Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of activated transforming genes was investigated in four patients with therapy-related leukemia and in three with therapy-related myelodysplastic syndrome. DNA of bone marrow cells from six of the patients exhibited transforming activity in the tumorigenicity assay. Five of the six patients who were positive in the tumorigenicity assay contained activated N-ras oncogenes, and three contained activated K-ras oncogenes. Thus, concurrent activation of N-ras and K-ras oncogenes was observed in two patients. In vitro DNA amplification followed by oligonucleotide dot-blot analysis was used to investigate mutations in codons 12, 13, and 61 of the N-ras and K-ras oncogenes. Two patients exhibited an N-ras mutation, substituting aspartic acid (GAT) for glycine (GGT), and three patients exhibited an N-ras codon 13 mutation, substituting valine (GTT) for glycine. Two patients exhibited K-ras codon 12 mutations, substituting aspartic acid (GAT) or cysteine (TGT) for glycine (GGT), respectively, and one case exhibited a K-ras codon 61 mutation, substituting lysine (AAA) for glutamic acid (CAA). Cytogenetic analysis revealed that loss of chromosome 7 was frequent (four patients: 57%). Our data indicate that activation of N-ras and K-ras genes, as well as loss of heterozygosity for specific alleles on chromosome 7, plays a more important role in the leukemogenesis of both therapy-related leukemia and myelodysplastic syndrome.
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PMID:Transforming genes and chromosome aberrations in therapy-related leukemia and myelodysplastic syndrome. 185 83

Apolipoprotein (apo-) B100 is the exclusive apolipoprotein of low density lipoproteins (LDL0, which transport most of the plasma cholesterol in humans. Mutations in apo-B100 can cause either hypocholesterolemia or hypercholesterolemia. Familial hypobetalipoproteinemia, which leads to hypocholesterolemia, has been shown to be caused by defects in the apo-B gene that terminate translation prematurely and result in the production of truncated proteins. The mutations responsible for the hypocholesterolemia have been either single nucleotide substitutions or deletions. Familial defective apo-B100, which leads to hypercholesterolemia, is caused by a point mutation in the receptor-binding domain of apo-B100. The mutation disrupts the binding of LDL to the LDL receptor, thereby disrupting LDL receptor-mediated catabolism and resulting in hypercholesterolemia. A variant form of apo-B, apo-B48, is also critical for lipoprotein metabolism. Apolipoprotein B48 is obligatory for the secretion of chylomicrons. It is formed from an RNA-edited apo-B mRNA in which codon 2153 has been converted from a CAA (glutamine) codon to a premature UAA (stop) codon. The first cytosine in this codon is deaminated to form uracil. The minimum nucleotide recognition sequence for the editing mechanism has been reported to be between 26 and more than 63 nucleotides surrounding codon 2153. The apo-B mRNA editing mechanism, which appears to be a cytosine deaminase, and its regulation are being actively investigated.
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PMID:Mutations and variants of apolipoprotein B that affect plasma cholesterol levels. 185 54

CAA is the infiltration of leptomeningeal and penetrating cortical vessels with amyloid, sparing the subcortical regions and the systemic vasculature. It occurs with increasing frequency after the sixth decade. The major clinical manifestation of CAA is lobar intracerebral hemorrhage, which can be sporadic or hereditary. CAA has also been associated with normal aging, Alzheimer's disease, cerebral infarction, and periventricular demyelination. Biochemical studies have shown that the amyloid deposits in the brains of patients with normal aging, sporadic CAA-associated hemorrhage, hereditary cerebral hemorrhage, and Alzheimer's disease are identical. The exact mechanism by which CAA produces lobar hemorrhages and the role of CAA in the development of dementia are unclear. Biopsy of the involved cerebral cortex and leptomeninges is the only definitive way to diagnose CAA. Acute management of CAA-associated lobar hemorrhage consists of aggressive control of associated hypertension and supportive care. Surgical removal of the hemorrhage has not been shown to improve survival. Antiplatelet and anticoagulant therapy should be avoided in elderly patients with known CAA.
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PMID:Diagnosis and treatment of cerebral amyloid angiopathy. 186 14

The Authors describe a new reconstructive model after total proctectomy: the S-E colo-anal anastomosis (S-E CAA). The technical requisites of this variant are discussed and compared with more traditional reconstruction models. At a first evaluation of the results, the S-E CAA seems to be able to sensibly ameliorate the course and the outcome of the anastomosis and to hasten the recovery of the normal sphincteric function.
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PMID:[A new reconstructive model after total proctectomy]. 187 54

