131 research outputs found
Low-Density Lipoprotein receptor: its structure, function, and mutations
No full textUptake of cholesterol, mediated by the low-density lipoprotein (LDL)-receptor, plays a crucial role in lipoprotein metabolism. The LDL-receptor is responsible for the binding and subsequent cellular uptake of apolipoprotein B- and E-containing lipoproteins. To accomplish this, the receptor has to be transported from the site of synthesis, the membranes of the rough endoplasmatic reticulum (ER), through the Golgi apparatus, to its position on the surface of the cellular membrane. The translation of LDL-receptor messenger RNA into the polypeptide chain for the receptor protein takes place on the surface-bound ribosomes of the rough ER. Immature O-linked carbohydrate chains are attached to this integral precursor membrane protein. The molecular weight of the receptor at this stage is 120.000 d. The precursor-protein is transported from the rough ER to the Golgi apparatus, where the O-linked sugar chains are elongated until their final size is reached. The molecular weight has then increased to 160.000 d. The mature LDL-receptor is subsequently guided to the "coated pits" on the cell surface. These specialized areas of the cell membrane are rich in clathrin and interact with the LDL-receptor protein. Only here can the LDL-receptor bind LDL-particles. Within 3 to 5 minutes of its formation, the LDL-particle-receptor complex is internalized through endocytosis and is further metabolized through the receptor-mediated endocytosis pathway. Mutations in the gene coding for the LDL-receptor can interfere to a varying extent with all the different stages of the posttranslational processing, binding, uptake, and subsequent dissociation of the LDL-particle-LDL-receptor complex, but invariably the mutations lead to familial hypercholesterolemia. Thus, mutations in the LDL-receptor gene give rise to a substantially varying clinical expression of familial hypercholesterolemi
Defining the challenges of FH screening for familial hypercholesterolemia
No full textThe purpose of this article is to briefly review but also to highlight the rationale, motivation, and methods in the process of identifying patients of all ages with familial hypercholesterolemia (FH), an often hidden but very important genetic disorder. Since the initiation of population screening for FH in 1994 in the Netherlands, a vast amount of experience has been gathered, addressing almost all issues that are encountered in population screenin
EFFICACY OF ALIROCUMAB IN 1,191 PATIENTS WITH A WIDE SPECTRUM OF MUTATIONS IN GENES CAUSATIVE FOR FAMILIAL HYPERCHOLESTEROLEMIA
No full textBackground: Next Generation Sequencing was performed to examine treatment response with alirocumab in patients carrying one or
more causative mutation(s) in five familial hypercholesterolemia (FH) genes.
Methods: From 6 clinical trials of alirocumab (one Phase 2, five Phase 3), 1191 patients with elevated LDL-C and phenotypic FH (including
758 treated with alirocumab) were sequenced for mutations using the SEQPRO LIPO platform in LDL receptor (LDLR), apolipoprotein B
(APOB), PCSK9 (PCSK9), LDL receptor adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 (STAP1) genes. New
mutations were confirmed by Sanger sequencing and MLPA analysis in case of large gene rearrangements in the original DNA samples.
Results: In total, 387 patients (32%) and 438 (37%) had single receptor defective and receptor negative mutations in LDLR, respectively;
46 (4%) had single mutations in APOB; 8 (0.7%) had single gain-of-function mutations in PCSK9; 2 (0.17%) were homozygous
for mutations in LDRAP1; 6 (0.5%) were double heterozygotes for mutations in both APOB and LDLR; 10 (0.8%) were compound
heterozygotes in LDLR; 1 (0.08%) was a double heterozygote for mutations in LDLR and PCSK9; 293 (25%) had no identifiable causative
mutation in any of the genes investigated. LDL-C reduction with alirocumab at week 12 was generally similar across background FH
mutations: LDLR defective heterozygotes -51.8% (N=231), LDLR negative heterozygotes -50.2% (N=289); APOB heterozygotes -45.5%
(N=26); PCSK9 heterozygotes -53.3% (N=5); subjects with no identifiable mutation -51.0% (N=171). A similar large decrease in LDL-C
was also seen in the 3 double heterozygotes (LDLR, APOB, -49.2%) and 6 potentially compound heterozygous (LDLR, -48.0%) patients.
Overall rates of TEAEs were similar for alirocumab vs controls, with a higher rate of injection site reactions with alirocumab.
