Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Elevated levels of plasma homocysteine is a risk factor in both birth defects and vascular disease. Methionine synthase (MS) is a cobalamin dependent enzyme which catalyzes methylation of homocysteine to methionine. Impaired MS activity is expected to lead to increased levels of plasma homocysteine. In addition, defects in this gene may underlie the methionine-dependence observed in a number of human tumor cell lines. We describe here the isolation and characterization of the human MS cDNA. It contains an open reading frame of 3798 nucleotides encoding a protein of 1265 amino acids with a predicted molecular mass of 140 kDa. The amino acid sequence of the human MS is 55% identical with that of the Escherichia coli enzyme (METH) and 64% identical with the predicted Caenorhabditis elegans enzyme. Seven peptide sequences derived from purified porcine MS have substantial similarity to the human protein. Northern analysis indicates that the MS RNA is present in a wide variety of tissues. We have mapped the human gene to chromosomal location 1q43, a region found monosomic in individuals with deletion 1q syndrome. The isolation of the MS cDNA will now allow the direct determination of whether mutations in this gene contribute to folate-related neural tube defects, cardiovascular diseases, and birth defects.
Hum Mol Genet 1996 Dec
PMID:Cloning, mapping and RNA analysis of the human methionine synthase gene. 896 35

A moderate increase in plasma homocysteine is increasingly considered an important risk factor of atherosclerosis and thrombosis. However, the mechanisms by which hyperhomocysteinemia induces vascular disease are not well defined. In vitro studies suggest that cysteine and homocysteine can induce oxidative modification of low-density lipoproteins (LDL). This suggestion is relevant because lipoprotein oxidation is thought to play a key role in the development of atherosclerosis and in the triggering of thrombotic events. An attractive model to study this topic is provided by patients with classical homocystinuria, an inherited disease characterized by severe hyperhomocysteinemia and a high incidence of thromboembolisms. We investigated the existence of oxidized LDL and the susceptibility to oxidation of the plasma cholesterol-rich lipoproteins in six patients with severe hyperhomocysteinemia, most likely due to classical homocystinuria, and compared the results with matched controls. The proportion of electronegative LDL and the concentration of thiobarbituric acid reactive substances in native LDL and high-density lipoproteins (HDL) did not differ between patients and controls, suggesting that the proportion of modified lipoproteins is not increased in patients with severe hyperhomocysteinemia. The susceptibility to oxidative modification of plasma LDL and HDL was also similar in the two groups, although the patients had homocysteine levels 18.3-fold higher than controls. Thus, increased oxidative modification is not likely to be a relevant mechanism in explaining their high incidence of vascular disease. A possible explanation for the lack of increased susceptibility to oxidation, as would be expected for the metabolic blockade that cause classical homocystinuria, is the 4.1-fold decrease in the concentration of cysteine in the plasma of patients. As a result the total concentration of homocysteine plus cysteine was slightly lower in patients than in controls. This interpretation implies that more studies are needed on lipoprotein susceptibility to oxidation in patients in which both plasma homocysteine and cysteine concentrations are increased. This metabolic situation may be frequent in the population with moderate hyperhomocysteinemia and vascular disease.
J Mol Med (Berl) 1996 Dec
PMID:Susceptibility of plasma low- and high-density lipoproteins to oxidation in patients with severe hyperhomocysteinemia. 897 13

Cyclic Amp (cAMP) levels were measured in the aortas of rabbits fed a cholesterol rich diet for either 24 days (Group I), 86 days (Group II) or 86 days followed by 54 days of a normal diet (Group III). Aortic levels of cholesterol and cholesterol esters, calcium and collagen and noncollagen protein synthetic rates were also measured at each time period. Cyclic AMP levels were unchanged in the Group I animals but were significantly elevated in Groups II & III. Aortic levels of cholesterol and cholesterol esters, calcium and collagen and noncollagen protein synthetic rates were also significantly elevated in Groups II & III but unchanged in Group I. Since cAMP levels were not changed in Group I animals the increase in cAMP appears to be a later, adaptive change in response to the feeding of a cholesterol rich diet. The observation that cAMP levels are increased in response to cholesterol feeding is important since cAMP is known to be involved with a wide range of metabolic functions, which may have a significant effect on the development of vascular disease.
Res Commun Mol Pathol Pharmacol 1996 Nov
PMID:Increased cyclic AMP in aortas of cholesterol fed rabbits. 898 16

