Gene/Protein Disease Symptom Drug Enzyme Compound
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Data on properties, structure and biological functions of a variety of thiol (cysteine) peptide hydrolases from animal tissues have been summarized. This large group of diverse intracellular enzymes involves both endo- and exopeptidases. Best studied are lysosomal thiol peptide hydrolases: cathepsins B, H and L, the primary structure of which is deciphered. They present a family of homologous proteins, structurally similar to papain. Ca2+-dependent neutral proteinases is another family of related proteins. The biological functions of various thiol peptide hydrolases are considered: their participation in protein turnover, post-translational processing, regulation of unidirectional biological processes and metabolic refolding. Data on endogenous inhibitors of thiol peptide hydrolases and on regulation of enzymic activity are presented.
Mol Biol (Mosk)
PMID:[Thiol peptide hydrolases from animal tissues, their structure and function]. 353 46

This review attempts a critical stock-taking of the current state of the science aimed at predicting structural features of proteins from their amino acid sequences. At the primary structure level, methods are considered for detection of remotely related sequences and for recognizing amino acid patterns to predict posttranslational modifications and binding sites. The techniques involving secondary structural features include prediction of secondary structure, membrane-spanning regions, and secondary structural class. At the tertiary structural level, methods for threading a sequence into a mainchain fold, homology modeling and assigning sequences to protein families with similar folds are discussed. A literature analysis suggests that, to date, threading techniques are not able to show their superiority over sequence pattern recognition methods. Recent progress in the state of ab initio structure calculation is reviewed in detail. The analysis shows that many structural features can be predicted from the amino acid sequence much better than just a few years ago and with attendant utility in experimental research. Best prediction can be achieved for new protein sequences that can be assigned to well-studied protein families. For single sequences without homologues, the folding problem has not yet been solved.
Crit Rev Biochem Mol Biol 1995
PMID:Protein structure prediction: recognition of primary, secondary, and tertiary structural features from amino acid sequence. 758 78

As a result of the spread of TYLCV on tomato crops, reliable and rapid diagnostic tools to identify and isolate new sources of infection are necessary. We tested several methods, based both on antibodies and on nonradioactive DNA probes. Indirect plate-trapping ELISA was only effective in detecting the virus in purified preparations, but not in crude extracts. Dot-ELISA with chemiluminescence detection gave satisfactory results when young stems were directly squashed on membranes. A digoxigenin-labeled probe, detected with chemiluminescence, was used in leaf squashes and dot blots. Best results were obtained with dot blots of total nucleic acids prepared with a fast and safe procedure. TYLCV DNA was readily and reliably detected in spots corresponding to 15 micrograms fresh weight. When weak signals were observed, total extracts were analyzed by Southern blotting, to confirm the presence of viral DNA forms.
Mol Biotechnol 1994 Dec
PMID:Advances in diagnosing tomato yellow leaf curl geminivirus infection. 786 78

The largest in-frame deletion in the dystrophin gene previously reported in a BMD patient encompasses exons 17 to 48, which corresponds to 46% of the coding region. Here we report a larger deletion of exons 13 to 48 in a 37 year-old BMD patient with a mild phenotype. Such deletion, which corresponds to 50% of the coding region is the largest reported so far associated with a benign clinical course. Dystrophin assessment (through immunofluorescence and Western blot) using antibodies against different regions of the dystrophin was concordant with his deletion. The observation of this patient has important implication for gene therapy trials based on minigenes, since it confirms that deletions of up to 66% of the rod domain are compatible with a mild phenotype.
Hum Mol Genet 1994 Jun
PMID:Half the dystrophin gene is apparently enough for a mild clinical course: confirmation of its potential use for gene therapy. 795 Dec 37

The development of highly specific and sensitive monoclonal antibodies directed against human estrogen (ER) and progesterone receptors (PR) provides a new approach in precise histochemical receptor location independent of hormone binding. Over the years receptor determination was the domain of the radioligand-binding assay, in which receptors are measured by tritiated ligand and unbound ligand is removed by the dextran-coated charcoal (DCC) procedure. Presented here are the results and experiences obtained by the classic DCC and the immunocytochemical method in the different normal and tumorous tissues of the female reproductive tract and the breast. The results of both methods were compared, and overall concordance of the results was found to vary considerably among the different types of tissue analyzed. Best agreement (86%) was found for PR determination in breast cancer, and the lowest rate of concordance for ER determination in fibrocystic disease of the breast. Special attention was directed toward the heterogeneity of receptor distribution in the specimens examined. In all tissues investigated, ER and PR were located in the nuclei of cells in both paraffin and frozen sections. Staining intensity varied among different cell types and from cell to cell for a single cell type, as well as in tumorous and normal tissues. In breast cancer, randomly scattered single cell receptor positivity was distinguished from focal/clonal positivity. Paraffin-embedded lymph node metastases showed significantly weaker staining as compared with their respective primary tumors. In the normal ovary, the corpus luteum and the stromal layer of the outer cortex were revealed as highly receptive elements for progestins, whereas ER was barely demonstrable in the normal ovary. Benign serous and mucinous ovarian tumors showed opposite ER and PR distribution among the stromal and epithelial components. Of special interest were the highly significant changes in ER and PR content in the stromal and glandular cells of the different layers of the normal endometrium throughout the menstrual cycle.
J Steroid Biochem Mol Biol 1994 Jun
PMID:Immunocytochemical versus biochemical receptor determination in normal and tumorous tissues of the female reproductive tract and the breast. 804 2