Conclusions: In this large cohort of FH patients, individuals with a wide spectrum of mutations in genes causative for FH responded
substantially to alirocumab treatment. LDL-C-lowering activity by alirocumab in compound heterozygotes and double heterozygotes is likely
attributable to the presence of at least one partially functional allele
NLA Symposium on Familial Hypercholesterolemia Defining the challenges of FH Screening for familial hypercholesterolemia
No full textAbstract: The purpose of this article is to briefly review but also to highlight the rationale, motivation, and methods in the process of identifying patients of all ages with familial hypercholesterolemia (FH), an often hidden but very important genetic disorder. Since the initiation of population screening for FH in 1994 in the Netherlands, a vast amount of experience has been gathered, addressing almost all issues that are encountered in population screening
Familial Defective Apolipoprotein B-100 Is Clinically Indistinguishable From Familial Hypercholesterolemia
No full textSuccessful Genetic Screening and Creating Awareness of Familial Hypercholesterolemia and Other Heritable Dyslipidemias in the Netherlands
No full textThe genetic screening program for familial hypercholesterolemia (FH) in the Netherlands, which was embraced by the Dutch Ministry of Health from 1994 to 2014, has led to twenty years of identification of at least 1500 FH cases per year. Although funding by the government was terminated in 2014, the approach had proven its effectiveness and had built the foundation for the development of more sophisticated diagnostic tools, clinical collaborations, and new molecular-based treatments for FH patients. As such, the community was driven to continue the program, insurance companies were convinced to collaborate, and multiple approaches were launched to find new index cases with FH. Additionally, the screening was extended, now also including other heritable dyslipidemias. For this purpose, a diagnostic next-generation sequencing (NGS) panel was developed, which not only comprised the culprit LDLR, APOB, and PCSK9 genes, but also 24 other genes that are causally associated with genetic dyslipidemias. Moreover, the NGS technique enabled further optimization by including pharmacogenomic genes in the panel. Using such a panel, more patients that are prone to cardiovascular diseases are being identified nowadays and receive more personalized treatment. Moreover, the NGS output teaches us more and more about the dyslipidemic landscape that is less straightforward than we originally thought. Still, continuous progress is being made that underlines the strength of genetics in dyslipidemia, such as discovery of alternative genomic pathogenic mechanisms of disease development and polygenic contribution
Cascade screening for familial hypercholesterolemia: Practical consequences
No full textFamilial Hypercholesterolemia (FH) is an autosomal dominant disorder mainly caused by mutations in the LDLR gene, resulting in elevated serum cholesterol levels and elevated risk of premature cardiovascular disease (CVD). Timely treatment with lipid lowering medication can lower the risk of CVD to the same level of the normal population. Currently the incidence of FH is estimated at 1 in 240 persons in the Caucasian population. A diagnosis of FH can be made on the basis of clinical criteria (including LDL cholesterol and family history) or DNA testing. When a mutation is known within a family an unequivocal diagnosis can be made by DNA testing in family members at any age. Genetic cascade screening is a cost-effective way to identify patients and prevent CVD. Between 1994 until 2014 a nationwide and government subsidized cascade screening program functioned to identify FH patients in the Netherlands. During this time more than 28,000 patients with FH have been identified and entered in a central, national database. Since 2014 cascade screening has been integrated in the regular Dutch health care system. Screening, counseling and treatment are now integrated in the care as a whole of FH patients and families, coordinated by the treating physician, while the national FH database is still maintained. However, since cascade screening by actively approaching family members cannot be applied anymore because of new regulations within the healthcare system, the number of family members participating in the cascade screening program, has plummeted. With this review we would like to highlight the practical consequences of implementing and executing a cascade screening program with a special focus on the lessons learned in the Netherlands. (C) 2017 Elsevier B.V. All rights reserve
Lysosomal acid lipase A and the hypercholesterolaemic phenotype
No full textMutations in lysosomal acid lipase A (LIPA) result in two phenotypes depending on the extent of lysosomal acid lipase (LAL) deficiency: the severe, early-onset Wolman disease or the less severe cholesteryl ester storage disease (CESD). In CESD, the severity of the symptoms, hepatomegaly and hypercholesterolaemia, can be highly variable, presenting in childhood or adulthood. Therefore, it is likely that many patients are undiagnosed or misdiagnosed. Nevertheless, LAL deficiency has been recognized for more than 25 years, but adequate therapeutic strategies are limited. CESD has an estimated prevalence of one in 90,000 to 170,000 individuals in the general population, confirming the likelihood that this disease is currently underdiagnosed. A number of studies have shown that in LIPA deficient patients the hypercholesterolaemic phenotype can be attenuated using statin therapy, and favourable effects on reduction of lipid accumulation in lysosomes have been reported. Targeting lysosomal exocytosis with LAL replacement therapy was shown to be successful in animal models and recently a phase I/II study demonstrated its safety and its potential metabolic efficacy on transaminase levels. The hypercholesterolaemic phenotype in CESD can be difficult to distinguish from other known hypercholesterolaemic disorders. In the majority of CESD cases with hypercholesterolaemia favourable responses on statin treatment are observed, but the effect on reduction of lipid accumulation in lysosomes needs to be further evaluated. Combining statins with LAL replacement therapy may provide a promising approach for optimal treatment of LIPA deficiencies in the futur
Beyond the Usual Suspects: Expanding on Mutations and Detection for Familial Hypercholesterolemia
No full textIntroduction: Familial hypercholesterolemia (FH) is a highly prevalent condition, predisposing individuals to premature cardiovascular disease and with a genetic basis more complex than initially thought. Advances in molecular technologies have provided novel insights into the role of next-generation-sequencing, the assessment and classification of newly found variants, the complex genotype-phenotype correlation, and the position of FH in the context of other dyslipidaemias. Areas covered: Understanding the scope of genetic determinants of FH has expanded substantially. This article reviews the current literature on the complexity that comes with this incremental knowledge and highlights the added value of genetic testing as an addition to phenotypic diagnosis of FH. Moreover, we discuss the broad genetic basis of FH, with a focus on the three main FH genes, but we also pay attention to polygenic hypercholesterolemia as well as minor and modulator genes involved in FH. Expert opinion: Both the availability and the need for genetic analysis of FH are on the rise as costs of sequencing continue to drop and new therapies require a genetic diagnosis for reimbursement. However, greater use of genetic testing requires more education of healthcare professionals, since molecular technologies will allow for rapid and accurate evaluation of large numbers of detected variants
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