| 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 PopulationPsoriasis (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/â…£ 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. |
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