Association of interleukin-4 and interleukin-1B gene variants with Larsen score progression in rheumatoid arthritis

OBJECTIVE: To perform a genetic association study using markers in the interleukin-1 (IL-1) gene cluster and the IL-4/IL-4 receptor system genes, seeking evidence for involvement in the onset or the erosive outcome of rheumatoid arthritis (RA).METHODS: We tested the allelic distribution of IL-1A (+4845), IL-1B (-511), IL-1B (+3954), IL-1RN (+2018), IL-4 variable number of tandem repeat (VNTR), and IL-4R (+1902) in 233 patients with RA, 99 with polymyalgia rheumatica, and 148 ethnically matched controls. We analyzed the frequency of these gene variants in respect to presence of disease, but also to the degree of radiologic erosions (Larsen score) as a function of disease duration in 157 patients who had available radiographs of both hands.RESULTS: None of the 6 genetic polymorphisms was significantly different in frequency between RA patients and healthy controls or patients with polymyalgia rheumatica. Among RA patients, the rarer (#2) alleles of IL-4 VNTR and IL-1B (-511) were both associated with a milder Larsen score progression: The slope of Larsen progression in the rare allele groups diverged significantly from those of the frequent allele groups after approximately 20 years of disease duration (P < 0.001).CONCLUSION: None of the markers tested were shown to be associated with increased or decreased risk of RA. The rarer alleles of IL-4 VNTR and IL-1B (-511) appear to be associated with a less severe course in RA of long duration.     

SAC phosphoinositide phosphatases at the tonoplast mediate vacuolar function in Arabidopsis

Phosphatidylinositol (PtdIns) is a structural phospholipid that can be phosphorylated into various lipid signaling molecules, designated polyphosphoinositides (PPIs). The reversible phosphorylation of PPIs on the 3, 4, or 5 position of inositol is performed by a set of organelle-specific kinases and phosphatases, and the characteristic head groups make these molecules ideal for regulating biological processes in time and space. In yeast and mammals, PtdIns3P and PtdIns(3,5)P₂ play crucial roles in trafficking toward the lytic compartments, whereas the role in plants is not yet fully understood. Here we identified the role of a land plant-specific subgroup of PPI phosphatases, the suppressor of actin 2 (SAC2) to SAC5, during vacuolar trafficking and morphogenesis in Arabidopsis thaliana. SAC2–SAC5 localize to the tonoplast along with PtdIns3P, the presumable product of their activity. In SAC gain- and loss-of-function mutants, the levels of PtdIns monophosphates and bisphosphates were changed, with opposite effects on the morphology of storage and lytic vacuoles, and the trafficking toward the vacuoles was defective. Moreover, multiple sac knockout mutants had an increased number of smaller storage and lytic vacuoles, whereas extralarge vacuoles were observed in the overexpression lines, correlating with various growth and developmental defects. The fragmented vacuolar phenotype of sac mutants could be mimicked by treating wild-type seedlings with PtdIns(3,5)P₂, corroborating that this PPI is important for vacuole morphology. Taken together, these results provide evidence that PPIs, together with their metabolic enzymes SAC2–SAC5, are crucial for vacuolar trafficking and for vacuolar morphology and function in plants.Polyphosphoinositides (PPIs) are a class of signaling membrane lipids, comprising the phosphorylated products of phosphatidylinositol (PtdIns). PPIs perform a dual function as scaffolding signals and precursors for other molecular messengers, which, together with their specific distribution at different intracellular membranes, makes PPIs important mediators of a wide variety of cellular processes, such as membrane trafficking and homeostasis, cytoskeleton organization, nuclear signaling, and stress responses (1–5). The metabolism of PPIs is regulated by specific kinases, phosphatases, and phospholipases to tightly control the concentration and intracellular localization of different lipid pools (2, 6, 7).In yeast, two phosphoinositide (PI) types, PtdIns3P and PtdIns(3,5)P₂, and their interconversion have been shown to play crucial roles in trafficking toward the vacuole, regulation of vacuolar pH, and vacuolar membrane fusion and fission (8–11). In yeast and mammals, production and degradation of PtdIns(3,5)P₂ involve the PtdIns3P 5-kinase Fab1p/PIKfyve and the antagonistic phosphatase factor-induced gene/suppressor of actin 3 (Fig4/Sac3), respectively (8, 12–14). Impairment of genes implicated in PtdIns(3,5)P₂ metabolism has deleterious consequences in yeast, plants, and mammals (8, 15–19), demonstrating an essential function of this minor phospholipid. Recent observations also hint at a role for PPIs in plant vacuoles (18–20), but the data are scarce and remain inconclusive.Advances in deciphering various cellular roles of PIs include insights into the phosphatases responsible for hydrolyzing PPIs. A group of phosphatases, designated suppressor of actin (SAC) domain phosphatases, has been identified in lower eukaryotes, mammals, and plants (21). Whereas yeast and humans have only five genes harboring the SAC domain, the genome of the model plant Arabidopsis thaliana contains nine genes, of which some have been functionally characterized and demonstrated to be involved in the regulation of stress responses (22–24), polarized root hair expansion (3), or cell wall formation (25).Here we show that the functionally uncharacterized group of Arabidopsis SAC2–SAC5 proteins that is orthologous to the yeast Fig4p is involved in PPI metabolism. SAC2–SAC5 localize along with PtdIns3P to the tonoplast and maintain the morphology of storage and lytic vacuoles. Our results demonstrate the crucial role of PPIs and SAC domain phosphatases in the function and morphology of vacuoles in plants.     

