaranta M, et al. (2008)Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene.Hum Mol Genet,17(13):1938.
[59]Zenz R,Eferl R,Kenner L, et al.(2005)Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins.Nature,437:369-375.
[60]Tomfohrde J,Silverman A,Barnes R, et al.(1994)Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.Science, 264:1141-1145.
[61]Matthews D,Fry L,Powles A, et al.(1995)Confirmation of genetic heterogeneity in familial psoriasis.J Med Genet,32:546-548.
[62]Nair R P,Guo S W,Jenisch S, et al.(1995)Scanning chromosome 17 for psoriasis susceptibility:lack of evidence for a distal 17q locus.Hum Hered,45: 219-230.
[63]Speckman RA,Wright Daw JA,Helms C, et al.(2003)Novel immunoglobulin superfamily gene cluster, mapping to a region of human chromosome 17q25, linked to psoriasis susceptibility.Hum Genet,112:34-41.
[64]Viertlboeck B C,Schmitt R,Gobel T W.(2006)The chicken immunoregulatory receptor families SIRP, TREM, and CMRF35/CD300L. Immunogenetics,58: 180-190.
[65]Helms C,Cao L,Krueger J G, et al.(2003)A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis.Nat Genet,35:349-356.
[66]Elder J T.(2007)IL-15 and psoriasis:another genetic link to Thl7?J Invest Dermatol,127:2495-2497.
[67]Baker B S,Ovigne J M,Powles A V, et al.(2003)Normal keratinocytes express Toll-like receptors (TLRs) 1,2 and 5:modulation of TLR expression in chronic plaque psoriasis.Br J Dermatol,148:670-679.
[68]Wongpiyabovorn J,Yooyongsatit S,Ruchusatsawat K, et al.(2008)Association of the CTG (-2578/-460/+405) haplotype within the vascular endothelial growth factor gene with early-onset psoriasis.Tissue Antigens,72:458-463.
[69]Parkinson J,Charon C,Baker B S, et al.(2004)Variation at the IRF2 gene and susceptibility to psoriasis in chromosome 4q-linked families.J Invest Dermatol, 122:640-643.
[70]Huffmeier U,Steffens M,Burkhardt H, et al.(2006)Evidence for susceptibility determinant(s) to psoriasis vulgaris in or near PTPN22 in German patients./ Med Genet,43:517-522.
[71]Tsunemi Y,Saeki H,Nakamura K, et al.(2002)Interleukin-12 p40 gene (IL12B) 3'-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris.J Dermatol Sci,30:161-166.
[72]Koks S,Kingo K,Ratsep R, et al.(2004)Combined haplotype analysis of the interleukin-19 and-20 genes:relationship to plaque-type psoriasis.Genes Immun,5:662-667.
[73]Foerster J,Nolte I,Schweiger S, et al.(2004)Evaluation of the IRF-2 gene as a candidate for PSORS3 JInvest Dermatol,122:61-64.
[74]Huffineier U,Uebe S,Ekici A B, et al.(2010)Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis.Nat Genet,42:996-999.
[75]Ellinghaus E,Ellinghaus D,Stuart P E, et al.(2010)Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.Nat Genet,42: 991-995.
[76]Strange A,Capon F,Spencer C C, et al.(2010)A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.Nat Genet,42:985-990.
[77]de Cid R,Riveira-Munoz E,Zeeuwen P L, et al.(2009)Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.Nat Genet,41:211-215.
[78]Cargill M,Schrodi S J,Chang M, et al.(2007)A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.Am J Hum Genet,80:273-290.
[79]Franke B,Neale B M,Faraone S V.(2009)Genome-wide association studies in ADHD.Hum Genet,126:13-50.
[80]Liu Y,Helms C,Liao W, et al.(2008)A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci.PLoS Genet,4: e1000041.
[81]McClellan J,King M C.(2010)Genetic heterogeneity in human disease. Cell, 141:210-217.
[82]Hoffjan S,Stemmler S.(2007)On the role of the epidermal differentiation complex in ichthyosis vulgaris, atopic dermatitis and psoriasis.Br J Dermatol, 157:441-449.
