Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several families with an early-onset form of familial Alzheimer's disease have been found to harbour mutations at a specific codon (717) of the gene for the beta-amyloid precursor protein (APP) on chromosome 21. We now report, a novel base mutation in the same exon of the APP gene which co-segregates in one family with presenile dementia and cerebral haemorrhage due to cerebral amyloid angiopathy. The mutation results in the substitution of alanine into glycine at codon 692. These results suggest that the clinically distinct entities, presenile dementia and cerebral amyloid angiopathy, can be caused by the same mutation in the APP gene.
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PMID:Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. 130 39

The isolated amyloid substance in hereditary cystatin C amyloid angiopathy (HCCAA) is mainly composed of a cystatin C variant devoid of the 10 amino terminal amino acid residues of extracellular cystatin C from healthy individuals. We have developed a procedure for protein sequencing directly from agarose gel electropherograms and used this in conjunction with isoelectric focusing to investigate the amino terminal sequence of cerebrospinal fluid (CSF) cystatin C in HCCAA patients. The amino-terminal sequence determined for cystatin C from a HCCAA patient CSF sample, Xaa-Ser-Pro-Gly-Lys-Pro-Pro-Xaa-Leu-Val-Gly-Gly-Pro-Met-Xaa-Ala-Xaa-Val, showed that the protein was not amino-terminally truncated. CSF cystatin C from all nine HCCAA patients investigated was found to have an isoelectric point identical to that of native cystatin C, and the truncated form of cystatin C isolated from amyloid deposits was shown to contribute to less than 1% of the total amount of cystatin C in CSF. The total cysteine proteinase inhibitory capacity of CSF from HCCAA patients was lower than that of CSF from other patients. This decreased CSF inhibitory capacity in HCCAA patients was caused by decreased levels of cystatin C, since the levels of the other two cysteine proteinase inhibitors found in CSF, alpha 2-macroglobulin and kininogen, were significantly higher than in CSF from non-HCCAA patients.
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PMID:The amino terminal portion of cerebrospinal fluid cystatin C in hereditary cystatin C amyloid angiopathy is not truncated: direct sequence analysis from agarose gel electropherograms. 231 47

The cardinal lesions of Alzheimer's disease are neurofibrillary tangles, senile neuritic plaques, and vascular amyloid, the latter generally involving cortical arteries and small arterioles. All three lesions are composed of amyloid-like, beta-pleated sheet fibrils. Recently, a 4,200-dalton peptide has been isolated from extraparenchymal meningeal vessels, neuritic plaques, and neurofibrillary tangles. The assumption of N-terminal homogeneity in vascular amyloid has been used as an argument for a neuronal (versus blood) origin of the peptide. However, intracortical microvessels from Alzheimer's disease have not been previously isolated. The present studies describe the isolation of a microvessel fraction from Alzheimer's disease and control fresh autopsy human brain. Alzheimer's disease isolated brain microvessels that were extensively laden with amyloid and control microvessels were solubilized in 90% formic acid and analyzed by urea sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The arteriole fraction from the Alzheimer's subject with extensive amyloid angiopathy contained a unique 4,200-dalton peptide, whereas the arterioles or capillaries isolated from two controls and two Alzheimer's disease subjects without angiopathy did not. This peptide was purified by HPLC and amino acid composition analysis showed the peptide is nearly identical to the 4,200-dalton peptide recently isolated from neuritic plaques or from neurofibrillary tangles. Sequence analysis revealed N-terminal heterogeneity. The N-terminal sequence was: Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr, which is identical to the N-terminal sequence of the 4,200-dalton peptide isolated previously from extraparenchymal meningeal vessels and neuritic plaques.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Amyloid angiopathy of Alzheimer's disease: amino acid composition and partial sequence of a 4,200-dalton peptide isolated from cortical microvessels. 331 95

Increased levels of homocysteine have been linked to both arterial and venous thromboembolic problems (1,2). Homocystinuria is a relatively rare disorder caused by a deficiency of cystathione synthase and is characterized by markedly increased levels of homocysteine and premature vascular disease (3-5). Epidemiological studies have suggested that mild elevations of homocysteine are also associated with vascular disease (2). Recent evidence suggests that a polymorphism of the gene encoding for 5,10-methylene tetrahydrofolate reductase (MTHFR) gives rise to a thermolabile form of the enzyme that is associated with increased levels of homocysteine when inherited as a homozygous trait (6). This polymorphism is due to a C --> T substitution at nucleotide 677 which converts an alanine to valine in a conserved portion of the molecule (6). The allele frequency for the thermolabile form of the enzyme was quite high (0.38) in a population of French Canadians. This polymorphism thus appears to be a common risk factor for increased plasma levels of homocysteine and vascular diseases. As the incidence of such genetic polymorphisms often varies among ethnic populations, we were interested in comparing the incidence of this polymorphism in Caucasians and African Americans.
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PMID:The incidence of the gene for thermolabile methylene tetrahydrofolate reductase in African Americans. 883 19

