Search Results (8)

Tangier disease (TD) is an extremely rare inherited disorder involving lipoprotein metabolism and high-density lipoprotein (HDL) recycling in particular. TD is linked with a mutation of the ABCA1 gene codifying for the transport protein ABCA1 which, in normal conditions, enables the efflux of cholesterol through the cell membrane to HDL and apolipoprotein A1. As such, early cardiovascular events and neuropathy are common in these patients, mostly in homozygous carriers. Here, we describe the unique case of a homozygous TD patient whose diagnosis was made in later life. He was affected by the A1046D protein mutation and suffered from mild neurological symptoms and asymptomatic atherosclerosis. Full article

The ATP-binding cassette (ABC) transporters are a vast group of 48 membrane proteins, some of which are of notable physiological and clinical importance. Some ABC transporters are involved in functions such as the transport of chloride ions, bilirubin, reproductive hormones, cholesterol, and iron. Consequently, genetic or physiological disruption in these functions is manifested in various disease processes like cystic fibrosis, Tangier disease, and sideroblastic anemia. Among other etiologies, primary sideroblastic anemia results from a genetic mutation in the ATP-binding cassette-7 (ABCB7), a member of the ABC transporter family. There are not many articles specifically tackling the disease processes caused by ABC transporters in detail. Some testing methodologies previously reported in the available literature for investigating sideroblastic anemia need updating. Here, we expound on the relevance of ABCB7 as a clinically important ABC transporter and a rare participant in the disease process of Sideroblastic anemia. The other genetic and secondary etiologies of sideroblastic anemia, which do not involve mutations in the ABCB7 protein, are also described. We review the pathophysiology, clinical course, symptoms, diagnosis, and treatment of sideroblastic anemia with a focus on modern technologies for laboratory testing. Full article

Poor sleep quality, a global public health concern, poses a significant burden on individuals, particularly health care university students facing intense academic stress. A three-center cross-sectional study was conducted at the Higher Institute of Nursing and Health Sciences in Tetouan (Morocco), Faculty of Medicine in Tangier (Morocco) and Faculty of Nursing in Valencia (Spain). We collected various data using a sociodemographic questionnaire, the Pittsburgh sleep quality questionnaire, the international physical activity questionnaire (IPAQ) and the smartphone addiction questionnaire short-version (SAS-SV). A total of 1210 students were included in our study (mean age 20.4 years, 67.2% female, nursing students (66.2%) and medical students (33.8%), 76.1% students from Morocco and 33.9% from Spain). Analysis revealed a higher prevalence of poor sleep quality among Moroccans students compared to Spanish ones (p < 0.001), that nursing students showed less favorable sleep quality than medical students (p < 0.011) and that living with a chronic disease was linked to less favorable sleep quality (p < 0.001). Lastly, intense or weak physical activity and smartphone addiction were correlated with poor sleep quality (p < 0.001). In the multivariate analysis, an association persisted between poor sleep quality and factors such as the country of study (Odds ratio (OR): 6.25 [95% Confidence Interval (CI): 4.34–9.09]), involvement in nursing studies (OR: 3.50 [95% CI: 2.36–5.27]), and the presence of chronic diseases (OR: 2.70 [95% CI: 1.72–4.16]), (p < 0.01 each). Our findings highlight the multifaceted factors affecting sleep quality in young university students. The implications underscore the imperative of interventions tailored to this demographic group. Full article

Tangier disease (TD) is a rare autosomal recessive disorder caused by a variant in the ABCA1 gene, characterized by significantly reduced levels of plasma high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 (ApoA-I). TD typically leads to accumulation of cholesterol in the peripheral tissues and early coronary disease but with highly variable clinical expression. Herein, we describe a case study of a 59-year-old male patient with features typical of TD, in whom a likely pathogenic variant in the ABCA1 gene was identified by whole-exome sequencing (WES), identified for the first time as homozygous (NM_005502.4: c.4799A>G (p. His1600Arg)). In silico analysis including MutationTaster and DANN score were used to predict the pathogenicity of the variant and a protein model generated by SWISS-MODEL was built to determine how the homozygous variant detected in our patient may change the protein structure and impact on its function. This case study describes a homozygous variant of the ABCA1 gene, which is responsible for a severe form of TD and underlines the importance of using bioinformatics and genomics for linking genotype to phenotype and better understanding and accounting for the functional impact of genetic variations. Full article