[83]Hwu W L,Yang C F,Fann C S, et al.(2005)Mapping of psoriasis to 17q terminus.J Med Genet,42:152-158.
[84]Birnbaum R Y,Zvulunov A,Hallel-Halevy D, et al.(2006)Seborrhea-like dermatitis with psoriasiform elements caused by a mutation in ZNF750, encoding a putative C2H2 zinc finger protein.Nat Genet,38:749-751.
[85]Huffmeier U,Traupe H,Oji V, et al.(2007)Loss-of-function variants of the filaggrin gene are not major susceptibility factors for psoriasis vulgaris or psoriatic arthritis in German patients.J Invest Dermatol,127:1367-1370.
[86]Nemoto-Hasebe I,Akiyama M,Nomura T, et al.(2009)FLG mutation p.Lys4021X in the C-terminal imperfect filaggrin repeat in Japanese patients with atopic eczema.Br J Dermatol,161:1387-1390.
[87]Li Z,Zhang Z,He Z, et al.(2009)A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers:update of the SHEsis (http://analysis.bio-x.cn).Cell Res,19:519-523.
[88]Zhao Y,Terron-Kwiatkowski A,Liao H, et al.(2007)Filaggrin null alleles are not associated with psoriasis.J Invest Dermatol,127:1878-1882.
[89]Thyssen J P,Johansen J D,Carlsen B C, et al.(2012)The filaggrin null genotypes R501X and 2282del4 seem not to be associated with psoriasis: results from general population study and meta-analysis. J Eur Acad Dermatol Venereol,26:782-784.
[1]Sandilands A,Sutherland C, Irvine A D, et al. (2009)Filaggrin in the frontline: role in skin barrier function and disease.J Cell Sci,122:1285-1294.
[2]Irvine A D, McLean W H. (2006)Breaking the (un)sound barrier:filaggrin is a major gene for atopic dermatitis J Invest Dermatol,126:1200-1202.
[3]Dale B A. (1977)Purification and characterization of a basic protein from the stratum corneum of mammalian epidermis..Biochim Biophys Acta,491: 193-204.
[4]Steinert PM, Cantieri JS, Teller DC, et al.(1981)Characterization of a class of cationic proteins that specifically interact with intermediate filaments.Proc Natl Acad Sci U S A,78:4097-4101.
[5]Fleckman P, Dale BA, Holbrook KA. (1985)Profilaggrin, a high-molecular-weight precursor of filaggrin in human epidermis and cultured keratinocytes.J Invest Dermatol,85:507-512.
[6]Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al.(2006)Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.Nat Genet,38:337-342.
[7]Presland RB, Haydock PV, Fleckman P, et al.(1992)Characterization of the human epidermal profilaggrin gene. Genomic organization and identification of an S-100-like calcium binding domain at the amino terminus.J Biol Chem, 267:23772-23781.
[8]Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al.(2006)Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.Nat Genet,38:441-446.
[9]Sandilands A, Terron-Kwiatkowski A, Hull P R, et al.(2007)Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.Nat Genet,39:650-654.
[10]Gan S Q, McBride O W, Idler W W, et al.(1990)Organization, structure, and polymorphisms of the human profilaggrin gene.Biochemistry,29:9432-9440.
[11]Brown SJ, Asai Y, Cordell HJ, et al.(2011)Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy.J Allergy Clin Immunol,127.661-667.
[12]de Guzman Strong C, Conlan S, Deming C B, et al.(2010)A milieu of regulatory elements in the epidermal differentiation complex syntenic block: implications for atopic dermatitis and psoriasis.Hym Mol Genet,19:1453-1460.
[13]de Cid R, Riveira-Munoz E, Zeeuwen P L, et al.(2009)Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.Nat Genet,41:211-215.
[14]Maestrini E, Monaco AP, McGrath J A, et al.(1996)A molecular defect in loricrin, the major component of the cornified cell envelope, underlies Vohwinkel's syndrome.Nat Genet,13:70-77.
[15]Irvine A D, McLean WH,Leung D Y.(2011)Filaggrin mutations associated with skin and allergic diseases.N EnglJ Med,365:1315-1327.
[16]Dale B A,Holbrook K A,Kimball J R, et al.(1985)Expression of epidermal keratins and filaggrin during human fetal skin development. J Cell Biol,101: 1257-1269.
