Published online before print June 30, 2005, doi: 10.1161/01.ATV.0000175751.30616.13
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
The Molecular Basis of Lecithin:Cholesterol Acyltransferase Deficiency Syndromes
A Comprehensive Study of Molecular and Biochemical Findings in 13 Unrelated Italian Families
From Center E. Grossi Paoletti (L.C., A.C., I.F., I.E., G.F.), Department of Pharmacological Sciences, University of Milano; Department of Internal Medicine (L.P., M.R., S.B.), University of Genova; Department of Internal Medicine (P.A., G.B.B.), S. Giovanni e Paolo Hospital, Venezia; Department of Clinical and Applied Medical Therapy (M.A., A.M.), University of Roma "La Sapienza"; Departments of Nephrology (G.B.) and of Pathology (S.P.), Santa Maria della Misericordia Hospital, Udine; Department of Nephrology, Dialysis, and Kidney Transplantation (G.B.), Niguarda Ca’ Granda Hospital, Milano; Nephrology Unit (G.F.), Ospedali Riuniti, Ancona; Department of Biomedical Sciences (L.G., M.G.), University of Foggia; Internal Medicine, Angiology, and Atherosclerosis (G.L., G.V.), Department of Clinical and Experimental Medicine, University of Perugia; Department of Pediatric Sciences (I.R.), University of Torino; San Raffaele Hospital (G.R.), Milano; Institute of Clinical Physiology (T.S.), CNR, Pisa; Department of Nephrology and Dialysis (A.S.), Vimercate Hospital; National Institute of Health (A.C.), Roma; Monzino Cardiologic Institute (F.V.), Milano; Department of Biomedical Sciences (S.C.), University of Modena and Reggio Emilia, Italy.
Correspondence to Guido Franceschini, Center E. Grossi Paoletti, Department of Pharmacological Sciences, Via Balzaretti 9, 20133 Milano, Italy. E-mail guido.franceschini{at}unimi.it
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
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-ß 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 HDL3 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.
The impact of mutations in the LCAT gene on the plasma lipid/lipoprotein profile was investigated in 13 families carrying 17 different LCAT mutations. The inheritance of a mutated LCAT genotype causes a gene- dose-dependent alteration in the lipid/lipoprotein profile, which is remarkably similar between subjects classified as FLD or FED.
Key Words: familial lecithin:cholesterol acyltransferase deficiency • fish eye disease • high-density lipoproteins • lecithin:cholesterol acyltransferase • mutation
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The 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 16.1 To date, 40 mutations in the human LCAT gene have been reported (HGMD; http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/119359.html). Based on strict biochemical criteria, homozygotes or compound heterozygotes for these mutations are classified into 2 distinct syndromes, familial LCAT deficiency (FLD) (MIM# 245900) and fish-eye disease (FED) (MIM# 136120).2,3 In FLD, plasma LCAT is either absent or completely lacks catalytic activity; in FED, the mutant LCAT lacks activity on HDL lipids but esterifies cholesterol bound to apolipoprotein (apo)B-containing lipoproteins. All reported FED and FLD cases have greatly reduced plasma HDL concentrations; the prevalence of coronary heart disease (CHD) may be higher in FED than FLD cases.2 Scattered reports of heterozygous carriers of LCAT mutations indicate they may have either low4,5 or normal6,7 plasma HDL cholesterol (HDL-C) levels without premature CHD. To gain a better understanding of the role of LCAT in health and disease, we started collecting cases/families with mutations in the LCAT gene. We report here the genetic and biochemical characterization of 13 families, in which 15 novel and 2 already described8,9 mutations in the LCAT gene have been identified.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
Probands 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 overnight fast. Blood and plasma aliquots were immediately frozen and stored at –80°C before shipment in dry ice for biochemical characterization and genotyping.
LCAT Gene Analysis
Please refer to supplementary data for details (please see http://atvb.ahajournals.org).
