MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion

The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that mouse MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with considerably modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg133, a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.

Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype

ObjectiveThere is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration.MethodsThe candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons.ResultsIn a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons.ConclusionsWe report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.

The Interaction of Homozygote 192-bp I nsulin-like growth factor-1 ( IGF-1) Polymorphisms and C igarette Smoking to End -stage renal disease ( ESRD)

Objective: Smoking and end-stage renal disease (ESRD) are the leading public health problems in Indonesia. Smoking is a known risk factor for the development and progression of ESRD. Specific genetic polymorphisms may modify the harmful effects of cigarette smoking and may also change the inherited risk. IGF-1 CA repeat polymorphism is thought to be associated with an increased incidence of chronic kidney disease in smokers. We investigated the impact of smoking interactions with IGF-1 CA repeat polymorphism with the rate of chronic kidney disease in Yogyakarta Special Region Indonesia. (YSRI) Result: Our study found that smoking and IGF-1 genotype 192 bp are risk factors for ESRD in Indonesia. The combination of genotype 192 bp and smoking is associated with increased ESRD events. Respondents with smoking habits and 192 bp homozygous genotype are at high risk of ESRD. Smoking habit and homozygous 192 bp genotype are strongly interaction.. There was a mild interaction between respondents with smoking habits and heterozygous 192 bp and 188 bp. There was no interaction between non-smokers with heterozygous 192 bp and 188 bp of the IGF-1 gene.

Design and application of circular RNAs with protein-sponge function

Circular RNAs (circRNAs) are a class of noncoding RNAs, generated from pre-mRNAs by circular splicing of exons and functionally largely uncharacterized. Here we report on the design, expression, and characterization of artificial circRNAs that act as protein sponges, specifically binding and functionally inactivating hnRNP (heterogeneous nuclear ribonucleoprotein) L. HnRNP L regulates alternative splicing, depending on short CA-rich RNA elements. We demonstrate that designer hnRNP L-sponge circRNAs with CA-repeat or CA-rich sequence clusters can efficiently and specifically modulate splicing-regulatory networks in mammalian cells, including alternative splicing patterns and the cellular distribution of a splicing factor. This new strategy can in principle be applied to any RNA-binding protein, opening up new therapeutic strategies in molecular medicine.

EGFR Polymorphism and Survival of NSCLC Patients Treated with TKIs: A Systematic Review and Meta-Analysis

Tyrosine kinase inhibitor- (TKI-) based therapy revolutionized the overall survival and the quality of life in non-small-cell lung cancer (NSCLC) patients that have epidermal growth factor receptor (EGFR) mutations. However, EGFR is a highly polymorphic and mutation-prone gene, with over 1200 single nucleotide polymorphisms (SNPs). Since the role of EFGR polymorphism on the treatment outcome is still a matter of debate, this research analyzed the available literature data, according to the PRISMA guidelines for meta-analyses. Research includes PubMed, Scopus, ISI Web of Science, and 14 of genome-wide association studies (GWAS) electronic databases in order to provide quantitative assessment of the association between ten investigated EGFR SNPs and the survival of NSCLC patients. The pooled HR and their 95% CI for OS and PFS for different EGFR polymorphisms using a random or fixed effect model based on the calculated heterogeneity between the studies was applied. The longest and the shortest median OSs were reported for the homozygous wild genotype and a variant allele carriers for rs712829 (-216G>T), respectively. Quantitative synthesis in our study shows that out of ten investigated EGFR SNPs (rs11543848, rs11568315, rs11977388, rs2075102, rs2227983, rs2293347, rs4947492, rs712829, rs712830, and rs7809028), only four, namely, rs712829 (-216G>T), rs11568315 (CA repeat), rs2293347 (D994D), and rs4947492, have been reported to affect the outcome of TKI-based NSCLC treatment. Of these, only -216G>T and variable CA repeat polymorphisms have been confirmed by meta-analysis of available data to significantly affect OS and PFS in gefitinib- or erlotinib-treated NSCLC patients.