Apolipoprotein (apo) B48 is produced in the mammalian intestine by a tissue-specific RNA-editing mechanism, which mediates a C to U conversion at position 6666 in apoB mRNA. This generates an inframe translation stop codon (UAA) in place of glutamine (CAA) at position 2153. To establish the sequences required for editing we have used an in vitro conversion assay to monitor the editing of synthetic RNAs by rat intestinal extracts. Transcripts containing 55 nucleotides (positions 6649-6703) or more of human apoB mRNA sequence were edited in vitro. Transcripts containing 42 nucleotides (positions 6648-6689) and 26 nucleotides (positions 6662-6687) were edited at 62 and 24% efficiency, respectively, of the 55-nucleotide sequence. To delineate the precise sequence requirements for editing, mutants were generated where 6-nucleotide sections of the 55-base region were changed to anti-sense sequence. Mutation of the 12-nucleotide region immediately downstream of C-6666 abolished editing, and mutation of 6-base sequences immediately 3' and 5' of this 12-nucleotide region significantly reduced editing. Having identified the key region of interest, a panel of 46 mutant RNAs carrying single base substitutions or deletions between nucleotide positions 6657 and 6685 was constructed. Mutagenesis in the sequence 5'-TGATCAGTATA-3' (positions 6671-6681) downstream of C-6666 had the most dramatic effect, since almost all mutations abolished or greatly reduced conversion in vitro. These results suggest that editing is a highly sequence-specific process. We propose that this downstream region is a recognition and/or binding site for the editing enzyme. A search for this sequence in other genes may help to reveal other RNAs that undergo editing.
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PMID:Sequence requirements for the editing of apolipoprotein B mRNA. 188 64

Molecular analysis of the human beta-galactosidase gene revealed six different mutations in 10 of 11 Japanese GM1-gangliosidosis patients. They were the only abnormalities in each allele examined in this study. A 165-nucleotide duplication (positions 1103-1267) was found in two infantile patients, producing an abnormally large mRNA; one patient was probably a homozygote, and the other was a heterozygote of this mutation. The other two infantile patients had different mutations; a 123 Gly(GGG)----Arg(AGG) mutation in one patient and a 316 Tyr(TAT)----Cys(TGT) mutation in the other. A 201 Arg(CGC)----Cys(TGC) mutation, eliminating a BspMI site, was detected in a late-infantile/juvenile patient; the restriction-site analysis of amplified genomic DNA confirmed his heterozygosity for this mutation. A 51 Ile(ATC)----Thr(ACC) mutation was found in all five adult/chronic patients examined in this study. It created a SauI site, and restriction-site analysis confirmed that four patients were homozygous mutants. The other was a compound heterozygote for this mutation and another 457 Arg(CGA)----Gln(CAA) mutation. These mutant genes expressed markedly decreased or completely deficient enzyme activities in beta-galactosidase-deficient human fibroblasts transformed by adenovirus-SV40 recombinants. We conclude that gene mutations are heterogeneous in GM1-gangliosidosis but that the 51 Ile(ATC)----Thr(ACC) mutation is common among the Japanese adult/chronic cases. Genotype-phenotype correlations in GM1-gangliosidosis are briefly discussed.
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PMID:Human beta-galactosidase gene mutations in GM1-gangliosidosis: a common mutation among Japanese adult/chronic cases. 190

The goals in the treatment of hypertension have been outlined previously. The antihypertensive drugs should achieve as many of these criteria as possible. 1. Efficacious as monotherapy in more than 50% of all patients (demographics) 2. 24-hour blood pressure control during all activities 3. Once per day dosing 4. Hemodynamically logical and effective: reduces SVR, improves arterial compliance, preserves CO and maintains perfusion to all vital organs 5. Lack of tolerance or pseudotolerance: no reflex volume retention or stimulations of neurohumoral mechanisms 6. Favorable biochemical and metabolic effects 7. Reverses the structural, vascular smooth muscle, cardiac hypertrophy, LVH, and improves systemic and diastolic compliance, LV contractility and function, and reduces ventricular ectopy if present 8. Reduces all end-organ damage: cardiac, cerebrovascular, renal, retinal and large artery 9. Maintains normal hemodynamic response to aerobic and anerobic exercise 10. Low incidence of side effects and good quality of life 11. Good compliance with drug regimen 12. Good profile in concomitant diseases or problems The drugs that come closest to these characteristics include CCB, ACEI, CAA, and alpha blockers. All of these agents are effective as monotherapy and should be given as initial therapy to the maximum dose shown in Table 10 or until the advent of side effects, whichever occurs first. Combination therapy should be the next step, using the principal of go low, go slow, using additive or synergistic drug combinations. Therapy should be individualized using the subsets of hypertension approach: Diuretics in particular, especially high-dose diuretics, and BB to a lesser extent, should be reserved as second- or third-line drugs and used for specific indications and in the lowest dose possible to achieve clinical results. For example, diuretics would be reserved for volume overload states, systolic CHF, and volume-resistant hypertension. Beta blockers would be reserved for patients after a Q-wave myocardial infarction, those with obstructive angina, specific cardiac arrhythmias, and other like conditions. Long-term, prospective, clinical trials will be needed to confirm that CCB, ACEI, CAA, and alpha blockers reduce end-organ damage more effectively than diuretics, BB, direct vasodilators, and older antihypertensive drugs. Until then, one must rely on scientific evidence, discussed here, that strongly suggests that reduction in risk factors for end-organ damage will reduce the end-organ damage in heart, brain, kidney, and large arteries.
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PMID:Hypertension strategies for therapeutic intervention and prevention of end-organ damage. 194 95

