Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe the first Finnish LCAT-deficient family with two affected, one questionably affected and one healthy family member. The affected family members presented stomatocytes in the peripheral blood, exhibited low serum levels of total, LDL and HDL cholesterol, triglycerides, phospholipids and apolipoprotein A-I and especially A-II. Apolipoprotein A-I catabolism was accelerated to moderately high and very high levels in the two affected subjects. Cholesterol esterification percentage was low in all lipoprotein fractions. The intestinal cholesterol absorption efficiency and cholesterol and bile acid synthesis were within normal limits. The esterification percentage of demethylated cholesterol precursor sterols, cholestanol and plant sterols resembled mostly that of cholesterol, while those of VLDL and LDL methostenols, precursor sterols esterified by acyl-CoA:cholesterol acyltransferase (ACAT), suggested normal ACAT activity. In HDL all sterols were poorly esterified. The observations on stomatocytes, normal absorption and synthesis of cholesterol and bile acids, abnormal kinetics of apolipoprotein A-I, evidence of normal ACAT activity and abnormal esterification of non-cholesterol sterols are findings presented for the first time in LCAT deficiency.
Atherosclerosis 1992 Jul
PMID:Non-cholesterol sterols, absorption and synthesis of cholesterol and apolipoprotein A-I kinetics in a Finnish lecithin-cholesterol acyltransferase deficient family. 164 89

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a hereditary disorder with clinical manifestations including corneal opacity, premature atherosclerosis and renal failure. In this study, we analyzed the molecular base underlying a case of Japanese LCAT deficiency, in which both LCAT mass and activity of the proband were nearly absent. DNA blot hybridization analysis showed no gross rearrangement in the LCAT gene of the proband. The nucleotide sequence analysis of the cloned LCAT gene demonstrated only an extra nucleotide "C" insertion at the first exon, when compared to the sequence of wild type. This single base insertion caused a shift of the following reading frame, probably resulting in a truncated abnormal LCAT polypeptide that consist of only 16 amino acids. The direct sequence analysis of PCR-amplified DNA showed only the same insertion, indicating that the LCAT-deficient proband is a homozygote for the mutant allele. These results indicate that the clinical and biochemical feature of the patient is mainly caused by a complete deficiency of the enzyme based on a homozygous abnormality of LCAT gene.
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PMID:Molecular defect in familial lecithin:cholesterol acyltransferase (LCAT) deficiency: a single nucleotide insertion in LCAT gene causes a complete deficient type of the disease. 166 3

A Caucasian family of mediterranean origin comprising a patient whose parents were first cousins, his wife and their three children, and his two sisters have been studied. The patient and his two daughters were afflicted with the same corneal opacities and hypoalphalipoproteinaemia. The disease was shown to be transmitted as a non-sex-linked recessive trait. The corneal opacities develop at the end of the second decade of life and consist of numerous minute greyish dots in the entire corneal stroma that give the cornea a misty appearance. Vision slowly deteriorated from 40 years of age. At about 50 years of age, except in one of the two daughters who showed Marfanoid syndrome, the three patients had good general health and no symptoms of atherosclerosis. Biochemical investigations showed hypoalphalipoproteinaemia (with a faint fast-moving HDL band on polyacrylamide gel gradient electrophoresis and small arcs of HDL2 and HDL3 of low mobility determined by agarose gel immunoelectrophoresis), low total cholesterol (3.5-4.9 mmol l-1), slightly decreased cholesteryl ester/total cholesterol ratio (0.52-0.63), extremely low HDL cholesterol (0.20-0.21 mmol l-1), mild hypertriglyceridaemia (1.94-3.80 mmol l-1), and striking deficiency in apo A-I and apo A-II (0.45-0.72, 0.08-0.16 g l-1, respectively). The esterification of HDL cholesterol was low while that of LDL and VLDL was nearly normal. Other laboratory values were normal. The HDL subspecies and major apolipoprotein isoforms have been studied to differentiate FED from Tangier disease, LCAT deficiency, as Apo A-I, A-II, C-II, C-III deficiencies and variants.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A 'Fish-eye disease' familial condition with massive corneal opacities and hypoalphalipoproteinaemia: clinical, biochemical and genetic features. 177 23