[17]Oyoshi M K,Murphy G F,Geha R S.(2009)Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen.JAllergy Clin Immunol,124:485-493,493 e481.
[18]Nemes Z,Steinert P M.(1999)Bricks and mortar of the epidermal barrier.Exp Mol Med,31:5-19.
[19]Candi E,Schmidt R,Melino G.(2005)The cornified envelope:a model of cell death in the skin.Nat Rev Mol Cell Biol,6:328-340.
[20]List K,Szabo R,Wertz P W, et al.(2003)Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1.J Cell Biol,163: 901-910.
[21]Leyvraz C,Charles R P,Rubera I, et al.(2005)The epidermal barrier function is dependent on the serine protease CAP1/Prss8.J Cell Biol,170:487-496.
[22]Matsui T,Miyamoto K,Kubo A, et al.(2011)SASPase regulates stratum corneum hydration through profilaggrin-to-filaggrin processing.EMBO Mol Med,3:320-333.
[23]Descargues P,Deraison C,Bonnart C, et al.(2005)Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity.Nat Genet,37:56-65.
[24]Takahashi M,Tezuka T,Katunuma N.(1996)Filaggrin linker segment peptide and cystatin alpha are parts of a complex of the cornified envelope of epidermis.Arch Biochem Biophys,329:123-126.
[25]Nachat R,Mechin M C,Takahara H, et al.(2005)Peptidylarginine deiminase isoforms 1-3 are expressed in the epidermis and involved in the deimination of Kl and filaggrin.J Invest Dermatol,124:384-393.
[26]Scott I R,Harding C R.(1986)Filaggrin breakdown to water binding compounds during development of the rat stratum corneum is controlled by the water activity of the environment.Dev Biol,115:84-92.
[27]Kamata Y,Taniguchi A,Yamamoto M, et al.(2009)Neutral cysteine protease bleomycin hydrolase is essential for the breakdown of deiminated filaggrin into amino acids JBiol Chem,284:12829-12836.
[28]Barresi C,Stremnitzer C,Mlitz V, et al.(2011)Increased sensitivity of histidinemic mice to UVB radiation suggests a crucial role of endogenous urocanic acid in photoprotection.JInvest Dermatol,131:188-194.
[29]Walterscheid J P,Nghiem D X,Kazimi N, et al.(2006)Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor.Proc Natl Acad Sci U S A,103:17420-17425.
[30]DeLapp N W,Dieckman D K.(1988)Gamma glutamyl peptidase:a novel enzyme from hairless mouse epidermis J Invest Dermatol,90:490-494.
[31]Miajlovic H,Fallon P G,Irvine A D, et al.(2010)Effect of filaggrin breakdown products on growth of and protein expression by Staphylococcus aureus.J Allergy Clin Immunol,126:1184-1190 e1183.
[32]O'Regan G M,Kemperman P M,Sandilands A, et al.(2010)Raman profiles of the stratum corneum define 3 filaggrin genotype-determined atopic dermatitis endophenotypes.J Allergy Clin Immunol,126:574-580 e571.
[33]Kezic S,O'Regan G M,Yau N, et al.(2011)Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity.Allergy,66:934-940.
[34]Presland R B,Boggess D,Lewis S P, et al.(2000)Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice:an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris.J Invest Dermatol,115:1072-1081.
[35]Mildner M,Jin J,Eckhart L, et al.(2010)Knockdown of filaggrin impairs diffusion barrier function and increases UV sensitivity in a human skin model. J Invest Dermatol,130:2286-2294.
[36]Gruber R,Elias P M,Crumrine D, et al.(2011)Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function.Am J Pathol,178:2252-2263.
[37]de Juanes S,Epp N,Latzko S, et al.(2009)Development of an ichthyosiform phenotype in Aloxl2b-deficient mouse skin transplants.J Invest Dermatol,129: 1429-1436.
[38]Yanagi T,Akiyama M,Nishihara H, et al.(2010)Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice.Am JPathol,177:106-118.
[39]Brown S J,Relton C L,Liao H, et al.(2008)Filaggrin null mutations and childhood atopic eczema:a population-based case-control study.J Allergy Clin Immunol,121:940-946 e943.
