The genetic basis of epidermolysis bullosa, a group of genetic disorders characterized by the mechanically induced formation of skin blisters, is largely known, but a number of cases still remain ...genetically unsolved. Here, we used whole-exome and targeted sequencing to identify monoallelic mutations, c.1A>G and c.2T>C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes. Remarkably, mutation c.1A>G occurred de novo and was recurrent in families originating from different countries. The striking similarities of the clinical features of the affected individuals point to a unique and very specific pathomechanism. We showed that mutations in the translation initiation codon of KLHL24 lead to the usage of a downstream translation initiation site with the same reading frame and formation of a truncated polypeptide. The pathobiology was examined in keratinocytes and fibroblasts of the affected individuals and via expression of mutant KLHL24, and we found mutant KLHL24 to be associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts. In particular, KLHL24 mutations were associated with irregular and fragmented keratin 14. Recombinant overexpression of normal KLHL24 promoted keratin 14 degradation, whereas mutant KLHL24 showed less activity than the normal molecule. These findings identify KLHL24 mutations as a cause of skin fragility and identify a role for KLHL24 in maintaining the balance between intermediate filament stability and degradation required for skin integrity.
To the Editor: Netherton syndrome (NS; OMIM no. 266500) is an autosomal recessive genodermatosis with atopic dermatitis (AD)-like erythroderma, a bamboo-like hair-shaft defect, and multiple atopic ...manifestations: asthma, urticaria, angioedema, allergic rhinitis, increased IgE levels, and blood hypereosinophilia.1 NS is caused by serine protease inhibitor, Kazal type 5 (SPINK5) mutations leading to defective lymphoepithelial Kazal-type related inhibitor (LEKTI), a serine protease inhibitor expressed in the upper epidermal skin layers.1 Loss of LEKTI inhibition results in a severe skin barrier defect.1SPINK5 polymorphisms, especially the 420Lys LEKTI variant, have been associated with atopy and AD.2 We studied in detail the atopic symptoms in 10 Finnish patients with NS with SPINK5 mutations. ...considering that our study was not a case-control study, a cohort of 140 German pediatric patients with AD studied on an ISAC microarray with 95 allergen components showed mean sensitization to 7.6 ± 7.7 of allergens, ranging from 0% (in 14% of patients) to 34%, and higher numbers of sIgE responses associated with higher total IgE levels (3-26,567 kU/L).3 All our patients with NS had IgE antibodies to multiple potentially anaphylactic stable allergens, such as lipid transfer proteins (LTPs; 83%), storage proteins (17% to 33%), and tropomyosin (33%; see Table E1).4 Interestingly, patients with NS were sensitized to 1 to 8 different LTPs, especially hazelnut, peach, and mugwort, each in 4 of 6 patients, although LTP allergy is rare in Northern Europe.4 LTPs are important allergens in the Mediterranean region, but in Finland only 20% of 100 children (2-13 years old) and 12% of 100 adults (40-60 years old) studied for various allergies were sensitized to at least 1 of the 9 LTPs on the microarray (own unpublished data).
Netherton syndrome (NS) is a rare and severe genodermatosis caused by SPINK5 mutations leading to the loss of lymphoepithelial Kazal-type-related inhibitor (LEKTI). Netherton syndrome is ...characterized by neonatal scaling erythroderma, a bamboolike hair defect, a substantial skin barrier defect, and a profound atopic diathesis. Netherton syndrome has been proposed to be a primary immunodeficiency syndrome because of the high frequency of infections. The precise mechanisms underlying the disease are not fully understood.
To study the association of the SPINK5 mutation with the NS phenotype and the extent of immunologic deficiencies in NS.
Relevant tissue samples and follow-up data from 11 patients with NS from 7 families, including 3 multiplex families, were collected, constituting all known patients with NS in Finland. Another patient with NS from a neighboring country was included. Data were collected from August 10, 2011, to February 20, 2015. SPINK5 mutations were sequenced, and thorough clinical evaluation and histopathologic and immunohistochemical evaluations of skin samples were performed. The function of natural killer cells, lymphocyte phenotype, and serum immunoglobulin subclass levels were evaluated. Data analysis was conducted from October 19, 2011, to February 20, 2015.
The nature of SPINK5 mutations and their correlation with phenotypes in Finnish patients with NS, intrafamilial phenotype variations, and the type of immunologic defects in NS were evaluated.
Among the 11 Finnish patients with NS (8 male 73%; 3 female 27%; mean SD age, 30.1 9.1 years), a Finnish founder mutation c.652C>T (p.Arg218*) in SPINK5 was identified in 10 patients from 6 families who all originated from the same region. Eight patients were homozygotes for this mutation and 2 siblings were compound heterozygotes with a splice site mutation c.1220 + 1G>C (IVS13 + 1 G>C). Phenotypes were comparable, but some intrafamilial and interfamilial variations were noted. Compound heterozygous patients had a milder phenotype and showed residual LEKTI expression. A previously unreported c.1772delT (p.Leu591Glnfs124*) mutation was found in 1 patient with a phenotype similar to the patients homozygous for the founder mutation. The patient from the neighboring country had a distinct phenotype and different mutations. Immunologically, natural killer cells had an immature phenotype and impaired cytotoxicity and degranulation, levels of memory B cells were reduced, and serum IgG4 levels were elevated. Intravenous immunoglobulin treatment has been beneficial in 1 patient with NS.
This report discloses a prevalent SPINK5 founder mutation in Finland and illustrates NS phenotype variability. Our results also point to a possible role of immature immunity in the frequent infections seen in NS.
