The Molecular Basis of Lecithin:Cholesterol Acyltransferase Deficiency Syndromes

Abstract

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...

Nephrotic Syndrome Caused by Immune-Mediated Acquired LCAT Deficiency

“…6 In FLD, plasma LCAT is either absent or completely lacks catalytic activity, whereas in fish-eye disease, the mutant LCAT exerts partial LCAT activity (i.e., it fails to exert activity on the HDL lipids, but esterifies cholesterol bound to apoB-containing lipoproteins). 7 Therefore, homozygous patients for FLD gene mutation exhibit more severe clinical manifestations, such as normochromic anemia and renal failure. 3 Renal disease is the major cause of morbidity and mortality in patients with FLD.…”

Premature and severe cardiovascular disease in a Mexican male with markedly low high-density-lipoprotein-cholesterol levels and a mutation in the lecithin:cholesterol acyltransferase gene: A family study

“…Compared to LDL from control subjects, LDL particles from carriers of two mutant LCAT alleles are smaller (12), have an abnormal composition (poor in cholesteryl esters and rich in TG and phospholipids) (38), and are more easily oxidized. Oxidation results in a cytotoxic LDL with pro-inflammatory and atherogenic properties.…”

“…In a large series of LCAT-deficient subjects, Calabresi et al (12) demonstrated that HDL particle size distribution in carriers of two mutant LCAT alleles is characterized by the lack of particles in the HDL 2 size range and the presence of a single HDL 3 subpopulation of particles, with an average size smaller than that of control HDL 3 . This is in agreement with our findings of reduced large HDL and increased small HDL subclasses, and lower HDL size in the homozygous and the Table III.…”

“…Atherosclerosis susceptibility has been extensively investigated in FED and FLD patients (10). Studies assessing the association between the inherited LCAT functional defect and CAD have been limited to measurements of only some variables, such as the HDL subclasses (11)(12) size (9) and function (13)(14), apoA-I and apoA-II plasma concentrations (9), inflammation (15), and carotid intima-media-thickness (cIMT) (15)(16). This study aimed to provide more information on the LCAT-deficient state and its association with CAD by describing LDL susceptibility to oxidation in addition to the above-mentioned variables, in a LCAT-deficient patient with severe premature CAD and his nuclear family.…”

Hypolipodemias in children

“…LCAT aktivitesi ise yoktur. Bir çalış-mada LCAT mutasyonu olan (homozigot / "compound" heterozigot) 19-70 yaş arası, 4'ü FED, 11'i klasik, LCAT eksikliği tanılı 15 erişkin hasta incelenerek, koroner kalp hastalığı (%0), hipertansiyon (%30), korneal opasite (%100), anemi (%80), böbrek hastalığı (%60) oranında saptanmıştır (36) . Tedavide total kolesterol ve trigliserit düzeyleri yüksek hastalarda hastalarda plazma lipid düzeyini düşürmeye yönelik tedavinin böbrek hastalığının ilerlemesine engel olabileceği düşünülüyor.…”