Plasma Lipids and Lipoproteins
Plasma total and unesterified cholesterol, HDL-C, and triglyceride levels were determined with standard enzymatic techniques. Plasma very-low-density lipoprotein and low-density lipoprotein (LDL) were separated by sequential ultracentrifugation. The plasma concentration of apolipoprotein (apo) A-I, A-II, and B, and of lipoprotein particles containing only apoA-I (LpA-I) and of particles containing both apoA-I and apoA-II (LpA-I: A-II) was determined by immunoturbidimetry and electroimmunodiffusion. The content of pre-ß HDL was assessed by 2-dimensional electrophoresis and expressed as percentage of total plasma apoA-I.10 LDL and HDL particle size was determined by nondenaturing polyacrylamide gradient gel electrophoresis.11
The esterification of cholesterol within endogenous lipoproteins (cholesterol esterification rate [CER]) or incorporated into an exogenous standardized substrate (LCAT activity) was determined as previously described.11,12 Plasma LCAT concentration was measured by an immunoenzymatic assay.11
Statistical Analyses
Data are reported as means±SEM, if not otherwise stated. The principal end point was the comparison of biochemical parameters between cases, heterozygous relatives, and noncarrier family members (controls). When cases were compared, the variable used for proband selection (HDL-C) was excluded. Variables with a skewed distribution were log-transformed before analysis. The gene–dose effect was assessed by ANCOVA, taking as independent variable the number of mutant alleles (0, 1, or 2) in the genotype and testing for trend. Analyses were adjusted for age, sex, and family. Post-hoc comparisons were corrected for multiple testing by the Turkey method. Correlation coefficients were calculated and the significance of the correlation determined by the Pearson method. A 2-tailed P<0.05 was considered as significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Identification of Mutations in the LCAT Gene
The pedigrees of the 13 probands’ families are shown in the Figure. DNA samples were obtained from peripheral blood leukocytes of the 13 probands, 62 relatives, and 7 spouses (Figure). Sequence analysis of probands’ DNA identified 17 different mutations (Table 1). All mutations were unique to a single family. Analysis using a computer program that predicts the effect of amino acid changes on protein function13 indicated that 77% of the identified missense mutations were likely to adversely affect protein function (Table 1). Fifteen of the identified mutations are novel; the Y83X and R147W mutations have been previously reported in an FLD patient of unknown origin and in an Italian compound heterozygote for another unidentified mutation, respectively.8,9 Overall, 15 of the 82 examined individuals carried 2 mutant LCAT alleles (9 homozygotes and 6 compound heterozygotes), 44 carried 1 mutant LCAT allele, and 23 (including 7 spouses) had a normal genotype (Figure). Analysis of 140 unrelated individuals with low, average, or high plasma HDL-C levels failed to identify any of the described mutations, indicating they are not polymorphisms.
|
|
Differential Diagnosis
Seven of the 13 probands had undetectable CER and LCAT activity and were diagnosed as FLD cases (Table 1). Three probands had detectable CER and undetectable LCAT activity, and were classified as FED cases. The remaining 3 probands had detectable CER and LCAT activity and could not be classified as either FLD or FED (Table 1).
Clinical Findings
Seven of the 13 probands were recruited by Lipid Clinics, and 6 by Departments of Nephrology. The anthropometric and clinical findings in the 15 carriers of 2 mutant LCAT alleles are shown in Table 2. None had cardiovascular disease; 5 were hypertensive and none had abnormalities of glucose metabolism. The most frequent clinical findings were bilateral corneal opacity (15/15) since early adolescence and normochromic anemia of varying severity (12/15). Nine cases (8 FLD and 1 FED) had proteinuria; 6 FLD cases had end-stage renal failure, requiring hemodialysis treatment, and 3 of them underwent an orthotopic kidney transplantation. Thirty-four of the 44 heterozygotes were apparently healthy. Five heterozygotes had high blood pressure and elevated blood lipids, and 2 were overweight and had diabetes mellitus type 2; 2 had a stroke and 1 had proteinuria caused by IgA nephropathy.
|
Biochemical Findings
Plasma samples from 66 of the 82 examined subjects were available for biochemical evaluation; these included samples from 15 carriers of 2 mutant LCAT alleles, 38 heterozygotes, and 13 noncarrier family members.
