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)

A man and his three daughters had massive corneal opacities called in their home village "fish-eye disease" because of the resemblance of the eyes to those of boiled fish. The two living daughters had the same dyslipoproteinaemia, characterised by normal serum cholesterol but raised serum triglycerides, raised very-low-density lipoproteins, strikingly high levels of low-density lipoprotein (LDL) triglycerides. LDL contained normal sized as well as abnormally large particles and a 90% reduction in the level of high-density lipoprotein (HDL) cholesterol. Lecithin:cholesterol acyltransferase (LCAT) activity and the percentage of plasma cholesterol esters were normal, with excluded LCAT-deficiency. Normal electrophoretic mobility of HDL as well as other lipoprotein findings excluded Tangier disease. The clinical and laboratory abnormalities in fish-eye disease are atherosclerosis at old age, visual impairment, and dense corneal opacification. Fish-eye disease thus differs both clinically and in its lipoprotein abnormalities from LCAT-deficiency and Tangier disease.
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PMID:Fish-eye disease. A new familial condition with massive corneal opacities and dyslipoproteinaemia. 9 Oct 22

Epidemiologic data of recent years have identified an important role of HDL deficiency in the etiology of atherosclerosis. Biochemical data suggest that some of these deficiencies may be a consequence of defects in the structural genes of HDL apolipoproteins or of plasma enzymes that modify HDL. We analyzed the genetic defect in a 42-yr-old patient suffering from corneal opacities and complete absence of HDL cholesterol but not of coronary artery disease, thus clinically resembling fish eye disease. The observation of an abnormal immunoblot banding pattern of apolipoprotein A-I (apo A-I) and of reduced lecithin: cholesterol acyltransferase (LCAT) activity in plasma led to sequence analysis of the genes for apo A-I and LCAT in this patient and his family. Direct sequencing of polymerase chain reaction amplified DNA segments containing the exons of the candidate genes, resulted in the identification of a frameshift mutation in apo A-I while the LCAT sequence was identical to the wild type. The apo A-I mutation was predictive for an extensive alteration of the COOH-terminal sequence of the encoded protein. Evidence for the release of this mutant protein into the plasma compartment and for the absence of normal apo A-I was derived from ultraviolet laser desorption/ionization mass spectrometry analysis. Our results suggest that a defective apo A-I is the causative defect in this case of HDL deficiency with corneal opacities.
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PMID:A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithin: cholesterol-acyltransferase deficiency, and corneal opacities. 189 57

This review assesses current knowledge of the clinical, genetic, and biochemical features of familial high density lipoprotein (HDL) deficiency syndromes. The focus is on HDL deficiency states occurring in the absence of severe hypertriglyceridemia or lecithin/cholesterol acyltransferase deficiency. Specific entities falling within this category include Tangier disease, familial HDL deficiency with planar xanthomas, familial apolipoprotein A-I and C-III deficiency (formerly known as apolipoprotein A-I absence), familial deficiency of apolipoprotein A-I and C-III, fish-eye disease, familial hypoalphalipoproteinemia, and apolipoprotein A-I variants (apo A-I Milano, apo A-I Marburg, apo A-I Giessen, and apo A-I Munster 1-3). Diffuse corneal opacification and premature coronary artery disease are common features in many of these kindreds. No striking clinical abnormalities have been noted in patients with currently known apolipoprotein A-I variants, possibly because these subjects are heterozygotes for their respective defects. The HDL deficiency in many of these disorders has been associated with abnormalities or deficiencies of apolipoprotein A-I. Further research will undoubtedly define the defects in all the disorders that have been described, uncover new mutations, as well as provide additional insights into the precise relationship between HDL deficiency and atherosclerosis.
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PMID:Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. 643 53

