Objective-To better understand the role of lecithin:cholesterol acyltransferase (LCAT) in lipoprotein metabolism through the genetic and biochemical characterization of families carrying mutations in the LCAT gene. Methods and Results-Thirteen families carrying 17 different mutations in the LCAT gene were identified by Lipid Clinics and Departments of Nephrology throughout Italy. DNA analysis of 82 family members identified 15 carriers of 2 mutant LCAT alleles, 11 with familial LCAT deficiency (FLD) and 4 with fish-eye disease (FED). Forty-four individuals carried 1 mutant LCAT allele, and 23 had a normal genotype. Plasma unesterified cholesterol, unesterified/total cholesterol ratio, triglycerides, very-low-density lipoprotein cholesterol, and pre- high-density lipoprotein (LDL) were elevated, and high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, apolipoprotein A-II, apolipoprotein B, LpA-I, LpA-I:A-II, cholesterol esterification rate, LCAT activity and concentration, and LDL and HDL 3 particle size were reduced in a gene-dose-dependent manner in carriers of mutant LCAT alleles. No differences were found in the lipid/lipoprotein profile of FLD and FED cases, except for higher plasma unesterified cholesterol and unesterified/total cholesterol ratio in the former. Conclusion-In a large series of subjects carrying mutations in the LCAT gene, the inheritance of a mutated LCAT genotype causes a gene-dose-dependent alteration in the plasma lipid/lipoprotein profile, which is remarkably similar between subjects classified as FLD or FED. Key Words: familial lecithin:cholesterol acyltransferase deficiency Ⅲ fish eye disease Ⅲ high-density lipoproteins Ⅲ lecithin:cholesterol acyltransferase Ⅲ mutation T he lecithin:cholesterol acyltransferase (LCAT) (phosphatidylcholine:sterol-O-acyltransferase; EC 2.3.1.43) enzyme is responsible for the synthesis of cholesteryl esters (CE) in plasma. 1 Through this action, LCAT plays a central role in the formation and maturation of high-density lipoproteins (HDL), and in the intravascular stage of reverse cholesterol transport, the major mechanism by which HDL modulate the development and progression of atherosclerosis. A defect in LCAT function would be expected to enhance atherosclerosis by interfering with this process.The human LCAT gene encompasses 4.2 kilobases and is localized in the q21-22 region of chromosome 16.
Methods
SubjectsProbands with primary hypoalphalipoproteinemia (HALP), defined by a plasma HDL-C level below the fifth percentile for the age-and sex-matched general population, were identified by Lipid Clinics and Departments of Nephrology throughout Italy. Plasma samples were analyzed for total and unesterified cholesterol; in 18 unrelated index cases, the results were suggestive of a defect in the LCAT gene. Genetic analysis revealed that 13 of 18 index cases carried at least 1 mutant LCAT allele. Relatives of the 13 probands were invited to participate in the study. All subjects gave an informed consent. Blood samples were collected after an overni...
Mutations in the APOA5 gene, leading to truncated apolipoprotein A-V devoid of lipid-binding domains located in the carboxy-terminal end of the protein, if present in the homozygous state, are expected to cause severe type V hyperlipidemia in patients with no mutations in LPL or APOC2 genes. If present in the heterozygous state, these mutations predispose to hypertriglyceridemia in combination with other genetic factors or pathological conditions.
