Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate

Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction

Summary: Mutations of the transcription factor FoxP3 in patients with “IPEX” (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) disrupt regulatory T cells (Treg), causing an array of multiorgan autoimmunity. To understand the functional impact of mutations across FoxP3 domains, without genetic and environmental confounders, six human FOXP3 missense mutations are engineered into mice. Two classes of mutations emerge from combined immunologic and genomic analyses. A mutation in the DNA-binding domain shows the same lymphoproliferation and multiorgan infiltration as complete FoxP3 knockouts but delayed by months. Tregs expressing this mutant FoxP3 are destabilized by normal Tregs in heterozygous females compared with hemizygous males. Mutations in other domains affect chromatin opening differently, involving different cofactors and provoking more specific autoimmune pathology (dermatitis, colitis, diabetes), unmasked by immunological challenges or incrossing NOD autoimmune-susceptibility alleles. This work establishes that IPEX disease heterogeneity results from the actual mutations, combined with genetic and environmental perturbations, explaining then the intra-familial variation in IPEX

Aspirin Use is Associated With Lower Risk of Barrett’s Esophagus in Women

Objectives: Barrett’s esophagus (BE) is the only known precursor to esophageal adenocarcinoma. Data examining the association of aspirin with the onset of BE, particularly for women, are scant and conflicting. Methods: We leveraged data from 121,700 women enrolled in the Nurses’ Health Study, a large prospective cohort study, who biennially provided detailed information regarding endoscopy and use of aspirin. We used unconditional logistic regression to obtain multivariable (MV)-adjusted odds ratios (ORs) and 95% confidence intervals (CI) to estimate the risk of BE in regular aspirin users (≥2 times/week) compared to non-regular users. Results: Among 27,881 women who had undergone upper GI endoscopy, we documented 667 BE cases over 18 years of follow-up. Compared to non-regular users, women who regularly used aspirin had a MV-adjusted OR for BE of 0.85 (95%CI: 0.72, 0.99). The corresponding OR was 0.73 (95%CI: 0.56, 0.96) for BE at least 1 cm long. Compared with women who did not use any aspirin, the MV-adjusted OR for any BE was 0.91 (95% CI, 0.69, 1.20) for women taking 0.5-1.5 tablets/week; 0.92 (95%CI 0.76, 1.11) for 2–5 tablets/week; and 0.71 (95%CI 0.55, 0.92) for ≥6 tablets/week (p-trend=0.01). Compared with non-regular users, the MV-adjusted OR for BE risk was 0.90 (95%CI 0.67, 1.20) for women who regularly used aspirin for 1–5 years, 0.84 (95%CI 0.65, 1.09) for 6–10 years, and 0.81 (95%CI 0.67, 0.97) for >10 years (p-trend=0.03). Conclusion: Regular aspirin use was associated with a reduction in the risk of Barrett’s esophagus in women. The reduction in risk appeared related to higher dose and longer duration of use

Identification of Epigenetically Altered Genes in Sporadic Amyotrophic Lateral Sclerosis

<div><p>Amyotrophic lateral sclerosis (ALS) is a terminal disease involving the progressive degeneration of motor neurons within the motor cortex, brainstem and spinal cord. Most cases are sporadic (sALS) with unknown causes suggesting that the etiology of sALS may not be limited to the genotype of patients, but may be influenced by exposure to environmental factors. Alterations in epigenetic modifications are likely to play a role in disease onset and progression in ALS, as aberrant epigenetic patterns may be acquired throughout life. The aim of this study was to identify epigenetic marks associated with sALS. We hypothesize that epigenetic modifications may alter the expression of pathogenesis-related genes leading to the onset and progression of sALS. Using ELISA assays, we observed alterations in global methylation (5 mC) and hydroxymethylation (5 HmC) in postmortem sALS spinal cord but not in whole blood. Loci-specific differentially methylated and expressed genes in sALS spinal cord were identified by genome-wide 5mC and expression profiling using high-throughput microarrays. Concordant direction, hyper- or hypo-5mC with parallel changes in gene expression (under- or over-expression), was observed in 112 genes highly associated with biological functions related to immune and inflammation response. Furthermore, literature-based analysis identified potential associations among the epigenes. Integration of methylomics and transcriptomics data successfully revealed methylation changes in sALS spinal cord. This study represents an initial identification of epigenetic regulatory mechanisms in sALS which may improve our understanding of sALS pathogenesis for the identification of biomarkers and new therapeutic targets.</p> </div

Demographics of the subjects for methylation and expression profiling of postmortem spinal cord.

<p>(a) median (range); (b) mean ± standard deviation; PC, pulmonary complications; ASCVD, atherosclerotic cardiovascular disease; NS, not significant; NA, no data available.</p

Characteristics of sALS and control subjects used for global 5mC and 5 HmC in whole blood.

(a)<p>median (range);</p>(b)<p>mean ± standard deviation;</p>(c)<p>some patients presented more than one condition; NS, not significant; ‘–‘, value not available.</p

Confirmation of microarray differential expression in spinal cord using RT-PCR.

<p>‘Yes’ indicates the differential expression of the corresponding gene is statistically significant and demonstrated the same direction of change as in the microarray data.</p

Hyper-methylated and down-regulated concordant epigenes.

<p>Genes are ordered by expression fold change (FC). Percent methylation change (Δ5 mc (%)) is calculated by |Beta_ALS – Beta_control|/Beta_control. DiffScore (DF), Differential methylation (a transformation of the p-value; p = 0.05, p = 0.01, p = 0.001 are equivalent to DiffScore = ±13, ±20, ±30, respectively). Fold change (FC) in gene expression ‘✓’ indicates that the corresponding gene was identified as an ALS-associated gene by SciMiner (SM), the ALSoD database, and other high-throughput microarray studies (OS) on human ALS spinal cord samples, respectively. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052672#pone.0052672.s004" target="_blank">Table S2</a> more details.</p