Increased production of Th2 cytokines characterizes Sezary syndrome, the leukemic form of cutaneous T-cell lymphomas (CTCL). To identify the molecular background and to study whether shared by the ...most common CTCL subtype, mycosis fungoides, we analyzed the gene expression profiles in both subtypes.
Freshly isolated cells from 30 samples, representing skin, blood, and enriched CD4(+) cell populations of mycosis fungoides and Sezary syndrome, were analyzed with Affymetrix (Santa Clara, CA) oligonucleotide microarrays, quantitative PCR, or immunohistochemistry. The gene expression profiles were combined with findings of comparative genomic hybridization of the same samples to identify chromosomal changes affecting the aberrant gene expression.
We identified a set of Th1-specific genes e.g., TBX21 (T-bet), NKG7, and SCYA5 (RANTES) to be down-regulated in Sezary syndrome as well as in a proportion of mycosis fungoides samples. In both Sezary syndrome and mycosis fungoides blood samples, the S100P and LIR9 gene expression was up-regulated. In lesional skin, IL7R and CD52 were up-regulated. Integration of comparative genomic hybridization and transcriptomic data identified chromosome arms 1q, 3p, 3q, 4q, 12q, 16p, and 16q as likely targets for new CTCL-associated gene aberrations.
Our findings revealed several new genes involved in CTCL pathogenesis and potential therapeutic targets. Down-regulation of a set of genes involved in Th1 polarization, including the major Th1-polarizing factor, TBX21, was for the first time associated with CTCL. In addition, a plausible explanation for the proliferative response of CTCL cells to locally produced interleukin-7 was revealed.
Biological drugs are expensive, but can reduce symptoms and increase quality of life for patients with psoriasis. The aim of this study was to examine quality of life, disease severity and treatment ...satisfaction in Danish, Finnish and Swedish patients with psoriasis. Based on 12 months' data from patient surveys and chart reviews, 3 treatment groups were identified: topical, systemic and/or biological <12 months, and biological for 12 months. Regression analyses were performed to investigate influence on treatment satisfaction, disease problems and quality of life. Patients treated with biological drugs for 12 months showed the highest treatment satisfaction and the lowest Dermatology Life Quality Index score. A number of patients with topical treatment reported low quality of life, severe or very severe disease problems, and low treatment satisfaction. Some patients with psoriasis may be under-treated and might benefit from a more aggressive treatment strategy. It is important, however, that resource utilization is optimized and patients are not treated with more advanced agents than necessary.
Upon binding to pathogen or self-derived cytosolic nucleic acids cyclic GMP-AMP synthase (cGAS) triggers the production of cGAMP that further activates transmembrane protein STING. Upon activation ...STING translocates from ER via Golgi to vesicles. Monogenic STING gain-of-function mutations cause early-onset type I interferonopathy, with disease presentation ranging from fatal vasculopathy to mild chilblain lupus. Molecular mechanisms underlying the variable phenotype-genotype correlation are presently unclear. Here, we report a novel gain-of-function G207E STING mutation causing a distinct phenotype with alopecia, photosensitivity, thyroid dysfunction, and features of STING-associated vasculopathy with onset in infancy (SAVI), such as livedo reticularis, skin vasculitis, nasal septum perforation, facial erythema, and bacterial infections. Polymorphism in
and
showed variable penetrance in the affected family, implying contribution to varying phenotype spectrum. The G207E mutation constitutively activates inflammation-related pathways
, and causes aberrant interferon signature and inflammasome activation in patient PBMCs. Treatment with Janus kinase 1 and 2 (JAK1/2) inhibitor baricitinib was beneficiary for a vasculitic ulcer, induced hair regrowth and improved overall well-being in one patient. Protein-protein interactions propose impaired cellular trafficking of G207E mutant. These findings reveal the molecular landscape of STING and propose common polymorphisms in
and
as likely modifiers of the phenotype.
Patient registries often lack indicators of the disease as experienced by patients, e.g. treatment satisfaction and self-assessed disease severity. There is scarce information about the relationship ...between these assessments and currently existing instruments used in treatment evaluation. Our objective was to explore the importance of these indicators among patients with psoriasis in Finland and Sweden, in relation to treatment patterns and current measures of health-related quality of life. Data were collected from a patient survey and a retrospective chart review for 273 patients over 12 months. To assess psoriasis treatment completely, it is necessary to consider the impact of the disease on the patient in terms of treatment satisfaction, disease severity and health-related quality of life. The individual disease burden on patients should play a central role in formulating treatment goals. Clinician- and patient-based perspectives of the overall impact of psoriasis can assist clinical decision-making and evaluations of treatments.
A 5-year retrospective multicenter study was performed for microascaceous moulds (Microascaceae, Ascomycetes) in Finnish clinical specimens. The files from 1993-1997 of six clinical mycology ...laboratories in Finland were searched for reports of these fungi, mainly Scopulariopsis and Scedosporium anamorphs in keratinous specimens. From the 521 primary findings, 165 cases were selected for further study based on direct microscopy, colony numbers and accompanying fungi. The clinical records of 148 cases (141 Scopulariopsis, 7 Scedosporium) were studied. Of the nail infections from which Scopulariopsis was recovered, 39 cases were further separated which showed clinical or laboratory-based evidence of dermatophytosis. In the remaining 90 'non-dermatophyte' nail cases, Scopulariopsis spp. were the only documented fungal agents (c. 6 cases/million/year). The patients were mainly elderly, 66% of whom had problems involving their big toe nails. For 74% of them, the nail problem was mentioned as their reason for visiting the physician. However, only 18% had documented benefit from treatment. The Scopulariopsis nail infections seem to be treatment-resistant and the pathogenesis and etiological role of Scopulariopsis remain poorly understood.
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