Don’t miss patients with atypical FMR1 mutations: dysmorphism and clinical features in a boy with a partially methylated FMR1 full mutation

Fragile X syndrome characterized by intellectual disability (ID), facial dysmorphism, and postpubertal macroorchidism is the most common monogenic cause of ID. It is typically induced by an expansion of a CGG repeat in the fragile X mental retardation 1 (FMR1) gene on Xq27 to more than 200 repeats. Only rarely patients have atypical mutations in the FMR1 gene such as point mutations, deletions, or unmethylated/partially methylated full mutations. Most of these patients show a minor phenotype or even appear clinically healthy. Here, we report the dysmorphism and clinical features of a 17-year-old boy with a partially methylated full mutation of approximately 250 repeats. Diagnosis was made subsequently to the evaluation of a FMR1 premutation as the cause for maternal premature ovarian failure. Dysmorphic evaluation revealed no strikingly long face, no prominent forehead/frontal bossing, no prominent mandible, no macroorchidism, and a head circumference in the lower normal range. Acquisition of a driving license for mopeds and unaccompanied rides by public transport in his home province indicate rather mild ID (IQ?=?58). Conclusion: This adolescent demonstrates that apart from only minor ID, patients with a partially methylated FMR1 full mutation present less to absent pathognomonic facial dysmorphism, thus emphasizing the impact of family history for a straightforward clinical diagnosis.     

Impact of the Omicron variant on SARS-CoV-2 reinfections in France,March 2021 to February 2022

Since the first reports in summer 2020, SARS-CoV-2 reinfections have raised concerns about the immunogenicity of the virus, which will affect SARS-CoV-2 epidemiology and possibly the burden of COVID-19 on our societies in the future. This study provides data on the frequency and characteristics of possible reinfections, using the French national COVID-19 testing database. The Omicron variant had a large impact on the frequency of possible reinfections in France, which represented 3.8% of all confirmed COVID-19 cases since December 2021.     

A rare variant of incontinentia pigmenti - disseminated papules and vesicles

The case report of a 2 week-old Turkish girl suffering from incontinently pigmenti (IP) with atypical disseminated papules and vesicles as a rare clinical manifestation at the onset is presented.
The diagnosis result from the histological examination with eosinophilic spongiosis, the peripheral blood eosinophilia and the development of typical striated lesions is the course of the disease.