Fish eye disease (FED) is characterized by severe corneal opacities, causing impaired vision, and dyslipoproteinaemia: hypertriglyceridaemia, raised levels of very low density lipoproteins (VLDL), triglyceride enrichment of low density lipoproteins (LDL) and reduction of high density lipoproteins (HDL). The disease is described in two unrelated families. In both there was a high proportion of low HDL in relatives without eye disease. VLDL, LDL and HDL had normal electrophoretic mobilities. The concentrations of VLDL cholesterol and triglycerides were increased fivefold. LDL cholesterol levels were normal but LDL triglycerides markedly increased. HDL cholesterol was reduced by 90% as were the levels of HDL apolipoproteins. The major part of HDL cholesterol was in the HDL3 fraction. FED HDL were smaller than normal with molecular weights of 115,000 daltons. Lecithin: cholesterol acyltransferase activity and amount of cholesterol esters in serum were normal. Postheparin lipoprotein and hepatic lipases showed normal or subnormal values. Clinically FED differs from other familial conditions with deficiency of HDL such as Tangier disease, LCAT-deficiency and Milano-AI-apoprotein disease. In spite of the extremely low HDL cholesterol FED is not characterized by premature atherosclerosis. Mechanisms for the dyslipoproteinaemia are discussed.
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PMID:Fish eye disease: a new familial condition with massive corneal opacities and dyslipoproteinaemia. 680 51

Evidence is accumulating that most of the degenerative diseases that afflict humanity have their origin in deleterious free radical reactions. These diseases include atherosclerosis, cancer, inflammatory joint disease, asthma, diabetes, senile dementia and degenerative eye disease. The process of biological ageing might also have a free radical basis. Most free radical damage to cells involves oxygen free radicals or, more generally, activated oxygen species (AOS) which include non-radical species such as singlet oxygen and hydrogen peroxide as well as free radicals. The AOS can damage genetic material, cause lipid peroxidation in cell membranes, and inactivate membrane-bound enzymes. Humans are well endowed with antioxidant defences against AOS; these antioxidants, or free radical scavengers, include ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), beta-carotene, coenzyme Q10, enzymes such as catalase and superoxide dismutase, and trace elements including selenium and zinc. The eye is an organ with intense AOS activity, and it requires high levels of antioxidants to protect its unsaturated fatty acids. The human species is not genetically adapted to survive past middle age, and it appears that antioxidant supplementation of our diet is needed to ensure a more healthy elderly population.
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PMID:The role of free radicals in disease. 761 52

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

Schnyder's crystalline corneal dystrophy (SCCD) is an autosomal dominant eye disease characterized by a bilateral clouding of the central cornea, arcus lipoides and/or visible crystalline deposits of cholesterol in the stroma. There is accumulation of phospholipid, unesterified cholesterol and cholesterol ester in the corneal stroma; this is believed to be due to an imbalance in the local factors affecting lipid/cholesterol transport or metabolism. The cellular mechanism of abnormal lipid transport and metabolism in SCCD is of interest due to its potential involvement in atherosclerosis, and its implications for the pathogenesis of cerebrovascular, coronary and peripheral vascular disease as well as corneal opacification. To determine the chromosomal location of the SCCD locus, genome-wide linkage analysis has been performed in two large Swede-Finn kindreds recently identified in central Massachusetts. After analysing 300 microsatellite markers > 90% of the genome was excluded from linkage to the SCCD locus. We now report the chromosomal assignment of the gene for SCCD in both families to be 1p34.1-p36; the maximum multipoint lod-score was 8.48 in the interval between D1S214 and D1S503. From haplotype analysis, the SCCD locus lies in the 16 cM interval between markers D1S2663 and D1S228. Several candidate genes for SCCD have been localized to the 1p34.1-p36 interval.
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PMID:The gene for schnyder's crystalline corneal dystrophy maps to human chromosome 1p34.1-p36. 889 5

Lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes represent a group of rare genetic disorders of HDL metabolism that have been the subject of a large number of clinical, biochemical, and genetic studies. Of special interest are patients with LCAT-related disorders with severe HDL deficiency and the apparent absence of premature atherosclerosis. This finding is inconsistent with the general concept that low HDL cholesterol levels are an obligate risk factor for atherosclerosis. In this review, we describe 36 natural mutations in the LCAT gene that result in either familial LCAT deficiency (FLD) or the milder phenotype known as fish-eye disease (FED). We propose a new classification of the natural mutations of the LCAT gene that are described to date. The defects are divided into four classes based on both the clinical and biochemical characterization of the patient and data that were obtained from the functional assessment of the mutant proteins. We define FLD-associated mutations that underlie a complete or nearly complete loss of LCAT activity due to null mutations (Class 1), and missense mutations (Class 2), respectively. In addition, we distinguish two classes of FED-associated mutations (Classes 3, 4) that underlie a partial impairment of LCAT activity but differ in their lipoprotein substrate specificity. In addition, we review the evidence of atherosclerosis in subjects with LCAT deficiency syndromes. The observation that 6 (all males) of a total of 19 FED subjects suffered from premature CAD (as defined by < 55 years of age and < 60 years of age for women and men, respectively) challenges the earlier assumption that the FED phenotype is not associated with increased risk of CAD. However, premature CAD remains an unusual clinical complication in FLD subjects.
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PMID:The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. 916 40