Supravalvular aortic stenosis (SVAS) is an inherited obstructive vascular disease that affects the aorta, carotid, coronary and pulmonary arteries. Previous molecular genetic data have led to the hypothesis that SVAS results from mutations in the elastin gene, ELN. In these studies, the disease phenotype was linked to gross DNA rearrangements (35 and 85 kb deletions and a translocation) in three SVAS families. However, gross rearrangements of ELN have not been identified in most cases of autosomal dominant SVAS. To define the spectrum of ELN mutations responsible for this disorder, we refined the genomic structure of human ELN and used this information in mutational analyses. ELN point mutations co-segregate with the disease in four familial cases and are associated with SVAS in three sporadic cases. Two of the mutations are nonsense, one is a single base pair deletion and four are splice site mutations. In one sporadic case, the mutation arose de novo. These data demonstrate that point mutations of ELN cause autosomal dominant SVAS.
Hum Mol Genet 1997 Jul
PMID:Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. 921 70

Pseudoxanthoma elasticum (PXE) is a classic inherited disorder of the elastic tissue characterized by progressive calcification of elastic fibers with a pathognomonic histological appearance. The clinical manifestations of PXE typically involve the skin, the eye and the cardiovascular system, resulting in skin lesions, decreased vision and vascular disease. Clinically, a more common autosomal recessive and a less common autosomal dominant pattern of inheritance, with high penetrance, have been described; the estimated prevalence of the disease is 1 in 70,000-100,000. Previous failure to link the disease to any of several candidate genes prompted us to conduct a genome-wide screen on a collection of 38 families with two or more affected siblings, using allele sharing algorithms. Excess allele sharing was found on the short arm of chromosome 16 and confirmed by conventional linkage analysis, localizing the disease gene under a recessive model with a maximum two point lod score of 21.27 on chromosome 16p13.1, an area so far devoid of any obvious candidate genes. Under a dominant transmission pattern linkage with a maximum two point lod score of 14.53 was observed to the same region. Linkage heterogeneity analysis predicted the presence of allelic heterogeneity with different variants of a single gene that resides in this chromosomal region accounting for recessive and dominant forms of PXE.
Hum Mol Genet 1997 Oct
PMID:Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1. 930 59

To investigate the relationship between cerebral amyloid angiopathy (CAA) and cystatin C, we studied five CAA patients on whose cerebral blood vessels colocalization of cystatin C and beta-protein was recognized immunohistochemically. One patient was suspected as familial CAA and the other patients were sporadic cases. Two patients had low concentration of cystatin C in their cerebrospinal fluid (CSF) as we have previously reported in CAA patients. Enzyme-linked immunosorbent assay (ELISA) revealed that cystatin C and beta-protein have been included at the ratio of about 1:100 in the crude amyloid fibrils of one patient. Using a monoclonal antibody (MAb) against cystatin C, we performed affinity chromatography and immunoblotting on her amyloid fibril fraction. Eluate showed a band with a mol wt of 14,000 and the N-terminal 14 amino acid residues of 14-kDa protein were identical with that of cystatin C. This molecular weight is not identical to that of the truncated form of cystatin C deposited in hereditary cerebral hemorrhage with amyloidosis in Iceland (HCHWA-I), but that of normal cystatin C. DNA sequence analysis of five patients showed no point mutations in the cystatin C gene. Cystatin C and beta-protein colocalization, which was recognized in amyloid lesions of CAA, suggests that cystatin C deposition may be related to beta-protein deposition. We hypothesize that cystatin C deposition in sporadic cerebral amyloid angiopathy with cystatin C deposition (SCCAA) involves a different mechanism from that in HCHWA-I, which may be related to low CSF concentration of cystatin C without amino acid substitutions.
Mol Chem Neuropathol 1998 Jan
PMID:No mutations in cystatin C gene in cerebral amyloid angiopathy with cystatin C deposition. 949 77

Emphasis has recently been placed on the roles of chemotactic cytokines called chemokines to explain the accumulation of inflammatory cells in the lung that may precede or accompany pulmonary fibrosis in interstitial lung diseases. We hypothesized that RANTES, a member of the C-C chemokines, is one such chemokine. Bronchoalveolar lavage was done in 20 patients with sarcoidosis, 10 patients with interstitial pneumonia associated with collagen vascular disease (CVD-IP), 10 patients with idiopathic pulmonary fibrosis (IPF), and eight healthy volunteers (HV), all of whom were never-smokers. We semiquantitated the spontaneous RANTES mRNA expression by a competitive reverse transcription-polymerase chain reaction (RT-PCR) technique, and measured the levels of RANTES protein by enzyme-linked immunosorbent assay. In all disease groups the expression of RANTES mRNA by bronchoalveolar lavage fluid (BALF) cells and the levels of RANTES protein in BALF were significantly increased compared with those in HV. Patients with sarcoidosis and CVD-IP had a significant positive correlation between the expression of RANTES mRNA by BALF cells and BALF lymphocytosis. The amounts of RANTES mRNA expressed by peripheral blood mononuclear cells and the levels of RANTES protein in serum did not differ among all study groups. Our study demonstrates the adaptability of a semiquantitative RT-PCR method for determining cytokine mRNA expression in vivo. Our results suggest that RANTES may be one of the chemokines that are involved in the mechanism for the accumulation of inflammatory cells in the lung of some distinct interstitial lung diseases.
Am J Respir Cell Mol Biol 1998 Apr
PMID:Expression of RANTES by bronchoalveolar lavage cells in nonsmoking patients with interstitial lung diseases. 953 40