[40]Manabe M,Sanchez M,Sun T T, et al.(1991)Interaction of filaggrin with keratin filaments during advanced stages of normal human epidermal differentiation and in ichthyosis vulgaris.Differentiation,48:43-50.
[41]Sybert V P,Dale B A,Holbrook K A.(1985)Ichthyosis vulgaris:identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules.J Invest Dermatol,84:191-194.
[42]Fleckman P,Holbrook K A,Dale B A, et al.(1987)Keratinocytes cultured from subjects with ichthyosis vulgaris are phenotypically abnormal.J Invest Dermatol,88:640-645.
[43]Nirunsuksiri W,Presland R B,Brumbaugh S Q et al.(1995)Decreased profilaggrin expression in ichthyosis vulgaris is a result of selectively impaired posttranscriptional control. J Biol Chem,270:871-876.
[44]Nirunsuksiri W,Zhang S H,Fleckman P.(1998)Reduced stability and bi-allelic, coequal expression of profilaggrin mRNA in keratinocytes cultured from subjects with ichthyosis vulgaris.J Invest Dermatol,110:854-861.
[45]Mischke D,Korge B P,Marenholz I, et al.(1996)Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex ("epidermal differentiation complex") on human chromosome 1q21 J Invest Dermatol,106:989-992.
[46]Compton J QDiGiovanna J J,Johnston K A, et al.(2002)Mapping of the associated phenotype of an absent granular layer in ichthyosis vulgaris to the epidermal differentiation complex on chromosome 1.Exp Dermatol,11:518-526.
[47]Shaw T E,Currie G P,Koudelka C W, et al.(2011)Eczema prevalence in the United States:data from the 2003 National Survey of Children's Health.J Invest Dermatol,131:67-73.
[48]Al-Rawas O A,Al-Riyami B M,Al-Maniri A A, et al.(2008)Trends in asthma prevalence and severity in Omani schoolchildren:comparison between ISAAC phases I and Ⅲ.Respirology,13:670-673.
[49]Kay J,Gawkrodger D J,Mortimer M J, et al.(1994)The prevalence of childhood atopic eczema in a general population.J Am Acad Dermatol,30:35-39.
[50]Lewis-Jones S.(2006)Quality of life and childhood atopic dermatitis:the misery of living with childhood eczema.Int J Clin Pract,60:984-992.
[51]Williams H C.(2005)Clinical practice. Atopic dermatitis.N Engl J Med,352: 2314-2324.
[52]Mancini A J,Kaulback K,Chamlin S L.(2008)The socioeconomic impact of atopic dermatitis in the United States:a systematic review.Pediatr Dermatol, 25:1-6.
[53]Spergel J M,Paller A S.(2003)Atopic dermatitis and the atopic march.J Allergy Clin Immunol,112:S118-127.
[54]van den Oord R A,Sheikh A.(2009)Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders:systematic review and meta-analysis.BMJ,339:b2433.
[55]Rodriguez E,Baurecht H,Herberich E, et al.(2009)Meta-analysis.of filaggrin polymorphisms in eczema and asthma:robust risk factors in atopic disease.J Allergy Clin Immunol,123:1361-1370 e1367.
[56]Barker J N,Palmer C N,Zhao Y, et al.(2007)Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood.J Invest Dermatol,127:564-567.
[57]Brown S J,Sandilands A,Zhao Y, et al.(2008)Prevalent and low-frequency null mutations in the filaggrin gene are associated with early-onset and persistent atopic eczema.J Invest Dermatol,128:1591-1594.
[58]Weidinger S,Illig T,Baurecht H, et al.(2006)Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations./ Allergy Clin Immunol,118:214-219.
[59]Weidinger S,Rodriguez E,Stahl C, et al.(2007)Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis.J Invest Dermatol, 127:724-726.
[60]Carlsen B C,Thyssen J P,Menne T, et al.(2011)Association between filaggrin null mutations and concomitant atopic dermatitis and contact allergy.Clin Exp Dermatol,36:467-472.