Measurement of plasma lecithin:cholesterol acyltransferase (LCAT) activity was used to segregate unaffected family members (n = 8) from heterozygotes (n = 8) and homozygotes (n = 2) in a large LCAT-deficient kindred. The activity was absent in the homozygotes and was decreased to 50% of normal in the heterozygotes. Endogenous cholesterol esterification rate measurements did not differentiate the heterozygotes from the unaffected family members or normal subjects. The heterozygotes had significantly higher fasting plasma triglycerides, apo B, and lower HDL-cholesterol and apo AI than the unaffected family members. The HDL of the heterozygotes had the same mass of free cholesterol and triglyceride, but the mass of cholesteryl ester was reduced by 47%. The differences were not related to abnormal postheparin lipolytic activities. However, cholesteryl ester transfer activity in the lipoprotein-free (d greater than 1.21 bottom) fraction of plasma was significantly (P less than .05) decreased in the heterozygotes when compared to unaffected members. We conclude that the low LCAT activity is the likely cause of the qualitative and quantitative differences in the plasma lipoproteins of the heterozygotes in this family with LCAT deficiency. However, the low HDL and apo A-I levels are not associated with either a family or personal history of premature atherosclerosis.
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PMID:Plasma lipoprotein abnormalities in heterozygotes for familial lecithin:cholesterol acyltransferase deficiency. 312 80

Bilateral corneal opacities are the first clinical sign of a familial lecithin-cholesterol acyltransferase (LCAT) deficiency and can be found in early childhood. Familial LCAT deficiency includes the following typical clinical findings: corneal opacification, proteinuria, anemia, turbid or milky plasma, very low plasma HDL, very low plasma cholesterol esters and lysolecithin, hyperlipidemia, and very low or absent LCAT enzymatic activity. Several patients have had fundus findings including angioid streaks and papilledema. This disease is autosomal recessive and has been reported in a total of 19 patients previously. Progression of the disease has resulted in premature atherosclerosis, renal failure and transplantation, decreasing visual acuity and corneal transplantation.
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PMID:Corneal opacification and lecithin-cholesterol acyltransferase (LCAT) deficiency: a case report. 647 90

Plasma unesterified cholesterol is converted to cholesteryl ester by the enzyme lecithin-cholesterol acyltransferase (LCAT). Plasma levels of LCAT were measured by a sensitive double antibody radioimmunoassay in a sample from an adult employee population, ages 20-59 years, in the Pacific Northwest. After adjusting for differences in relative body mass, women had significantly higher LCAT levels (5.90 +/- 1.06, n = 154) than men (5.49 +/- 0.89, n = 83). For ages 20-59 years, LCAT levels showed a slight association with age: r = 0.13 for men and 0.29 for women. LCAT was positively correlated with relative body mass, total cholesterol, and LDL cholesterol. Men who smoked cigarettes had significantly lower LCAT mass than men who did not smoke cigarettes. No statistical differences in mean LCAT values were found between drinkers and nondrinkers. The 5th percentile LCAT value was 4.3 micrograms/ml for both men and women not using hormones. The 95th percentile value was 7.3 micrograms/ml for men and 7.8 micrograms/ml for women regardless of hormone use. Subjects phenotypically LCAT-deficient by clinical criteria and by the absence or near absence of LCAT activity had levels of LCAT mass well below the reference values: 0.73 +/- 0.70, range 0.10 micrograms/ml to 2.65 micrograms/ml, n = 20. Parents or children of LCAT-deficient subjects, i.e., obligate heterozygotes for familial LCAT deficiency, had reduced levels: 3.59 +/- 0.69, range 2.59-4.61 micrograms/ml, n = 19.
Atherosclerosis 1982 Jun
PMID:Population-based reference values for lecithin-cholesterol acyltransferase (LCAT). 711 67

