Browsing by Issue Date, starting with "2017-03-08"
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- Familial Hypercholesterolaemia: molecular and functional study of LDLR mutationsPublication . Pinto Pereira, Andreia SofiaCardiovascular disease (CVD) remains the most common cause of death globally. Dyslipidaemia is one of the most important risk factors that leads to CVD. It can be due to a monogenic condition or to polygenic/environmental causes as diabetes, obesity, tobacco use, excess of alcohol or reduced physical activity. The identification of the individuals at risk and the distinction of these two types of dyslipidaemia is important for a correct cardiovascular risk assessment, counselling, and treatment reducing, this way, cardiovascular mortality. Familial hypercholesterolaemia (FH) is an autosomal dominant disorder of cholesterol metabolism. Most commonly, FH results from inherited defects in the Low-Density Lipoprotein Receptor Gene (LDLR) leading to increased levels of circulating LDL cholesterol and lipid accumulation in arteries and tendons. Mutations in other genes as the apolipoprotein B gene (APOB) and proprotein convertase subtilisin/kexin type 9 gene (PCSK9), are also responsible for FH. The distribution pattern of apolipoprotein E gene (APOE) polymorphisms affects the affinity to lipoprotein receptors and, consequently, the clearance of dietary fat from the blood, also causing dyslipidaemia.
- How mRNA translation can modulate nonsense-mediated decayPublication . Romão, LuísaAbout one third of the gene mutations found in human genetic disorders, including cancer, result in premature translation-termination codons (PTCs) and the rapid degradation of the corresponding mRNAs by nonsense-mediated decay (NMD). However, we have found that human mRNAs with a PTC in close proximity to the translation initiation codon (AUG-proximal PTC) can substantially escape NMD, which contradicts the current models for this mechanism. In fact, our data support a model in which cytoplasmic poly(A)-binding protein 1 (PABPC1) is brought into close proximity with an AUG-proximal PTC via interactions with the translation initiation complexes. This proximity of PABPC1 to the AUG-proximal PTC allows PABPC1 to interact with eukaryotic release factor 3 (eRF3) with a consequent enhancement of the termination reaction and repression of the NMD response. Here, I will provide strong evidence that the eukaryotic initiation factor 3 (eIF3) is involved in delivering eIF4G-associated PABPC1 into the vicinity of the AUG-proximal PTC, and I will dissect the biochemical interactions of the eIF3 subunits in bridging PABPC1/eIF4G complex to the 40S ribosomal subunit.