The plasma lipid/lipoprotein and LCAT levels in the 15 carriers of 2 mutant LCAT alleles are shown in Table 3. Plasma total and LDL cholesterol and triglyceride levels showed a wide interindividual variability, even among cases carrying the same mutation(s) in the LCAT gene (Table 3). No clear relationship between plasma lipid levels and differential diagnosis was found. All had remarkably low plasma HDL-C (less than fifth percentile for age- and sex-matched controls), but individual levels were quite variable among families; no significant correlation was found between HDL-C and either plasma LDL-cholesterol or triglycerides. Except for proband 2, who is homozygous for a truncating mutation at position –14 and completely lacks plasma enzyme, all cases had detectable but remarkably low plasma LCAT concentrations (Table 3); a highly significant positive correlation (R=0.814, P=0.0002) was found between plasma LCAT and HDL-C concentrations.
|
In a first analysis, the average plasma lipid, lipoprotein, and cholesterol esterification values were calculated for carriers of 2 and 1 mutant LCAT alleles, and for noncarrier family members (controls); comparisons were then made using covariance analysis, with age, sex, and family as covariates (Tables 4 and 5
). Carriers of 2 mutant LCAT alleles tended to have lower plasma total and LDL cholesterol levels and smaller LDL particles than controls, but the differences did not achieve statistical significance. Unesterified cholesterol, the unesterified/total cholesterol ratio, very-low-density lipoprotein cholesterol, and triglycerides were significantly elevated, whereas HDL-C, apoA-I, apoA-II, and apoB were significantly reduced compared with controls. The HDL-C/apoA-I ratio (0.24±0.04) was significantly lower, and the apoA-I/A-II ratio (5.57±0.64) was significantly greater than in controls (0.43±0.04 and 3.80±0.20, respectively). Plasma CER and LCAT concentration were significantly lower than in controls; LCAT activity was undetectable. The average plasma concentration of both LpA-I and LpA-I:A-II particles was significantly reduced compared with controls; the decrease in the levels of LpA-I:A-II particles was much greater (78%) than the decrease in the levels of LpA-I (51%). The plasma content of pre-ß HDL was 3.5-fold higher than in controls. The HDL particle size distribution was characterized by the lack of particles in the HDL2 size range and the presence of a single HDL3 subpopulation of particles, with an average size smaller than that of control HDL3. When carriers of 2 mutant LCAT alleles were divided in homozygotes and compound heterozygotes, no significant difference was found in any of the measured parameters. Nineteen carriers of 1 mutant LCAT allele (50%) had a low plasma HDL-C (defined as <40 mg/dL); the average plasma HDL-C and apoA-I levels in the heterozygotes were significantly lower than controls. Plasma LCAT activity was also significantly lower than in controls, whereas CER was normal.
|
|
In a second analysis, the effect of the number of copies of mutated alleles (gene–dose effect) on plasma lipid/lipoprotein and cholesterol esterification parameters was investigated by ANCOVA, with the number of mutant alleles (0, 1, or 2) as independent variable and testing for trend (Tables 4 and 5
). A mutation in the LCAT gene had a significant gene–dose-dependent effect on a number of biochemical parameters, including the plasma unesterified/total cholesterol ratio, LCAT activity and concentration, HDL cholesterol and apolipoproteins, and HDL subpopulations.
In a third analysis, a comparison was made between FLD and FED cases; no significant differences were found in the lipid/lipoprotein profile except for higher plasma unesterified cholesterol levels and unesterified/total cholesterol ratio in the former (153.2±21.3 versus 68.7±23.9 mg/dL and 0.94±0.03 versus 0.62±0.03, respectively).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In the present study, 13 families were identified carrying 17 different mutations in the LCAT gene. Forty mutations in the human LCAT gene have been reported up to now (HGMD; http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/119359.html). Most of them have been identified through the investigation of single families; general conclusions on the impact of such mutations on LCAT function in human health and disease have been attempted through a systematic review of the data published in these scattered reports.2,3 The collaboration of nephrologists and lipidologists throughout Italy allowed us to collect the largest series of families carrying mutations in the LCAT gene to date.
The 17 mutations were spread from residue –14 to 372; 2 were nonsense mutations, 2 were deletions resulting in frameshift and premature termination, and 13 were missense mutations. All missense mutations involve residues which are highly conserved in the LCAT sequence of vertebrate species for which the LCAT sequence is known.14 The effect of each amino acid substitution on protein function was predicted with the use of PolyPhen program.13 Such analysis indicated that 77% of the identified missense mutations were likely to adversely affect protein function. Previous studies using the same algorithm revealed that 
70% of missense mutations associated with a functional disorder were predicted to be damaging, compared with 32% of mutations identified in DNA samples from arbitrarily selected individuals.13,15 Thus, the proportion of LCAT missense mutations predicted to be damaging with the use of PolyPhen was comparable to that obtained for other disease-associated sequence variants.