We investigated the cholesterol reducing capacity of two species of lipoproteins containing apo A-I, one containing only apo A-I (LpA-I) and the other containing apo A-I and apo A-II (LpA-I/A-II), in 7 patients (4 homozygotes and 3 heterozygotes) with familial lecithin: cholesterol acyltransferase (LCAT) deficiency. Interaction of normal LpA-I or LpA-I/A-II with macrophage foam cells induced a mass reduction in cholesterol from these cells and the cholesterol reducing capacity of LpA-I was greater than that of LpA-I/A-II. When foam cells were incubated with these lipoproteins from homozygotes or heterozygotes, the capacity of LpA-I and LpA-I/A-II particles to reduce cellular cholesterol was decreased by approx. 50% in the homozygotes but was increased by 25-50% in the heterozygotes. These results suggest that LpA-I and LpA-I/A-II isolated from homozygotes and from heterozygotes differ in their ability to accept cellular cholesterol. The former are poor and the latter good acceptors of intracellular cholesterol. We conclude that factors other than reverse cholesterol transport via apo A-I containing lipoproteins have to be considered to explain why homozygotes for LCAT deficiency are not at high risk for premature atherosclerosis.
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PMID:Evidence for impaired cellular cholesterol removal mediated by apo A-I containing lipoproteins in patients with familial lecithin: cholesterol acyltransferase deficiency. 804 42

Classic (complete) lecithin:cholesterol acyltransferase (LCAT) deficiency and Fish-eye disease (partial LCAT deficiency) are genetic syndromes associated with markedly decreased plasma levels of high density lipoprotein (HDL) cholesterol but not with an increased risk of atherosclerotic cardiovascular disease. We investigated the metabolism of the HDL apolipoproteins (apo) apoA-I and apoA-II in a total of five patients with LCAT deficiency, one with classic LCAT deficiency and four with Fish-eye disease. Plasma levels of apoA-II were decreased to a proportionately greater extent (23% of normal) than apoA-I (30% of normal). In addition, plasma concentrations of HDL particles containing both apoA-I and apoA-II (LpA-I:A-II) were much lower (18% of normal) than those of particles containing only apoA-I (LpA-I) (51% of normal). The metabolic basis for the low levels of apoA-II and LpA-I:A-II was investigated in all five patients using both exogenous radiotracer and endogenous stable isotope labeling techniques. The mean plasma residence time of apoA-I was decreased at 2.08 +/- 0.27 d (controls 4.74 +/- 0.65 days); however, the residence time of apoA-II was even shorter at 1.66 +/- 0.24 d (controls 5.25 +/- 0.61 d). In addition, the catabolism of apoA-I in LpA-I:A-II was substantially faster than that of apoA-I in LpA-I. In summary, genetic syndromes of either complete or partial LCAT deficiency result in low levels of HDL through preferential hypercatabolism of apoA-II and HDL particles containing apoA-II. Because LpA-I has been proposed to be more protective than LpA-I:A-II against atherosclerosis, this selective effect on the metabolism of LpA-I:A-II may provide a potential explanation why patients with classic LCAT deficiency and Fish-eye disease are not at increased risk for premature atherosclerosis despite markedly decreased levels of HDL cholesterol and apoA-I.
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PMID: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. 828 2