An increased total plasma homocysteine level is an established risk factor for atherosclerotic vascular disease. The plasma level of homocysteine is influenced by both environmental and genetic factors. An important genetic determinant of plasma homocysteine is a common amino acid dimorphism (Ala222Val) in the methylenetetrahydrofolate reductase (MTHFR) gene. Individuals homozygous for the Val allele have significantly higher homocysteine levels than those with an Ala/Val or Ala/Ala genotype. Moreover, the Val/Val genotype has been claimed to be a strong genetic risk factor for atherosclerosis. The aim of the present study is: (1) to determine the risk associated with the MTHFR dimorphism by comparing the genotype distribution in patients with premature atherosclerosis with that in a group of healthy controls; and (2) to investigate the relationship between the MTHFR genotype and parameters of homocysteine metabolism. The patient group consisted of 257 consecutive referred individuals with angiographically proven premature ( <50 years of age) arterial disease (coronary, and/or peripheral vascular disease). A total of 272 healthy hospital workers without a history of vascular disease were selected as a control group. The MTHFR-genotype was determined by PCR and gel-electrophoresis. A methionine-loading test was performed on 245 patients, and, in addition to homocysteine, levels of folate and vitamin B12 were measured. We found a strong correlation between MTHFR genotype and plasma homocysteine levels both before and after methionine loading. In addition, the MTHFR genotype seems important for the inverse relationship between homocysteine and folate and vitamin B12 levels. Lastly, the MTHFR genotype distribution was not different between patient and control groups. MTHFR genotype is a strong determinant of plasma homocysteine levels. Moreover, the plasma level of folate, which by itself influences homocysteine levels, is also dependent on the MTHFR genotype. In Val/Val genotypes, low levels of both folate and B12 lead to a relatively large increase in homocysteine levels. Nevertheless, the MTHFR genotype does not increase the risk for premature coronary artery disease.
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PMID:The effect of a common methylenetetrahydrofolate reductase mutation on levels of homocysteine, folate, vitamin B12 and on the risk of premature atherosclerosis. 986 49

We assessed the contribution of serum homocysteine levels, an independent risk factor for vascular disease, and of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation to the variability of carotid intimal-medial thickness (IMT) in patients with non-insulin-dependent diabetes mellitus (NIDDM). Ninety-five patients (33 males and 62 females, mean age 53 +/- 10 years) without nephropathy or other vascular complications were enrolled. Fasting total serum homocysteine and other biochemical analytes were measured. The MTHFR polymorphism was determined by the polymerase chain reaction. Common carotid IMT and plaques or stenoses in the carotid district were measured by ultrasonography. Serum total homocysteine concentrations were higher in subjects with the mutant (Val/Val) genotype than in those with the Ala/Val plus Ala/Ala genotypes (P = 0.02). On univariate analysis, carotid IMT was significantly associated with age, body mass index (BMI), systolic blood pressure, and total cholesterolemia. No significant association was found between IMT and serum homocysteine or the MTHFR polymorphism, although a slightly greater IMT was observed in the homozygous Val genotypes. On multiple regression analysis, only age and BMI were independently associated with IMT and explained about 40% of IMT variability. The results did not change when the analysis was restricted to the subgroups with or without atherosclerotic plaques in the carotid district. In 95 Italian NIDDM patients without nephropathy, neither basal levels of serum total homocysteine nor the MTHFR C677T polymorphism predicted significant changes in common carotid intimal-medial thickness.
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PMID:Serum homocysteine, MTHFR gene polymorphism, and carotid intimal-medial thickness in NIDDM subjects. 1050 Mar 10

Homocysteine is a sulphur-containing amino acid that is derived primarily from protein of animal origin. Classical homocystinuria is an inherited metabolic disorder that arises from defects in either the re-methylation or trans-sulphuration pathways of homocysteine metabolism and leads to skeletal abnormalities, mental retardation and a high risk of vascular disease. In contrast, moderate hyperhomocysteinaemia is associated with an increased risk of both arterial and venous thrombotic disease but no other abnormalities. This increased risk appears to be independent of other conventional risk factors. Many cases of hyperhomocysteineaemia have been attributed to defects in the enzyme cystathionine-beta-synthase (CBS) but this accounts for less than 1.5% of cases. A thermolabile variant of the enzyme methylenetetrahydrofolate reductase (MTHFR) arises from a C --> T transition at nucleotide 677 in the MTHFR gene resulting in an alanine-to-valine substitution. While the mutation does not appear to be associated with an increased risk of vascular disease, it results in excessively high homocysteine levels in response to a low or low-normal serum folate. Supplementation of the diet with folate, B6 and B12 can reduce homocysteine levels and this is the mainstay of treatment. Supplementation of grain with folate is undertaken in the USA to reduce the risk of neural tube defects in pregnant women. However, by reducing plasma homocysteine levels, it is estimated that this will save up to 50,000 lives per annum.
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PMID:Hyperhomocysteinaemia. 1085 81