[61]Gao P S,Rafaels N M,Hand T, et al.(2009)Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum J Allergy Clin Immunol,124:507-513,513 e501-507.
[62]Henderson J,Northstone K,Lee S P, et al.(2008)The burden of disease associated with filaggrin mutations:a population-based, longitudinal birth cohort study. J Allergy Clin Immunol,121:872-877 e879.
[63]Weidinger S,O'Sullivan M,Illig T, et al.(2008)Filaggrin mutations, atopic eczema, hay fever, and asthma in children.J Allergy Clin Immunol,121: 1203-1209 e1201.
[64]Ying S,Meng Q,Corrigan G J, et al.(2006)Lack of filaggrin expression in the human bronchial mucosa. J Allergy Clin Immunol,118:1386-1388.
[65]McLean W H,Palmer C N,Henderson J, et al.(2008)Filaggrin variants confer susceptibility to asthma. J Allergy Clin Immunol,121:1294-1295; author reply 1295-1296.
[66]Ziegler S F,Artis D.(2010)Sensing the outside world:TSLP regulates barrier immunity.Nat Immunol,11:289-293.
[67]Palmer C N,Ismail T,Lee S P, et al.(2007)Filaggrin null mutations are associated with increased asthma severity in children and young adults.J Allergy Clin Immunol,120:64-68.
[68]Illi S,von Mutius E,Lau S, et al.(2004)The natural course of atopic dermatitis from birth to age 7 years and the association with asthma.J Allergy Clin Immunol,113:925-931.
[69]Sicherer S H,Furlong T J,Maes H H, et al.(2000)Genetics of peanut allergy:a twin studyJAllergy Clin Immunol,106:53-56.
[70]Liao H,Waters A J,Goudie D R, et al.(2007)Filaggrin mutations are genetic modifying factors exacerbating X-linked ichthyosis.J Invest Dermatol,127: 2795-2798.
[71]Gruber R,Wilson N J,Smith F J, et al.(2009)Increased pachyonychia congenita severity in patients with concurrent keratin and filaggrin mutations.Br J Dermatol,161:1391-1395.
[72]de Jongh C M,Khrenova L,Verberk M M, et al.(2008)Loss-of-function polymorphisms in the filaggrin gene are associated with an increased susceptibility to chronic irritant contact dermatitis:a case-control study.Br J Dermatol,159:621-627.
[73]Nomura T,Akiyama M,Sandilands A, et al.(2009)Prevalent and rare mutations in the gene encoding filaggrin in Japanese patients with ichthyosis vulgaris and atopic dermatitis J Invest Dermatol,129:1302-1305.
[74]Betz R C,Pforr J,Flaquer A, et al.(2007)Loss-of-function mutations in the filaggrin gene and alopecia areata:strong risk factor for a severe course of disease in patients comorbid for atopic disease.J Invest Dermatol,127: 2539-2543.
[75]Huffmeier U,Traupe H,Oji V, et al.(2007)Loss-of-function variants of the filaggrin gene are not major susceptibility factors for psoriasis vulgaris or psoriatic arthritis in German patients J Invest Dermatol,127:1367-1370.
[76]Boguniewicz M,Leung D Y.(2010)Recent insights into atopic dermatitis and implications for management of infectious complications.J Allergy Clin Immunol,125:4-13; quiz 14-15.
[77]Bieber T.(2008)Atopic dermatitis.N Engl JMed,358:1483-1494.
[78]Elias P M,Feingold K R.(2001)Does the tail wag the dog? Role of the barrier in the pathogenesis of inflammatory dermatoses and therapeutic implications. Arch Dermatol,137:1079-1081.
[79]Werner Y,Lindberg M.(1985)Transepidermal water loss in dry and clinically normal skin in patients with atopic dermatitis.Acta Derm Venereol,65:102-105.
[80]Fartasch M,Diepgen T L.(1992)The barrier function in atopic dry skin. Disturbance of membrane-coating granule exocytosis and formation of epidermal lipids?Acta Derm Venereol Suppl (Stockh),176:26-31.
[81]Rodriguez E,Illig T,Weidinger S.(2008)Filaggrin loss-of-function mutations and association with allergic diseases.Pharmacogenomic,9:939:399-413.