Plasma of patients with Tangier disease (TD) is devoid of alpha-LpA-I (apolipoprotein A-I-containing lipoprotein), which in normolipidemic plasma constitutes the majority of high density lipoprotein (HDL). The residual amounts of apolipoprotein A-I (apo A-I) in TD plasma have electrophoretic prebeta1-LpA-I mobility. We have previously demonstrated that TD plasma does not convert prebeta1-LpA-I into alpha-LpA-I. In this study we found that plasmas of normolipidemic controls, apo A-I-deficient patients and patients with fish-eye disease, but not plasmas of six TD patients, convert biotinylated lipid-free apo A-I into alpha-LpA-I. Supplementation of plasma with free oleic acid or fatty acid free albumin neither inhibited conversion activity in normal plasmas nor reconstituted it in TD plasma. In normal plasma the conversion activity was assessed in HDL and in the lipoprotein-free fraction. The latter fraction, however, generated larger particles only in the presence of exogenous phospholipid vesicles. To obtain particles with alpha-mobility, these vesicles had to contain phosphatidylinositol and/or cholesterol. Lipoprotein-depleted TD plasma did not convert lipid-free apo A-I into alpha-LpA-I even in the presence of exogenous vesicles with phospholipids or cholesterol. Taken together we conclude that disturbed transfer of glycerophospholipds onto apo A-I or prebeta1-LpA-I prevents maturation of HDL and thereby possibly causes deficiency of HDL cholesterol in patients with TD. Moreover, the lack of alpha-LpA-I in TD plasma together with its failure to convert exogenous apo A-I into an alpha-migrating particle provide specific tests for the diagnosis of TD.
Atherosclerosis 1998 May
PMID:Lipid-free apolipoprotein (apo) A-I is converted into alpha-migrating high density lipoproteins by lipoprotein-depleted plasma of normolipidemic donors and apo A-I-deficient patients but not of Tangier disease patients. 967 68

The esterification of free cholesterol (FC) in plasma, catalyzed by the enzyme lecithin:cholesterol acyltransferase (LCAT; EC 2.3.1.43), is a key process in lipoprotein metabolism. The resulting cholesteryl esters (CE) represent the main core lipids of low (LDL) and high density lipoproteins (HDL). Primary (familial) LCAT-deficiency (FLD) is a rare autosomal recessive genetic disease caused by the complete or near absence of LCAT activity. In fish-eye disease (FED), residual LCAT activity is still detectable. Here, we describe a 32-year-old patient with corneal opacity, very low LCAT activity, reduced amounts of CE (low HDL-cholesterol level), and elevated triglyceride (TG) values. The lipoprotein pattern was abnormal with regard to lipoprotein composition and concentration, but distinct lipoprotein classes were still present. Despite of typical features of glomerular proteinuria, creatinine clearance was normal. DNA sequencing and restiction fragment analyses revealed two separate mutations in the patient's LCAT gene: a previously described G to A transition in exon 4 converting Arg140 to His, inherited from his mother, and a novel G to C transversion in exon 2 converting Gly71 to Arg, inherited from his father, indicating that M.P. was a compound heterozygote. Determination of enzyme activities of recombinant LCAT proteins obtained upon transfection of COS-7 cells with plasmids containing G71R-LCAT or wild-type LCAT cDNA revealed very low alpha- and absence of beta-LCAT activity for the G71R mutant. The identification of the novel G71R LCAT mutation supports the proposed molecular model for the enzyme implying that the "lid" domain at residues 50-74 is involved in enzyme:substrate interaction. Our data are in line with the hypothesis that a key event in the etiology of FLD is the loss of distinct lipoprotein fractions.
Atherosclerosis 2006 Jul
PMID:Compound heterozygosity (G71R/R140H) in the lecithin:cholesterol acyltransferase (LCAT) gene results in an intermediate phenotype between LCAT-deficiency and fish-eye disease. 1621 49


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