We assessed the contribution of the serum homocysteine (Hcy) level, an independent risk factor for vascular disease, and methylene tetrahydrofolate reductase (MTHFR) gene polymorphism to the variability of intimal-medial thickness (IMT) of the common carotid artery in middle-aged non-insulin-dependent diabetes mellitus (NIDDM) subjects. One hundred thirty NIDDM patients (60 males and 70 females) with a mean age of 53 +/- 10 years and a mean diabetes duration of 11.3 +/- 7.9 years were enrolled for the study. Exclusion criteria included liver, heart, kidney, or other major-organ disease. Fasting total serum Hcy, folate, and vitamin B12 and clinical chemistry analyte levels were measured. MTHFR polymorphism was determined by polymerase chain reaction (PCR). IMT and plaques or stenosis in the common carotid were measured by ultrasonography. Serum Hcy was inversely correlated with vitamin levels and was slightly higher in subjects with the Val/Val genotype versus Ala/Val and Ala/Ala (P = .02); no differences in genotype were found in subjects with folate or vitamin B12 at or above the median level. In univariate analysis, common carotid IMT was significantly associated with age (P = .00001), the body mass index ([BMI] P = .0003), uric acid (P = .004), systolic blood pressure (P = .03), glycemia (P = .03), and total cholesterol (P = .04). No significant association was found between serum Hcy or MTHFR polymorphism and IMT. In multiple regression analysis, age (P = .0001), uric acid (P = .03), glycemia, and the BMI (P = .05) were independently associated with IMT and explained about 42% of IMT variability. In 130 NIDDM patients without nephropathy, basal levels of serum Hcy, as well as MTHFR polymorphism, did not predict significant changes in common carotid IMT.
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PMID:Lack of association between carotid intima-media thickness and methylenetetrahydrofolate reductase gene polymorphism or serum homocysteine in non-insulin-dependent diabetes mellitus. 1087 95

Methylenetetrahydrofolate reductase (MTHFR) catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor for homocysteine remethylation to methionine. Severe MTHFR deficiency is associated with hyperhomocysteinemia and homocystinuria. These patients show a wide variety of neurological and vascular symptoms, with variable age of onset. Residual enzyme activity is usually less than 20% of control values, and correlates reasonably well with age of onset of symptoms. A milder deficiency of MTHFR, with 30%-50% residual enzyme activity and increased enzyme thermolability, has been described as a risk factor for vascular disease and for neural tube defects. In earlier work, we isolated the human cDNA for MTHFR, and reported 14 mutations in severe MTHFR deficiency, as well as a common 677C-->T missense mutation (Ala-->Val) that encodes the thermolabile MTHFR. This variant has also been observed in some patients with severe MTHFR deficiency, in cis with their severe mutations. We report here the in vitro expression of seven severe MTHFR mutations in a bacterial expression system; six of these were expressed in cis with the Val allele to mimic the situation in the patients. We show that three of these constructs have significantly reduced enzyme activity (<10% of control); the presence of the thermolabile variant in these patients in cis is unlikely to affect enzyme function since activity is already low. One mutation causes a dramatic increase in activity when it is expressed in cis with the Ala allele, but is associated with extreme lability when in cis with the Val allele. Three mutations cause moderate decreases in enzyme activity, with a further decrease in activity when they are in cis with the Val allele. We hypothesize that deleterious mutations which alter stability may be compromised to a greater degree when the thermolabile variant is present on the same allele.
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PMID:The thermolabile variant 677C-->T can further reduce activity when expressed in cis with severe mutations for human methylenetetrahydrofolate reductase. 1092 34

With the identification of hyperhomocysteinemia as a risk factor for cardiovascular disease, an understanding of the genetic determinants of plasma homocysteine is important for prevention and treatment. It has been known for some time that homocystinuria, a rare inborn error of metabolism, can be due to genetic mutations that severely disrupt homocysteine metabolism. A more recent development is the finding that milder, but more common, genetic mutations in the same enzymes might also contribute to an elevation in plasma homocysteine. The best example of this concept is a missense mutation (alanine to valine) at base pair (bp) 677 of methylenetetrahydrofolate reductase (MTHFR), the enzyme that provides the folate derivative for conversion of homocysteine to methionine. This mutation results in mild hyperhomocysteinemia, primarily when folate levels are low, providing a rationale (folate supplementation) for overcoming the genetic deficiency. Additional genetic variants in MTHFR and in other enzymes of homocysteine metabolism are being identified as the cDNAs/genes become isolated. These variants include a glutamate to alanine mutation (bp 1298) in MTHFR, an aspartate to glycine mutation (bp 2756) in methionine synthase, and an isoleucine to methionine mutation (bp 66) in methionine synthase reductase. These variants have been identified relatively recently; therefore additional investigations are required to determine their clinical significance with respect to mild hyperhomocysteinemia and vascular disease.
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PMID:Genetic modulation of homocysteinemia. 1101 43


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