A common mutation in methylenetetrahydrofolate reductase (MTHFR), C677T, results in a thermolabile variant with reduced activity. Homozygous mutant individuals (approximately 10% of North Americans) are predisposed to mild hyperhomocysteinemia, when their folate status is low. This genetic-nutrient interactive effect is believed to increase the risk for neural tube defects and vascular disease. In this communication, we characterize a second common variant in MTHFR (A1298C), an E to A substitution. Homozygosity was observed in approximately 10% of Canadian individuals. This polymorphism was associated with decreased enzyme activity; homozygotes had approximately 60% of control activity in lymphocytes. Heterozygotes for both the C677T and the A1298C mutation, approximately 15% of individuals, had 50-60% of control activity, a value that was lower than that seen in single heterozygotes for the C677T variant. No individuals were homozygous for both mutations. Additional studies of the A1298C mutation, in the absence and presence of the C677T mutation, are warranted, to adequately address the role of this new genetic variant in complex traits. A silent genetic variant, T1317C, was identified in the same exon. It was relatively infrequent (allele frequency 5%) in our study group, but was quite common in a small sample of African individuals (allele frequency 39%).
Mol Genet Metab 1998 Jul
PMID:A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. 1060 82

The role of platelets in thrombotic vascular disease has been widely studied in rabbits. Yet, in rabbit platelets, there is little known about the alpha-granules, which contain many of the key effector molecules for thrombosis. In this comparative study of rabbit platelets, we have characterized the structure and expression of P-selectin, an alpha-granule membrane protein that mediates leukocyte adhesion and thrombus propagation. The sequences of tryptic peptides of rabbit P-selectin show an overall sequence identity of 74% with human P-selectin, and 69-77% identity with cow, dog, mouse, rat and sheep P-selectins. The mean (+/- S.D.) apparent molecular mass of reduced rabbit P-selectin is 117 +/- 7 kDa which is approximately 8 kDa larger than the unreduced protein (109 +/- 5 kDa). Rabbit P-selectin appears smaller than human P-selectin, but is comparable to other species P-selectins, that have fewer 'complement regulatory protein' repeat domains. Cell membrane labeling experiments and antibody binding studies indicate that rabbit P-selectin is nearly absent from the surface of platelets (290 +/- 30 molecules cell-1). However, cellular activation with thrombin causes nearly a 30-fold increase in expression to 14,200 +/- 1100 molecules cell-1. P-selectin is also be expressed on the surface of rabbit platelets activated by other agonists like ADP, A23817 and epinephrine. This selective expression is explained by immunoelectronmicroscopic studies, which show that rabbit P-selectin is sequestered in the intracellular granules of resting platelets. After cell activation by thrombin, P-selectin is found decorating the external membranes of platelet pseudopodia and the surface connected canalicular system. In summary, these studies of P-selectin in rabbit platelets indicate that it is similar in structure, cell localization and expression to human and other species P-selectins. This suggests that studies of P-selectin in thrombosis in rabbits are likely to provide useful insights into the role of this molecule in human thrombotic vascular disease and related conditions.
Comp Biochem Physiol B Biochem Mol Biol 1998 Apr
PMID:Comparative biochemical and ultrastructural studies of P-selectin in rabbit platelets. 978 64

Advanced glycation endproducts (AGEs) accumulate in uraemia as a consequence of diminished clearance of low molecular weight forms which retain their reactivity and may subsequently combine with circulating and tissue macromolecules. Successful renal transplantation is the only form of renal replacement therapy which effectively clears these circulating AGEs; both haemodialysis and peritoneal dialysis are comparatively ineffective although high-flux haemodialysis confers some benefits. De novo AGE formation may be accelerated in uraemia due to carbonyl and oxidative stress leading to further accumulation. The consequences for the patient with chronic renal failure may be acceleration of vascular disease, renal failure progression and dialysis-related amyloidosis. Accelerated peritoneal AGE formation as a consequence of treatment with peritoneal dialysis fluids may be detrimental to peritoneal membrane function but does not appear to contribute to systemic elevation of AGEs.
Cell Mol Biol (Noisy-le-grand) 1998 Nov
PMID:The pathogenesis and consequences of AGE formation in uraemia and its treatment. 984 90


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