Based on current biochemical criteria,2,3 7 of the 10 probands carrying 2 mutant LCAT alleles had FLD; only 3 had FED, probably reflecting a milder clinical phenotype3 rather than a lower prevalence of the disease in the population. The FLD cases were: (1) homozygous for a mutation that abolishes protein synthesis (a class 1 mutation according to Kuivenhoven et al2); (2) compound heterozygous for a truncating mutation (class 1 mutation) and for a damaging missense mutation that affects enzyme catalytic activity (class 2 mutation); or (3) homozygous for a missense mutation that abolishes enzyme activity (class 2 mutation). The 3 FED cases were: (1) homozygous for a damaging missense mutation (class 4 mutation); (2) compound heterozygous for benign missense mutations (class 4 mutation); or (3) compound heterozygous for a truncating (class 1 mutation) and for a damaging missense mutation (class 4 mutation).
The present study demonstrates that: (1) the inheritance of a mutated LCAT genotype causes a remarkable and gene–dose-dependent alteration in the plasma lipid/lipoprotein profile; and (2) the lipid/lipoprotein profile is indistinguishable between subjects classified as FLD or FED.
Plasma total and LDL cholesterol levels in carriers of 2 mutant LCAT alleles showed a wide interindividual variability, which may be caused by environmental, metabolic, or genetic factors.16 Elevated plasma triglycerides were a frequent finding among cases, and LCAT mutations had a gene–dose-dependent effect on plasma triglycerides and very-low-density lipoprotein cholesterol, which argues for a metabolic relationship between defective cholesterol esterification and hypertriglyceridemia. A decreased postheparin lipoprotein lipase activity has been detected in LCAT-deficient mice17 and in some FLD cases,4 suggesting that defective lipolysis may contribute to the elevated plasma triglycerides.
All carriers of 2 mutant LCAT alleles had remarkably low plasma HDL-C, apoA-I, and apoA-II levels; no significant difference was found between FLD and FED cases, confirming that the inheritance of a completely, or partially defective LCAT causes HALP.3 A remarkable variability in the severity of the HALP was, however, found among cases with different LCAT genotypes, as exemplified by the 6-fold variation in plasma HDL-C (Table 2). Such variability is clearly unrelated with the inherited defect in LCAT function, because FLD and FED cases had overlapping plasma HDL-C levels. The severe HALP in the carriers of 2 mutant LCAT alleles is associated with multiple alterations in HDL structure and particle distribution, with a selective depletion of LpAI:A-II particles, a predominance of small, pre-ß-migrating HDL3, and a complete lack of HDL2. Such changes likely reflect the accumulation in plasma of CE-poor, apoA-I-containing, discoidal HDL,18 which cannot mature into spherical HDL because of the lack of LCAT activity. These findings are consistent with an accelerated catabolism of LpA-I:A-II particles19 as a common metabolic cause of HALP in FLD and FED. With the exception of the homozygous carrier of the X-14 mutation, all FLD and FED cases had remarkably low plasma LCAT protein concentrations. The striking positive correlation between plasma LCAT and HDL-C levels suggests that HDL may function as a vehicle for LCAT in plasma, stabilizing the enzyme and preventing its catabolism. Consistent with this hypothesis is the repeated observation of partial LCAT deficiency in individuals with primary HALP caused by mutations in the apoA-I gene.12,20
The availability of a relatively large number of carriers of 2 and 1 mutant LCAT alleles allowed us to identify a significant LCAT gene–dose-dependent effect on cholesterol esterification measurements, as well as on a number of HDL-related parameters. These findings underline the importance of proper LCAT function for efficient plasma cholesterol esterification process and appropriate HDL maturation/metabolism. The inheritance of a single mutant LCAT allele leads to a biochemical phenotype intermediate between those of carriers of 2 or zero copies of mutant alleles, thus indicating that the biochemical abnormalities are expressed as codominant traits in families carrying mutations in the LCAT gene. The heterozygous carriers of mutant LCAT alleles had lower average plasma HDL cholesterol and apolipoproteins, apoA-I–containing lipoprotein particles, LCAT activity and concentration, and higher pre-ß HDL content than controls.