ATP-binding cassette transporter A1 (ABCA1) has been identified as the molecular defect in Tangier disease. It is biochemically characterized by absence of high-density lipoprotein cholesterol (HDL-C) in the circulation, resulting in the accumulation of cholesterol in lymphoid tissues. Accumulation of cholesterol in arteries is an underlying cause of atherosclerosis, and HDL-C levels are inversely associated with the presence of atherosclerotic cardiovascular disease (ASCVD). ABCA1 increases HDL-C levels by driving the generation of new HDL particles in cells, and cellular cholesterol is removed in the process of HDL generation. Therefore, pharmacological strategies that promote the HDL biogenic process by increasing ABCA1 expression and activity have been intensively studied to reduce ASCVD. Many ABCA1-upregulating agents have been developed, and some have shown promising effects in pre-clinical studies, but no clinical trials have met success yet. ABCA1 has long been an attractive drug target, but the failed clinical trials have indicated the difficulty of therapeutic upregulation of ABCA1, as well as driving us to: improve our understanding of the ABCA1 regulatory system; to develop more specific and sophisticated strategies to upregulate ABCA1 expression; and to search for novel druggable targets in the ABCA1-dependent HDL biogenic process. In this review, we discuss the beginning, recent advances, challenges and future directions in ABCA1 research aimed at developing ABCA1-directed therapies for ASCVD. Full article

Rationale: While high low-density lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDL-C) levels are positively associated with cardiovascular events, it is still unclear whether familial hypercholesterolemia (FH) and Tangier’s disease (TD), caused by mutations in LDLR and ABCA1, respectively, influence ischemic stroke (IS) in humans. Objective: We sought to establish an easier, more effective, and time-saving method to induce IS, then studied the precise effects of different types of lipoproteins on IS. Methods and Results: A new technique termed contralateral middle cerebral artery occlusion (c-MCAO) was introduced to human-like hamster models to induce IS. Compared to traditional distal MCAO (d-MCAO) induced by electrocoagulation, c-MCAO resulted in a more severe IS with larger infarct sizes and more blood–brain barrier (BBB) disruption after 24 h. It was shown that c-MCAO markedly elicited an increase in brain infarct volume and BBB leakage in both homozygous LDLR (LDLR^–/–) and ABCA1 knockout (ABCA1^–/–) hamsters, but not in heterozygous LDLR knockout (LDLR^+/–) hamsters when compared to wild-type (WT) controls. Conclusions: Using human-like genetically engineered hamsters, our findings demonstrated that both high LDL-C level caused by homozygous LDLR deficiency and severe low HDL-C level caused by deleting ABCA1 were risk factors of IS. As such, we believe the development of this novel IS hamster model is suitable for future ischemic/reperfusion studies. Full article

Single nucleotide polymorphisms located in 5′ untranslated regions (5′UTRs) can regulate gene expression and have clinical impact. Recognition of functionally significant sequences within 5′UTRs is crucial in next-generation sequencing applications. Furthermore, information about the behavior of 5′UTRs during gene evolution is scarce. Using the example of the ATP-binding cassette transporter A1 (ABCA1) gene (Tangier disease), we describe our algorithm for functionally significant sequence finding. 5′UTR features (upstream start and stop codons, open reading frames (ORFs), GC content, motifs, and secondary structures) were studied using freely available bioinformatics tools in 55 vertebrate orthologous genes obtained from Ensembl and UCSC. The most conserved sequences were suggested as hot spots. Exon and intron enhancers and silencers (sc35, ighg2 cgamma2, ctnt, gh-1, and fibronectin eda exon), transcription factors (TFIIA, TATA, NFAT1, NFAT4, and HOXA13), some of them cancer related, and microRNA (hsa-miR-4474-3p) were localized to these regions. An upstream ORF, overlapping with the main ORF in primates and possibly coding for a small bioactive peptide, was also detected. Moreover, we showed several features of 5′UTRs, such as GC content variation, hairpin structure conservation or 5′UTR segmentation, which are interesting from a phylogenetic point of view and can stimulate further evolutionary oriented research. Full article

Adenosine triphosphate (ATP)-binding cassette (ABC) transporters may play an important role in the pathogenesis of atherosclerotic vascular diseases due to their involvement in cholesterol homeostasis, blood pressure regulation, endothelial function, vascular inflammation, as well as platelet production and aggregation. In this regard, ABC transporters, such as ABCA1, ABCG5 and ABCG8, were initially found to be responsible for genetically-inherited syndromes like Tangier diseases and sitosterolemia. These findings led to the understanding of those transporter’s function in cellular cholesterol efflux and thereby also linked them to atherosclerosis and cardiovascular diseases (CVD). Subsequently, further ABC transporters, i.e., ABCG1, ABCG4, ABCB6, ABCC1, ABCC6 or ABCC9, have been shown to directly or indirectly affect cellular cholesterol efflux, the inflammatory response in macrophages, megakaryocyte proliferation and thrombus formation, as well as vascular function and blood pressure, and may thereby contribute to the pathogenesis of CVD and its complications. Furthermore, ABC transporters, such as ABCB1, ABCC2 or ABCG2, may affect the safety and efficacy of several drug classes currently in use for CVD treatment. This review will give a brief overview of ABC transporters involved in the process of atherogenesis and CVD pathology. It also aims to briefly summarize the role of ABC transporters in the pharmacokinetics and disposition of drugs frequently used to treat CVD and CVD-related complications. Full article