[82]Scharschmidt T C,Man M Q,Hatano Y, et al.(2009)Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens.J Allergy Clin Immunol,124:496-506,506 e491-496.
[83]Moniaga C S,Egawa G,Kawasaki H, et al.(2010)Flaky tail mouse denotes human atopic dermatitis in the steady state and by topical application with Dermatophagoides pteronyssinus extract.Am J Pathol,176:2385-2393.
[84]De Benedetto A,Rafaels N M,McGirt L Y, et al.(2011)Tight junction defects in patients with atopic dermatitis.J Allergy Clin Immunol,127:773-786 e771-777.
[85]Krien P M,Kermici M.(2000)Evidence for the existence of a self-regulated enzymatic process within the human stratum corneum-an unexpected role for urocanic acid. J Invest Dermatol,115:414-420.
[86]Bisgaard H,Simpson A,Palmer C N, et al.(2008)Gene-environment interaction in the onset of eczema in infancy:filaggrin loss-of-function mutations enhanced by neonatal cat exposure.PLoS Med,5:e131.
[87]Schuttelaar M L,Kerkhof M,Jonkman M F, et al.(2009)Filaggrin mutations in the onset of eczema, sensitization, asthma, hay fever and the interaction with cat exposure.Allergy,64:1758-1765.
[88]Nemoto-Hasebe I,Akiyama M,Nomura T, et al.(2009)Clinical severity correlates with impaired barrier in filaggrin-related eczema. J Invest Dermatol, 129:682-689.
[89]Bisgaard H,Halkjaer L B,Hinge R, et al.(2009)Risk analysis of early childhood eczema.J Allergy Clin Immunol,123:1355-1360 e1355.
[90]Cramer C,Link E,Horster M, et al.(2010)Elder siblings enhance the effect of filaggrin mutations on childhood eczema:results from the 2 birth cohort studies LISAplus and GINIplus.J Allergy Clin Immunol,125:1254-1260 e1255.
[91]Schreiber S,Rosenstiel P,Albrecht M, et al.(2005)Genetics of Crohn disease, an archetypal inflammatory barrier disease.Nat Rev Genet,6:376-388.
[92]Ruether A,Stoll M,Schwarz T, et al.(2006)Filaggrin loss-of-function variant contributes to atopic dermatitis risk in the population of Northern Germany.Br J Dermatol,155:1093-1094.
[93]Sanmarti R,Graell E,Perez M L, et al.(2009)Diagnostic and prognostic value of antibodies against chimeric fibrin/filaggrin citrullinated synthetic peptides in rheumatoid arthritis Arthritis Res Ther,11:R135.
[94]Perez M L,Gomara M J,Ercilla G, et al.(2007)Antibodies to citrullinated human fibrinogen synthetic peptides in diagnosing rheumatoid arthritis.J Med Chem,50:3573-3584.
[95]Choi K H, Lee E B, Yoo C D, et al.(2005)Clinical significance of anti-filaggrin antibody recognizing uncitrullinated filaggrin in rheumatoid arthritis.Exp Mol Med,37:546-552.
[96]Van Steendam K, Tilleman K, Deforce D.(2011)The relevance of citrullinated vimentin in the production of antibodies against citrullinated proteins and the pathogenesis of rheumatoid arthritis.Rheumatology (Oxford),50:830-837.
[97]Huffmeier U, Boiers U, Lascorz J, et al.(2008)Loss-of-function mutations in the filaggrin gene:no contribution to disease susceptibility, but to autoantibody formation against citrullinated peptides in early rheumatoid arthritis.Ann Rheum Dis,67:131-133.
[98]Petukhova L, Duvic M, Hordinsky M, et al.(2010)Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature, 466:113-117.
[99]Elias P M.(2010)Therapeutic Implications of a Barrier-based Pathogenesis of Atopic Dermatitis Ann Dermatol,22:245-254.
[100]Jensen JM, Pfeiffer S, Witt M, et al.(2009)Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis.J Allergy Clin Immunol,124:R19-28.
[101]Rowe SM, Clancy JP.(2009)Pharmaceuticals targeting nonsense mutations in genetic diseases:progress in development.BioDrugss,23:165-174.