Expression of the RNA replicase domain of tobacco mosaic virus (TMV) and certain protein-coding regions in other plant viruses, is mediated by translational readthrough of a leaky UAG stop codon. It has been proposed that normal tobacco tyrosine tRNAs are able to read the UAG codon of TMV by non-conventional base-pairing but recent findings that stop codons can also be bypassed as a result of extended translocational shifts (tRNA hopping) have encouraged a re-examination. In light of the alternatives, we investigated the sequences flanking the leaky UAG codon using an in vivo assay in which bypass of the stop codon is coupled to the transient expression of beta-glucuronidase (GUS) reporter genes in tobacco protoplasts. Analysis of GUS constructions in which codons flanking the stop were altered allowed definition of the minimal sequence required for read through as UAG-CAA-UUA. The effects of all possible single-base mutations in the codons flanking the stop indicated that 3' contexts of the form CAR-YYA confer leakiness and that the 3' context permits read through of UAA and UGA stop codons as well as UAG. Our studies demonstrate a major role for the 3' context in the read through process and do not support a model in which teh UAG is bypassed exclusively as a result of anticodon-codon interactions. No evidence for tRNA hopping was obtained. The 3' context apparently represents a unique sequence element that affects translation termination.
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PMID:The signal for a leaky UAG stop codon in several plant viruses includes the two downstream codons. 201 Sep 14

Recently, it was shown that wild-type glutamine tRNAs in yeast cause low-level nonsense suppression that can be enhanced by increasing glutamine tRNA gene copy number. In order to investigate glutamine tRNA behavior further, anticodon mutations that confer nonsense suppression were identified in yeast sup70 gene, which codes for glutamine tRNA(CAG). In this study we show that suppressors derived by mutation severely limit growth such that suppressor-bearing spores germinate but arrest cell division at approximately the 50 cell stage. Analysis of a sup70 deletion was used to establish that growth limitation results from loss of wild-type glutamine tRNA(CAG) function. By exploiting the growth inhibition of sup70 alleles, some exceptional codon recognition properties of glutamine tRNAs were revealed. Our results indicate that amber suppressor glutamine tRNA(UAG) can translate 5'-CAG-3' glutamine codons with low efficiency in the presence of an A/C mismatch at the first position of the codon, suggesting that reading may occur at a low level by a two-out-of-three reading mechanism. In addition, when glutamine tRNA(CAA) is over-expressed in vivo, it translates 5'-CAG-3' codons using a mechanism that resembles prokaryotic-like U/G wobble, which normally does not occur in yeast. Our studies also suggest that the yeast glutamine tRNA suppressors could potentially be exploited to express ciliated protozoan genes that normally contain internal 5'-UAG-3' and 5'-UAA-3' codons.
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PMID:Exceptional codon recognition by the glutamine tRNAs in Saccharomyces cerevisiae. 202 45

Human apolipoprotein (apo) B mRNA is edited in a tissue specific reaction, to convert glutamine codon 2153 (CAA) to a stop translation codon. The RNA editing product templates and hybridises as uridine, but the chemical nature of this reaction and the physical identity of the product are unknown. After editing in vitro of [32P] labelled RNA, we are able to demonstrate the production of uridine from cytidine; [alpha 32P] cytidine triphosphate incorporated into RNA gave rise to [32P] uridine monophosphate after editing in vitro, hydrolysis with nuclease P1 and thin layer chromatography using two separation systems. By cleaving the RNA into ribonuclease T1 fragments, we show that uridine is produced only at the authentic editing site and is produced in quantities that parallel an independent primer extension assay for editing. We conclude that apo B mRNA editing specifically creates a uridine from a cytidine. These observations are inconsistent with the incorporation of a uridine nucleotide by any polymerase, which would replace the alpha-phosphate and so rule out a model of endonucleolytic excision and repair as the mechanism for the production of uridine. Although transamination and transglycosylation remain to be formally excluded as reaction mechanisms our results argue strongly in favour of the apo B mRNA editing enzyme as a site-specific cytidine deaminase.
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PMID:Site-specific creation of uridine from cytidine in apolipoprotein B mRNA editing. 203 Sep 40


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