Major Adverse Cardiac Events after first time elective isolated Coronary Artery

Background Major adverse cardiovascular events (MACE) are useful endpoints to evaluate cardiovascular outcomes. The aim of this study was to report our results in concordance with the expected improvement of records after using the online Research Electronic Data Capture (RedCap) software. Methods: We included patients who benefited from first time elective isolated coronary bypass grafting (CABG) at Ain-Shams university main hospital, in the period between April 2014 and April 2016; providing a minimum 2 years follow-up . Incidences, risk factors and independent predictors for MACE were calculated including; mortality, the occurrence or re-hospitalization for: heart failure, recurrence of angina or myocardial infarction (MI), cerebrovascular stroke (CVS), need of coronary angiography (CA), repeat percutaneous intervention (PTCA) or CABG. Results: 607 cases met our inclusion criteria and 105 patients (18.7%) developed 184 MACE, including 45 hospital mortalities (7.4%), 13 late mortalities (2.1%) and 126 non-fatal events recorded in 47 patients (7.7%); a majority (40 patients; 6.6%) had suffered from at least 3 non-fatal events. Two-years follow-up was complete for the 562 hospital survivors with a total of 1113 patient-years. The annualized incidence rates of ICU admission, repeated angina or MI, need for CA, PTCA, or CABG, development of CVS, heart failure, and late mortality were: 3.6%, 2.8%, 1.8%, 0.5%, 0.09%, 0.35%, 2% and 1.2% per patient-year; respectively. Independent predictors of hospital mortality were: advanced age at surgery (OR 1.06: 1-1.12; P = 0.049), female sex (OR 3.4: 1.3-8.9; P = 0.01), prolonged durations of: cardiopulmonary bypass CPB (OR 1.02: 1.01- 1.04; P < 0.001), mechanical ventilation (OR 1.07: 1.04- 1.09; P < 0.001) positive inotropic support (OR 1.03: 1.02- 1.05; P < 0.001) and ICU stay (OR 1.09: 1.07- 1.11; P < 0.001). Independent predictors of overall MACE were advanced age at surgery (OR 1.04: 1.01-1.07; P = 0.011), prolonged durations of: aortic cross clamp (OR 1.09: 1.04-1.11; P = 0.003), CPB (OR 1.06: 1.04-1.08; P < 0.001) and mechanical ventilation (OR 1.02: 1.01-1.03; P < 0.001). Conclusion: Our results suggested that more care should be given to females, elderly and to shorten and improve the quality of our operative times. The repetition of non-fatal MACE could be modified by closer observation of the patient, once developing his first event.

Polymorphisms and endometriosis: a systematic review and meta-analyses

BACKGROUND Endometriosis is an estrogen-dependent gynecological disorder that affects at least 10% of women of reproductive age. It may lead to infertility and non-specific symptoms such as chronic pelvic pain. Endometriosis screening and diagnosis are difficult and time-consuming. Late diagnosis (with a delay ranging from 3.3 to 10.7 years) is a major problem and may contribute to disease progression and a worse response to treatment once initiated. Efficient screening tests might reduce this diagnostic delay. As endometriosis is presumed to be a complex disease with several genetic and non-genetic pathogenic factors, many researchers have sought to identify polymorphisms that predispose to this condition. OBJECTIVE AND RATIONALE We performed a systematic review and meta-analysis of the most regularly reported polymorphisms in order to identify those that might predispose to endometriosis and might thus be of value in screening. SEARCH METHODS The MEDLINE database was searched for English-language publications on DNA polymorphisms in endometriosis, with no date restriction. The PubTator text mining tool was used to extract gene names from the selected publications’ abstracts. We only selected polymorphisms reported by at least three studies, having applied strict inclusion and exclusion criteria to their control populations. No stratification based on ethnicity was performed. All steps were carried out according to PRISMA guidelines. OUTCOMES The initial selection of 395 publications cited 242 different genes. Sixty-two genes (corresponding to 265 different polymorphisms) were cited at least in three publications. After the application of our other selection criteria (an original case-control study of endometriosis, a reported association between endometriosis and at least one polymorphism, data on women of reproductive age and a diagnosis of endometriosis in the cases established by surgery and/or MRI and confirmed by histology), 28 polymorphisms were eligible for meta-analysis. Only five of the 28 polymorphisms were found to be significantly associated with endometriosis: interferon gamma (IFNG) (CA) repeat, glutathione S-transferase mu 1 (GSTM1) null genotype, glutathione S-transferase pi 1 (GSTP1) rs1695 and wingless-type MMTV integration site family member 4 (WNT4) rs16826658 and rs2235529. Six others showed a significant trend towards an association: progesterone receptor (PGR) PROGINS, interCellular adhesion molecule 1 (ICAM1) rs1799969, aryl-hydrocarbon receptor repressor (AHRR) rs2292596, cytochrome family 17 subfamily A polypeptide 1 (CYP17A1) rs743572, CYP2C19 rs4244285 and peroxisome proliferator-activated receptor gamma (PPARG) rs1801282), and 12 showed a significant trend towards the lack of an association: tumor necrosis factor (TNF) rs1799964, interleukin 6 (IL6) rs1800796, transforming growth factor beta 1 (TGFB1) rs1800469, estrogen receptor 1 (ESR1) rs2234693, PGR rs10895068, FSH receptor (FSHR) rs6166, ICAM1 rs5498, CYP1A1 rs4646903, CYP19A1 rs10046, tumor protein 53 (TP53) rs1042522, X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) rs25487 and serpin peptidase inhibitor clade E member 1 (SERPINE1) rs1799889; however, for the 18 polymorphisms identified in the latter two groups, further studies of the potential association with the endometriosis risk are needed. The remaining five of the 28 polymorphisms were not associated with endometriosis: glutathione S-transferase theta 1 (GSTT1) null genotype, vascular endothelial growth factor alpha (VEGFA) rs699947, rs833061, rs2010963 and rs3025039. WIDER IMPLICATIONS By carefully taking account of how the control populations were defined, we identified polymorphisms that might be candidates for use in endometriosis screening and polymorphisms not associated with endometriosis. This might constitute the first step towards identifying polymorphism combinations that predispose to endometriosis (IFNG (CA) repeat, GSTM1 null genotype, GSTP1 rs1695, WNT4 rs16826658 and WNT4 rs2235529) in a large cohort of patients with well-defined inclusion criteria. In turn, these results might improve the diagnosis of endometriosis in primary care. Lastly, our present findings may enable a better understanding of endometriosis and improve the management of patients with this disease.