According to the present knowledge, the abnormalities in the HDL profile of carriers of either 2 or 1 mutant LCAT alleles are all indicative of a high CHD risk. No evidence of increased CHD in LCAT-deficient families was instead found in the present study. The association between inheritance of a functional defect in LCAT and CHD risk remains debated, based on contradictory findings in both humans and animals.2,21,22 Large follow-up studies in carriers of LCAT mutations are needed to clarify this issue.
|
Acknowledgments |
|---|
This work was supported by grants from Telethon-Italy (GGP02264 to L.C.), from Fondazione CARIPLO (to G.F.), and from Fondazione Cassa di Risparmio di Modena (to S.C.).
Received February 23, 2005; accepted June 8, 2005.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Jonas A. Lecithin cholesterol acyltransferase. Biochim Biophys Acta. 2000; 1529: 245–256.[Medline] [Order article via Infotrieve]
- Kuivenhoven JA, Pritchard H, Hill J, Frohlich J, Assmann G, Kastelein J. The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. J Lipid Res. 1997; 38: 191–205.[Abstract]
- Santamarina-Fojo S, Hoeg JM, Assmann G, Brewer HB, Jr. Lecithin Cholesterol Acyltransferase Deficiency and Fish Eye Disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Diseases. New York: McGraw-Hill; 2001: 2817–2833.
- Frohlich JJ, McLeod R, Pritchard PH, Fesmire J, McConathy WJ. Plasma lipoprotein abnormalities in heterozygotes for familial lecithin:cholesterol acyltransferase deficiency. Metabolism. 1988; 37: 3–8.[CrossRef][Medline] [Order article via Infotrieve]
- Kasid A, Rhyne J, Zeller K, Pritchard H, Miller M. A novel TC deletion resulting in Pro(260)–>Stop in the human LCAT gene is associated with a dominant effect on HDL-cholesterol. Atherosclerosis. 2001; 156: 127–132.[CrossRef][Medline] [Order article via Infotrieve]
- Funke H, von Eckardstein A, Pritchard PH, Albers JJ, Kastelein JJ, Droste C, Assmann G. A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of
-LCAT activity. Proc Natl Acad Sci U S A. 1991; 88: 4855–4859.[Abstract/Free Full Text] - Klein HG, Santamarina-Fojo S, Duverger N, Clerc M, Dumon MF, Albers JJ, Marcovina S, Brewer HB, Jr. Fish eye syndrome: a molecular defect in the lecithin-cholesterol acyltransferase (LCAT) gene associated with normal alpha-LCAT-specific activity. Implications for classification and prognosis. J Clin Invest. 1993; 92: 479–485.
- Taramelli R, Pontoglio M, Candiani G, Ottolenghi S, Dieplinger H, Catapano AL, Albers J, Vergani C, McLean J. Lecithin cholesterol acyl transferase deficiency: molecular analysis of a mutated allele. Hum Genet. 1990; 85: 195–199.[Medline] [Order article via Infotrieve]
- Klein HG, Lohse P, Duverger N, Albers JJ, Rader DJ, Zech LA, Santamarina-Fojo S, Brewer HB, Jr. Two different allelic mutations in the lecithin:cholesterol acyltransferase (LCAT) gene resulting in classic LCAT deficiency: LCAT (tyr83–>stop) and LCAT (tyr156–>asn). J Lipid Res. 1993; 34: 49–58.[Abstract]
- Favari E, Lee M, Calabresi L, Franceschini G, Zimetti F, Bernini F, Kovanen PT. Depletion of pre-{beta}-high density lipoprotein by human chymase impairs ATP-binding Cassette Transporter A1- but not Scavenger Receptor Class B Type I-mediated lipid efflux to high density lipoprotein. J Biol Chem. 2004; 279: 9930–9936.
[Abstract/Free Full Text] - Murakami T, Michelagnoli S, Longhi R, Gianfranceschi G, Pazzucconi F, Calabresi L, Sirtori CR, Franceschini G. Triglycerides are major determinants of cholesterol esterification/transfer and HDL remodeling in human plasma. Arterioscler Thromb Vasc Biol. 1995; 15: 1819–1828.
[Abstract/Free Full Text] - Franceschini G, Baio M, Calabresi L, Sirtori CR, Cheung MC. Apolipoprotein A-IMilano. Partial lecithin:cholesterol acyltransferase deficiency due to low levels of a functional enzyme. Biochim Biophys Acta. 1990; 1043: 1–6.[Medline] [Order article via Infotrieve]
- Sunyaev S, Ramensky V, Koch I, Lathe W, III, Kondrashov AS, Bork P. Prediction of deleterious human alleles. Hum Mol Genet. 2001; 10: 591–597.
