Epidermolysis bullosa simplex (EBS) is a hereditary genodermatosis characterised by trauma-induced intraepidermal blistering of the skin. EBS is mostly caused by mutations in the KRT5 and KRT14 genes. Disease severity partially depends on the affected keratin type and may be modulated by mutation type and location. The aim of our study was to identify the molecular defects in KRT5 and KRT14 in a cohort of 46 Polish and one Belarusian probands with clinical suspicion of EBS and to determine the genotype–phenotype correlation. The group of 47 patients with clinical recognition of EBS was enrolled in the study. We analysed all coding exons of KRT5 and KRT14 using Sanger sequencing. The pathogenic status of novel variants was evaluated using bioinformatical tools, control group analysis (DNA from 100 healthy population-matched subjects) and probands’ parents testing. We identified mutations in 80 % of patients and found 29 different mutations, 11 of which were novel and six were found in more than one family. All novel mutations were ascertained as pathogenic. In the majority of cases, the most severe genotype was associated with mutations in highly conserved regions. In some cases, different inheritance mode and clinical significance, than previously reported by others, was observed. We report 11 novel variants and show novel genotype–phenotype correlations. Our data give further insight into the natural history of EBS molecular pathology, epidemiology and mutation origin.
Netherton Syndrome (NS) is a very rare genetic skin disease resulting from defects in the SPINK5 gene (encoding the protease inhibitor lympho-epithelial Kazal type inhibitor 1, LEKTI1). In this report, we provide a detailed clinical description of a Polish patient with two SPINK5 mutations, the novel c.1816_1820+21delinsCT and possibly recurrent c.1431-12G>A. A detailed pathogenesis of Netherton Syndrome, on the basis of literature review, is discussed in the view of current knowledge about the LEKT1 molecular processing and activity.
Usher syndrome is rare genetic disorder impairing two human senses, hearing and vision, with the characteristic late onset of vision loss. This syndrome is divided into three types. In all cases, the vision loss is postlingual, while loss of hearing is usually prelingual. The vestibular functions may also be disturbed in Usher type 1 and sometimes in type 3. Vestibular areflexia is helpful in making a proper diagnosis of the syndrome, but, often, the syndrome is misdiagnosed as a nonsyndromic hearing loss. Here, we present a Polish family with hearing loss, which was clinically classified as nonsyndromic. After excluding mutations in the DFNB1 locus, we implemented the next-generation sequencing method and revealed that hearing loss was syndromic and mutations in the USH2A gene indicate Usher syndrome. This research highlights the importance of molecular analysis in establishing a clinical diagnosis of congenital hearing loss.
Mental disorders participate in the development of psoriasis as predisposing factors; a correlation of dermatological diseases with pathological anxiety and stress was shown. The aim of this study is to find the associations between SNV in genes COMT (rs4680), DBH (rs141116007), CCKAR (rs1800857), CCKBR (rs1805002), and psoriasis. In our study The c 2 test revealed an association with psoriasis only for the COMT gene, which encodes catechol-O-methyltransferase. Results of polygenic analysis also showed a significant influence of gene polymorphism COMT (rs4680) in the development of psoriasis. The carrying of both alleles in combinations with alleles of other genes forms the strongly associated patterns. Besides, the G allele, both alone and in combination with other genes and / or A allele, forms markers of strong predisposition to the disease. The AA genotype in the meantime is protective. This indicates the dominant manifestation of the G allele in the case of psoriasis. The association of GA genotype of COMT gene with psoriasis found in our study has no direct explanation of its functional activities. The most interesting hypothesis, which could explain the effect of the GA heterozygote of the COMT gene on the pathogenesis of psoriasis, from our point of view, is the possibility of changing the activity of the heterodimer. Thus, it was shown that COMT enzyme can exist in three forms: a monomer, a membrane-bound monomer and a dimer. The structure of proteins COMT 158Val and COMT 158Met is different, which results in different affinity to substrates and different stability of the enzyme. Thus, patients with psoriasis have an increased excretion of adrenaline in stressful situations.
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