A 53-year-old man with a severely reduced HDL cholesterol level, dense corneal opacities, normal renal function, and premature coronary artery disease was investigated together with 16 members of his family. The proband was diagnosed with fish eye disease. As in previously reported patients with fish eye disease, the endogenous plasma cholesterol esterification rate was near normal, yet lecithin:cholesterol acyltransferase (LCAT) activity was almost absent when measured with exogenous HDL analogues used as substrate. Direct sequencing of the LCAT gene revealed two novel missense mutations in exon 1 and exon 4, resulting in the substitution of Pro10 with Gln (P10Q) and Arg135 with Gln (R135Q), respectively. Both missense mutations were located on different alleles. Genetic analysis by polymerase chain reaction revealed 4 carriers of the P10Q and 3 carriers of the R135Q defect. Functional assessment of both missense mutations revealed that when exogenous HDL analogues were used as substrate, the specific activity of rLCAT p10Q was 18% of wild type (WT); however, when LDL was used as substrate, the activity was 146% of WT. By contrast, rLCATR135Q was inactive against both substrates. Thus, we conclude that the LCATR135D mutation is causative for complete LCAT deficiency and that the clinical phenotype of fish eye disease seen in this patient is due to the Pro10 mutation. The presence of premature coronary artery disease in the absence of other risk factors in this new case of fish eye disease raises questions regarding the risk of atherosclerosis, which has previously been reported to be nonexistent.
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PMID:Two novel molecular defects in the LCAT gene are associated with fish eye disease. 862 Mar 46

The concentration of high density lipoproteins (HDL) is inversely related to the risk of atherosclerosis. The two major protein components of HDL are apolipoprotein (apo) A-I and apoA-II. To study the role of apoA-II in lipoprotein metabolism and atherosclerosis, we have developed three lines of C57BL/6 transgenic mice expressing human apoA-II (lines 25.3, 21.5, and 11.1). Northern blot experiments showed that human apoA-II mRNA was present only in the liver of transgenic mice. SDS-polyacrylamide gel electrophoresis and Western blot analysis demonstrated a 17.4-kDa human apoA-II in the HDL fraction of the plasma of transgenic mice. After 3 months on a regular chow, the plasma concentrations of human apoA-II were 21 +/- 4 mg/dl in the 25.3 line, 51 +/- 6 mg/dl in the 21.5 line, and 74 +/- 4 mg/dl in the 11.1 line. The concentration of cholesterol in plasma was significantly lower in transgenic mice than in control mice because of a decrease in HDL cholesterol that was greatest in the line that expressed the most apoA-II (23 mg/dl in the 11.1 line versus 63 mg/dl in control mice). There was also a reduction in the plasma concentration of mouse apoA-I (32 +/- 2, 56 +/- 9, 91 +/- 7, and 111 +/- 2 mg/dl for lines 11.1, 21.5, 25.3, and control mice, respectively) that was inversely correlated with the amount of human apoA-II expressed. Additional changes in plasma lipid/lipoprotein profile noted in line 11.1 that expressed the highest level of human apoA-II include elevated triglyceride, increased proportion of total plasma, and HDL free cholesterol and a marked (>10-fold) reduction in mouse apoA-II. Total endogenous plasma lecithin:cholesterol acyltransferase (LCAT) activity was reduced to a level directly correlated with the degree of increased plasma human apoA-II in the transgenic lines. LCAT activity toward exogenous substrate was, however, only slightly decreased. The biochemical changes in the 11.1 line, which is markedly deficient in plasma apoA-I, an activator for LCAT, are reminiscent of those in patients with partial LCAT deficiency. Feeding the transgenic mice a high fat, high cholesterol diet maintained the mouse apoA-I concentration at a normal level (69 +/- 14 mg/dl in line 11.1 compared with 71 +/- 6 mg/dl in nontransgenic controls) and prevented the appearance of HDL deficiency. All this happened in the presence of a persistently high plasma human apoA-II (96 +/- 14 mg/dl). Paradoxical HDL elevation by high fat diets has been observed in humans and is reproduced in human apoA-II overexpressing transgenic mice but not in control mice. Finally, HDL size and morphology varied substantially in the three transgenic lines, indicating the importance of apoA-II concentration in the modulation of HDL formation. The LCAT and HDL deficiencies observed in this study indicate that apoA-II plays a dynamic role in the regulation of plasma HDL metabolism.
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PMID:Functional lecithin:cholesterol acyltransferase deficiency and high density lipoprotein deficiency in transgenic mice overexpressing human apolipoprotein A-II. 863 92


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