[Abstract/Free Full Text] - Peelman F, Vanloo B, Verschelde JL, Labeur C, Caster H, Taveirne J, Verhee A, Duverger N, Vandekerckhove J, Tavernier J, Rosseneu M. Effect of mutations of N- and C-terminal charged residues on the activity of LCAT. J Lipid Res. 2001; 42: 471–479.
[Abstract/Free Full Text] - Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science. 2004; 305: 869–872.
[Abstract/Free Full Text] - Pisciotta L, Calabresi L, Lupattelli G, Siepi D, Mannarino MR, Moleri E, Bellocchio A, Cantafora A, Tarugi P, Calandra S, Bertolini S. Combined monogenic hypercholesterolemia and hypoalphalipoproteinemia caused by mutations in LDL-receptor and LCAT genes. Atherosclerosis 2005. In press.
- Ng DS, Xie C, Maguire GF, Zhu X, Ugwu F, Lam E, Connelly PW. Hypertriglyceridemia in lecithin-cholesterol acyltransferase-deficient mice is associated with hepatic overproduction of triglycerides, increased lipogenesis, and improved glucose tolerance. J Biol Chem. 2004; 279: 7636–7642.
[Abstract/Free Full Text] - Forte TM, Norum KR, Glomset JA, Nichols AV. Plasma lipoproteins in familial lecithin:cholesterol acyltransferase deficiency. Structure of low and high density lipoproteins as revealed by electron microscopy. J Clin Invest. 1971; 50: 1141–1148.
- Rader DJ, Ikewaki K, Duverger N, Schmidt H, Pritchard H, Frohlich JJ, Clerc M, Dumon MF, Fairwell T, Zech L, Santamarina-Fojo S, Brewer HB, Jr. Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin: cholesterol acyltransferase deficiency and fish-eye disease. J Clin Invest. 1994; 93: 321–330.
- Funke H, von Eckardstein A, Pritchard PH, Karash M, Albers JJ, Assmann G. A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithin:cholesterol acyltransferase deficiency, and corneal opacities. J Clin Invest. 1991; 87: 371–376.
- Ayyobi AF, McGladdery SH, Chan S, John Mancini GB, Hill JS, Frohlich JJ. Lecithin: cholesterol acyltransferase (LCAT) deficiency and risk of vascular disease: 25 year follow-up. Atherosclerosis. 2004; 177: 361–366.[CrossRef][Medline] [Order article via Infotrieve]
- Ng DS. Insight into the Role of LCAT from Mouse Models. Rev Endocr Metab Disord. 2004; 5: 311–318.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  V. Charlton-Menys, L. Pisciotta, P. N. Durrington, R. Neary, C. D. Short, L. Calabresi, S. Calandra, and S. Bertolini Molecular characterization of two patients with severe LCAT deficiency Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2379 - 2382. [Full Text] [PDF]
|
|
|
|
|
|
C. L. Weber, J. Frohlich, J. Wang, R. A. Hegele, and C. Chan-Yan Stability of lipids on peritoneal dialysis in a patient with familial LCAT deficiency Nephrol. Dial. Transplant., July 1, 2007; 22(7): 2084 - 2088. [Full Text] [PDF]
|
|
|
|
 |
|
 B. F. Asztalos, E. J. Schaefer, K. V. Horvath, S. Yamashita, M. Miller, G. Franceschini, and L. Calabresi Role of LCAT in HDL remodeling: investigation of LCAT deficiency states J. Lipid Res., March 1, 2007; 48(3): 592 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Favari, M. Gomaraschi, I. Zanotti, F. Bernini, M. Lee-Rueckert, P. T. Kovanen, C. R. Sirtori, G. Franceschini, and L. Calabresi A Unique Protease-sensitive High Density Lipoprotein Particle Containing the Apolipoprotein A-IMilano Dimer Effectively Promotes ATP-binding Cassette A1-mediated Cell Cholesterol Efflux J. Biol. Chem., February 23, 2007; 282(8): 5125 - 5132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Berglund Lipoprotein Metabolism: A Well-Tried Tool to Characterize Dyslipidemic Mechanisms. Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1201 - 1203. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||