Background: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by elevated plasma levels of LDLcholesterol that confers an increased risk of premature atherosclerotic cardiovascular disease. Early identification and treatment of FH patients can improve prognosis and reduce the burden of cardiovascular mortality.Aim of this study was to perform the mutational analysis of FH patients identified through a collaboration of 20 Lipid Clinics in Italy (LIPIGEN Study). Methods: We recruited 1592 individuals with a clinical diagnosis of definite or probable FH according to the Dutch Lipid Clinic Network criteria. We performed a parallel sequencing of the major candidate genes for monogenic hypercholesterolemia (LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1). Results: A total of 213 variants were detected in 1076 subjects. About 90% of them had a pathogenic or likely pathogenic variants. More than 94% of patients carried pathogenic variants in LDLR gene, 27 of which were novel. Pathogenic variants in APOB and PCSK9 were exceedingly rare. We found 4 true homozygotes and 5 putative compound heterozygotes for pathogenic variants in LDLR gene, as well as 5 double heterozygotes for LDLR/APOB pathogenic variants. Two patients were homozygous for pathogenic variants in LDLRAP1 gene resulting in autosomal recessive hypercholesterolemia. One patient was found to be heterozygous for the ApoE variant p.(Leu167del), known to confer an FH phenotype. Conclusions: This study shows the molecular characteristics of the FH patients identified in Italy over the last two years. Full phenotypic characterization of these patients and cascade screening of family members is now in progress.
Objective: Menopause is associated with critical changes in the cardiovascular system, and the possible effect of hormonal replacement therapy (HRT) on these changes is under investigation. The aim of our study was to evaluate in postmenopausal women the effects of HRT and clonidine on the response of plasma calcitonin gene-related peptide (CGRP) and plasma atrial natriuretic peptide (ANP) to the upright posture test and the saline infusion test respectively. Methods: CGRP and ANP levels were measured with specific radioimmunological assays and expressed in pmol/l (meansϮS.E.M). Design: Postmenopausal women (age 46-53 years) (n=18) were studied before and after 3 months of HRT (n=13) or clonidine treatment (n=5). Results: After HRT or clonidine treatment plasma CGRP levels (14·9Ϯ1·6 and 15·9Ϯ3·8 pmol/l) were significantly higher than before (9·8Ϯ0·6 and 10·5Ϯ1·6 pmol/l) (P<0·01). The assumption of upright posture caused no change in plasma CGRP levels before treatment, while after HRT, but not after clonidine treatment, an increase in plasma CGRP levels was observed (P<0·01 at 5 and 20 min). Basal plasma ANP levels significantly decreased after both HRT and clonidine treatment (P<0·01). In untreated women the saline infusion test did not induce any change in plasma ANP levels; a significant response to the test was restored after HRT but not after clonidine treatment (P<0·01 at 90 and 120 min).
Conclusions:The results show that some of the adaptive responses modified by menopausal changes are restored by HRT but not clonidine treatment, suggesting a modulatory role for sex steroid hormones in cardiovascular function and salt and water balance.
European Journal of Endocrinology 137 664-669
Familial hypercholesterolemia (FH) is a codominant disorder due to a variety of mutations of the low-density lipoprotein (LDL) receptor gene that result in an elevation of plasma LDL-cholesterol (LDL-C). Plasma levels of LDL-C show large interindividual variation even in subjects carrying the same mutation of the LDL receptor gene. This variability may be due to genetic factors (modifier genes). Several surveys indicate that the overall contribution of common polymorphisms of modifier genes (such as the genes encoding apolipoproteins E and B) to this variability is less than 10%. In contrast, beta-thalassemia has a profound LDL-lowering effect. This was documented in FH patients identified on the island of Sardinia, in Italy, where 12% of the inhabitants are carriers of beta-thalassemia due to a single mutation (Q39X) of the beta-globin gene that abolishes the synthesis of beta-globin chain of hemoglobin (beta(o)-thalassemia). Plasma LDL-C in FH heterozygotes carrying the beta(o)-thalassemia trait is 25% lower than in noncarriers, regardless of the LDL receptor gene mutation. It is likely that this effect is due to two main mechanisms: (1) increased uptake of LDL by the bone marrow to provide cholesterol for the increased proliferation of erythroid progenitor cells and (2) increased production of inflammatory cytokines that reduce the hepatic secretion and increase the catabolism of LDL. In view of its LDL-C-lowering effect, beta-thalassemia trait may protect FH heterozygotes against premature coronary atherosclerosis.
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