The primary genetic cause of familial hypercholesterolemia (FH) is related to mutations in the LDLR gene encoding the Low-density Lipoprotein Receptor. LDLR structure is organized in 5 different domains, including an EGF-precursor homology domain that plays a pivotal role in lipoprotein release and receptor recycling. Mutations in this domain constitute 51.7% of the total missense variants described in LDLR. The aim of the present work was to analyse how clinically significant variants in the EGF-precursor homology domain impact LDLR. The activity of sixteen LDLR variants was functionally characterized by determining LDLR expression by Western blot and LDLR expression, LDL binding capacity and uptake, and LDLR recycling activity by flow cytometry in transfected CHO-ldlA7 cells. Of the analysed variants, we found six non-pathogenic LDLR variants and ten pathogenic variants distributed as follow: three class 3 variants; four class 2 variants; and three class 5 variants. These results can be incorporated into clinical management of patients by helping guide the appropriate level of treatment intensity depending on the extent of loss of LDLR activity. This data can also contribute to cascade-screening for pathogenic FH variants.Familial hypercholesterolemia (FH; MIM# 143890) is a common genetic disorder that leads to severely high low density lipoprotein cholesterol (LDL-C) levels from birth. If untreated, FH significantly increases cardiovascular risk 1,2 and results in early onset of atherosclerosis which leads to increased risk of premature heart attack, stroke and death 3 . Among all the proteins implicated in the pathology of this disease, the low density lipoprotein receptor (LDLR) (MIM# 606945) is the most common genetic cause, and mutations within it are responsible of approximately 80-85% of FH cases 4 . To date, more than 2600 LDLR variants have been described (ClinVar database).The LDLR gene is located on the short arm of chromosome 19 (19p13.1-13.3) with a length of approximately 45 kb encoding 18 exons and 17 introns. LDLR is a protein of 839 amino acids that is synthesized in the endoplasmic reticulum (ER), where it folds and is partially glycosylated. Next, LDLR is further glycosylated in the Golgi apparatus, rendering the mature protein 5 . The LDLR is organized in five functionally distinct domains: the N-terminal ligand-binding domain, the epidermal growth factor (EGF)-precursor homology domain, the O-linked sugars containing domain, the trans-membrane and the C-terminal cytosolic domain 6 .Mutations in LDLR can impair LDLR activity at different levels and therefore are classified according to their phenotypic behaviour as: class 1 (no protein synthesis), class 2 (partial or complete retention of LDLR in the ER), class 3 (defective binding to apolipoprotein B (apoB), class 4 (defective endocytosis) and class 5 (diminished LDLR recycling capacity) 7,8 .The physiologic activity of LDLR is to carry lipoproteins into cells, most commonly low density lipoprotein (LDL) 9 . Upon LDL binding to LDLR, the li...
The use of marine sponges dates back thousands of years, and interest in these animals is increasing as new applications are discovered. Their potential is extensive, both in their ancient and still popular use as bath sponges for cosmetics and regarding the more recent discovery of bioactive secondary metabolites mainly of interest for the pharmaceutical industry and the less developed aquariology. Despite their proven biofiltration and ecosystem restoration ability and the biomass supply problem for the interested industries, few integrated multi-trophic aquaculture (IMTA) systems incorporate these invertebrates in their facilities. Therefore, in this brief review, the benefits that marine sponges could bring to rapidly growing IMTA systems are summarized, highlighting their suitability for a circular blue economy.
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