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New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes.

ABSTRACT: Mutations of CIAS1 have recently been shown to underlie familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS), in three families and one family, respectively. These rare autosomal dominant diseases are both characterized by recurrent inflammatory crises that start in childhood and that are generally associated with fever, arthralgia, and urticaria. The presence of sensorineural deafness that occurs later in life is characteristic of MWS. Amyloidosis of the amyloidosis-associated type is the main complication of MWS and is sometimes associated with FCU. In FCU, cold exposure is the triggering factor of the inflammatory crisis. We identified CIAS1 mutations, all located in exon 3, in nine unrelated families with MWS and in three unrelated families with FCU, originating from France, England, and Algeria. Five mutations--namely, R260W, D303N, T348M, A439T, and G569R--were novel. The R260W mutation was identified in two families with MWS and in two families with FCU, of different ethnic origins, thereby demonstrating that a single CIAS1 mutation may cause both syndromes. This result indicates that modifier genes are involved in determining either a MWS or a FCU phenotype. The finding of the G569R mutation in an asymptomatic individual further emphasizes the importance of such modifier a gene (or genes) in determining the disease phenotype. Identification of this gene (or these genes) is likely to have significant therapeutic implications for these severe diseases.

SUBMITTER: Dode C

PROVIDER: S-EPMC379138 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance. METHODS:We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays. Genetic studies included linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing. RESULTS:Cold urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, the presence of antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA and circulating natural killer cells and class-switched memory B cells were reduced. Linkage analysis showed a 7-Mb candidate interval on chromosome 16q in one family, overlapping by 3.5 Mb a disease-associated haplotype in a smaller family. This interval includes PLCG2, encoding phospholipase C?(2) (PLC?(2)), a signaling molecule expressed in B cells, natural killer cells, and mast cells. Sequencing of complementary DNA revealed heterozygous transcripts lacking exon 19 in two families and lacking exons 20 through 22 in a third family. Genomic sequencing identified three distinct in-frame deletions that cosegregated with disease. These deletions, located within a region encoding an autoinhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures. CONCLUSIONS:Genomic deletions in PLCG2 cause gain of PLC?(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function. (Funded by the National Institutes of Health Intramural Research Programs and others.).

Project description:BackgroundChronic urticaria (CU) is a common skin disorder, which can be further divided into chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU). Omalizumab is effective and safe for difficult-to-treat CSU based on clinical trials. However, there are limited data comparing the therapeutic effect of omalizumab for patients with CSU, CIndU, and CSU plus CIndU. Meanwhile, there is still no reliable predictor for treatment response or relapse. Our study was conducted to collect real-world clinical data on omalizumab treatment in patients with CSU, CIndU, and both.MethodsThis was an observational, retrospective chart review of patients with CU initiating omalizumab treatment between February 2018 and May 2020 (maximum 28 months follow-up).ResultsA total of 138 patients were included, 87 with CSU alone, 33 with different forms of CIndU, and 18 with both. A total of 87.0% (n = 120/138) of the CU patients responded to omalizumab therapy, among which 65.2% (n = 90/138) of the patients showed complete response and 21.7% (n = 30/138) of the patients showed partial response. The therapeutic effect and speed of onset of effect for omalizumab were comparable among patients with CSU, CIndU, or both. Autologous serum skin test (ASST)-positive patients were more likely to show a slow response to omalizumab therapy ( P = 0.043). Non-responders had lower baseline total IgE levels (35.0 vs 121.5 kU/L, P < 0.001). The proportion of patients with low total IgE levels in non-responders was significantly higher than that of responders (61.1% vs. 14.5%, P < 0.001). Also, more non-responder patients had elevated thyroid autoantibodies than responders (50.0% vs. 23.0%, P = 0.041). The median ratio of serum IgG-anti-TPO to serum total IgE in non-responders was significantly higher compared with responders (1.22 vs. 0.09, P < 0.001). Non-responders also had shorter treatment periods (4.5 vs 6.0 months, P = 0.035) compared with responders. Two of 3 patients (67.4%, n = 29/43) experienced relapse after ceasing omalizumab therapy. These patients had longer disease durations (52.0 vs. 15.0 months, P = 0.007) and higher baseline total IgE levels (179.9 vs. 72.5 kU/L, P = 0.020) than patients who did not relapse. We reinitiated omalizumab treatment for 10 relapsed patients, all of them reported a rapid response after the first injection within the first 4 weeks of retreatment.ConclusionOmalizumab is highly effective in patients with difficult-to-treat CSU, CIndU, or both. Responders tend to have unique immunological features and longer treatment periods. Patients with higher baseline total IgE levels and longer disease durations are more likely to experience rapid relapse after discontinuation of omalizumab.

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New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes.

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