Dowling-Degos disease (DDD), or reticular pigmented anomaly of the flexures, is a type of rare autosomal-dominant genodermatosis characterized by reticular hyperpigmentation and hypopigmentation of the flexures, such as the neck, axilla, and areas below the breasts and groin, and shows considerable heterogeneity. Loss-of-function mutations of keratin 5 (KRT5) have been identified in DDD individuals. In this study, we collected DNA samples from a large Chinese family affected by generalized DDD and found no mutation of KRT5. We performed a genome-wide linkage analysis of this family and mapped generalized DDD to a region between rs1293713 and rs244123 on chromosome 20 [corrected]. By exome sequencing, we identified nonsense mutation c.430G>T (p.Glu144(∗)) in POFUT1, which encodes protein O-fucosyltransferase 1, in the family. Study of an additional generalized DDD individual revealed the heterozygous deletion mutation c.482delA (p.Lys161Serfs(∗)42) in POFUT1. Knockdown of POFUT1 reduces the expression of NOTCH1, NOTCH2, HES1, and KRT5 in HaCaT cells. Using zebrafish, we showed that pofut1 is expressed in the skin and other organs. Morpholino knockdown of pofut1 in zebrafish produced a phenotype characteristic of hypopigmentation at 48 hr postfertilization (hpf) and abnormal melanin distribution at 72 hpf, replicating the clinical phenotype observed in our DDD individuals. At 48 and 72 hpf, tyrosinase activities decreased by 33% and 45%, respectively, and melanin protein contents decreased by 20% and 25%, respectively. Our findings demonstrate that POFUT1 mutations cause generalized DDD. These results strongly suggest that the protein product of POFUT1 plays a significant and conserved role in melanin synthesis and transport.
Objective. To investigate the effects of berberine on dendritic cell (DC) apoptosis and its potential as a therapeutic agent in rheumatoid arthritis (RA).Methods. Bone marrow (BM)-derived myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) were generated by culturing BM cells with granulocytemacrophage colony-stimulating factor/interleukin-4 or flt3L, respectively. Splenic DCs, T cells, and B cells were purified using a magnetic-activated cell sorting system. In vitro apoptosis was assessed by annexin V/propidium iodide or Hoechst 33258 staining. The in vivo effects of berberine were examined in mice with collagen-induced arthritis (CIA). Immune responses against type II collagen (CII) were determined by assaying serum antibody levels, lymphocyte proliferation, and cytokine production. The proportions of DCs and apoptosis of different immune cell subsets in spleens and lymph nodes were analyzed by flow cytometry and immunohistochemistry after subset-specific surface marker labeling and TUNEL staining.Results. Exposure of MDCs to berberine during BM cell differentiation reduced cell recovery by inducing apoptosis. Sensitivity to berberine-induced apoptosis was acquired starting on day 3 of DC differentiation, and mature DCs were more sensitive to berberine than immature DCs. Murine peritoneal macrophages, RAW 264.7 cells, and Jurkat cells were insensitive to berberine-induced apoptosis. Splenic DCs were more sensitive to berberine than T and B cells. Susceptibility of PDCs to berberine-induced apoptosis was similar to that of MDCs. In mice with CIA, berberine treatment ameliorated arthritis, suppressed CII-specific immune responses, and selectively increased the incidence of apoptosis in DCs within spleens and lymph nodes.Conclusion. These findings show that berberine selectively induces apoptosis in DCs. Berberine may thus represent a novel therapeutic agent for RA.
We are grateful to all patients and their parents for participation in this study. We thank Petra Badorf and Daniela Hemmeter for excellent technical assistance. We acknowledge Klaus Griewank for critically reviewing the manuscript. The study was partly supported by a grant from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung (BMBF); project ANCYLOSS, TP5).
Objective: Immunoglobulin E (IgE) and its receptor, FcɛRI, importantly contribute to the pathophysiology of chronic spontaneous urticaria (CSU). Recent findings point to a possible role of total IgE as a marker of CSU disease activity, endotypes, and responses to treatment. The evidence in support of total IgE included in the diagnostic workup of patients with CSU has not yet been reviewed. Methods: Publications were searched via PubMed. The search terms used were "chronic urticaria" and "total IgE." Studies were screened by titles and abstracts, and 141 were used in the review. Results: CSU patients frequently had elevated total IgE serum levels (up to 50%), but normal or very low total IgE levels also occurred. High total IgE may represent high disease activity, longer disease duration, high chance of responding to omalizumab treatment, quick relapse after stopping omalizumab, and lower chance of responding to cyclosporine. Low IgE, in contrast, may suggest Type IIb autoimmune CSU, poor response to treatment with omalizumab and a better chance to benefits from cyclosporine treatment. Furthermore, IgE in different CSU cohorts may have different physicochemical properties that could explain differences in treatment responses to IgE-directed therapies. Conclusion: The results of our review suggest that total IgE is a valuable marker for CSU, and we recommend its assessment in the routine diagnostic workup of CSU patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.