Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages.

Background: MEFV mutations and decreased expression level of the gene are related to FMF pathology. DNA methylation at CpG islands is a well-known mechanism for transcriptional silencing. MEFV has a CpG island, spanning a part of the first intron and the whole of the second exon of the gene covering 998 bp region. Here, we tested the hypothesis that the MEFV transcript level in FMF patients correlates with its methylation level, and methylation, by allowing transcription silencing, has a role in FMF ethiopathogenesis. Methods: The study group was composed of pediatric FMF patients (N = 51) and age-gender matched healthy controls (N = 21). The relative expression level of MEFV was assessed via quantitative real-time PCR (qRT-PCR) and bisulfite sequencing (BS) was performed to analyse the methylation level quantitatively. Results: MEFV expression in FMF patients were decreased compared to healthy controls (P = 0.031). Methylation level of exon 2 of MEFV was found to be slightly higher in FMF patients compared to healthy controls (76% versus 74%) (P = 0.049). The expression level of the MEFV was negatively correlated with the methylation level of the CpG island in both FMF and healthy controls groups (cor = -0.29, P = 0.041) but more so in the FMF only group (cor = -0.36, P = 0.035). Conclusions: In this study, the relation between reduced MEFV expression level and FMF was confirmed. Observed slight increase in methylation in FMF patients, and correlation of methylation with expression might be indicative of its role in FMF, however a larger dataset is needed to confirm our preliminary findings.

Juvenile idiopathic arthritis [JIA; Mendelian Inheritance in Man (MIM) 604302] is the most common chronic childhood arthritis, characterized by chronic articular findings of unknown origin, with heterogeneity in disease course and systemic involvement1,2. Epidemiologic studies based on different diagnostic criteria showed varying prevalence from 0.07 to 4.01 per 1000 children across populations, an increased risk for European descendants, and different subtype distributions among ethnic groups3,4. JIA is generally known as a complex genetic trait with non-Mendelian inheritance pattern possibly resulting from interactions of multiple genetic loci and environmental factors5. However, several studies have reported causative variants in the Laccase (multicopper oxidoreductase) domain-containing 1 ( LACC1 ; MIM 613409) gene in rare familial forms6,7,8. We present 17 patients (10 males and 7 females) from 7 families (5 with known parental consanguinity), each with 2–4 affected members diagnosed with JIA. This study was approved by the Institutional Review Board of Istanbul Technical University (MBG.22/2014) and carried out in compliance with the Declaration Helsinki. … Address correspondence to Dr. E. Tahir Turanlı, Dr. Orhan Öcalgiray Molecular Biology-Biotechnology and Genetics Research Centre, Istanbul Technical University, Ayazağa Campus, 34469 Maslak, Istanbul, Turkey. E-mail: turanlie{at}itu.edu.tr

Anti-apoptotic members of the Bcl-2 family proteins play central roles in the regulation of cell death in glioblastoma (GBM), the most malignant type of brain tumor. Despite the advances in GBM treatment, there is still an urgent need for new therapeutic approaches. Here, we report a novel 4-thiazolidinone derivative BH3 mimetic, BAU-243 that binds to Bcl-2 with a high affinity. BAU-243 effectively reduced overall GBM cell proliferation including a subpopulation of cancer-initiating cells in contrast to the selective Bcl-2 inhibitor ABT-199. While ABT-199 successfully induces apoptosis in highBCL2-expressing neuroblastoma SHSY-5Y cells, BAU-243 triggered autophagic cell death rather than apoptosis in GBM A172 cells, indicated by the upregulation ofBECN1, ATG5, andMAP1LC3Bexpression. Lc3b-II, a potent autophagy marker, was significantly upregulated following BAU-243 treatment. Moreover, BAU-243 significantly reduced tumor growth in vivo in orthotopic brain tumor models when compared to the vehicle group, and ABT-199 treated animals. To elucidate the molecular mechanisms of action of BAU-243, we performed computational modeling simulations that were consistent with in vitro results. Our results indicate that BAU-243 activates autophagic cell death by disrupting the Beclin 1:Bcl-2 complex and may serve as a potential small molecule for treating GBM.

Many multiple sclerosis (MS)-associated common risk variants as well as candidate low-frequency and rare variants have been identified; however, approximately half of MS heritability remains unexplained. We studied seven multiplex MS families, six of which with parental consanguinity, to identify genetic factors that increase MS risk. Candidate genomic regions were identified through linkage analysis and homozygosity mapping, and fully penetrant, rare, and low-frequency variants were detected by exome sequencing. Weighted sum score and polygenic risk score (PRS) analyses were conducted in MS families (24 affected, 17 unaffected), 23 sporadic MS cases, 63 individuals in 19 non-MS control families, and 1272 independent, ancestry-matched controls. We found that familial MS cases had a significantly higher common risk variation burden compared with population controls and control families. Sporadic MS cases tended to have a higher PRS compared with familial MS cases, suggesting the presence of a higher rare risk variation burden in the families. In line with this, score distributions among affected and unaffected family members within individual families showed that known susceptibility alleles can explain disease development in some high-risk multiplex families, while in others, additional genetic contributors increase MS risk.