PCR amplification has enabled a variety of studies to be performed on the murine dystrophin transcripts. Figure 7.12 displays a summary of the features of the murine dystrophin mRNA that have been described in this article. The location of the mutation in the original mdx mouse is indicated, as are the different spliced forms of the dystrophin transcript. Also shown are the location of various PCR primer binding sites that were used to deduce the alternative splicing pattern of the gene. It is likely that conventional cloning efforts aimed at identifying the variety of dystrophin spliced forms would have taken years to perform, particularly since several of the isoforms are expressed at levels significantly below the estimated 0.02% of total mRNA that dystrophin represents in skeletal muscle (Hoffman et al., 1987a, b). Amplification of dystrophin mRNA simplifies scanning methods for the identification of DNA sequence variations. Attempts to re-isolate and sequence the 14 kb cDNA to determine the mutation in separate strains of mdx mice are not likely to be time or cost effective. PCR enables these types of questions to be answered in a relatively short period of time, and similar types of analyses can be applied to human DMD tissues. Knowledge of the transcript diversity displayed by the dystrophin gene will enable the role of these separate isoforms to be addressed. Despite considerable effort by a variety of laboratories over the last five years, the precise functional role played by dystrophin remains unclear, and it can only be assumed that the separate isoforms act to modulate the functional role of dystrophin in separate tissues or in response to differing physiological states. PCR amplification of the dystrophin isoforms has enabled the variable regions of the transcript to be subcloned (Bies et al., 1992). These clones have been used to reintroduce the variable regions into full-length mini-gene expression vectors, which are currently being tested for functional activity through the generation of transgenic mdx mice. The transgenic mice can be easily identified through the PCR-ASO assays described in this article, and the reverse transcriptase PCR assays will enable a detailed analysis of the expression pattern of the introduced mini-genes. It is hoped that such analyses will further attempts to determine the feasibility of using gene therapy as a treatment for DMD/BMD.
Mol Cell Biol Hum Dis Ser 1993
PMID:PCR analysis of muscular dystrophy in mdx mice. 811 39

Transcriptional and translational fusions were made between the reading frame coding for beta-D-glucuronidase and sequences of either a constitutively expressed rice gene (GOS2) involved in initiation of translation or a light-inducible rice gene (GOS5). The transient expression of the fusions was studied via particle bombardment of seedling tissues of rice, perennial ryegrass and barley. Furthermore, the results of transient and stable expression were compared for cell suspensions of four rice varieties, one barley variety and one perennial ryegrass variety. The GOS2-gusA fusions were active in all three monocots studied. Best results were obtained for a construct having both a transcriptional and a translational fusion as well as intron and exon sequences (PORCEHyg). The level of GUS activity was in the range of activities as obtained by the 35S CaMV promoter transcriptionally fused to gusA. The gusA fusion with the light-inducible gene (GOS5) was active in green seedling tissues of all monocots studied. Also a weak expression compared to the GOS2 constructs was found in stably transformed rice callus. The gusA fusions with the mannopine synthase promoters 1' and 2' of the TR-DNA were transiently expressed at lower levels in cell suspensions than PORCEHyg. For stably transformed rice callus the expression of the GOS2-gusA fusion often decreased during prolonged subculture. This decrease in GUS activity and the various GUS-staining phenotypes of transgenic calli are explained by the presence of different cell types in the suspensions used and in the calli. It is presumed that the nature of the cells and their relative contribution in the calli change drastically upon further subculture.
Plant Mol Biol 1993 Nov
PMID:Transient and stable expression of gusA fusions with rice genes in rice, barley and perennial ryegrass. 825 21

Duchenne and Becker muscular dystrophies (DMD/BMD) are caused by mutations in the human dystrophin gene. About two-thirds of DMD/BMD patients exhibit gross rearrangements in the gene whereas the mutations in the remaining one third are thought to be point mutations or minor structural lesions. By means of various progressive PCR-based techniques hitherto a number of point mutations has been described that in most cases should cause premature translational termination. These data indicate a particular functional importance for the C-terminal region of dystrophin and consequently for its gene products Dp 71 and Dp 116. To screen for microheterogeneities in this gene region we applied PCR-SSCP analysis to exons 60-79 of twenty-six DMD/BMD patients without detectable deletions. The study identified seven point mutations and one intron polymorphism. Six point mutations, found in DMD patients, should cause premature translational termination. One point mutation, identified in a BMD patient, results in an amino acid exchange. Five of the DMD patients bearing a point mutation are mentally retarded suggesting that a disruption of the translational reading frame in the C-terminal region is associated with this clinical finding in DMD cases. Therefore our data raise the possibility, that Dp 71 and/or Dp 116, the C-terminal translational products of dystrophin, may be causally involved in cases of mental retardation that are associated with DMD.
Hum Mol Genet 1993 Nov
PMID:Point mutations at the carboxy terminus of the human dystrophin gene: implications for an association with mental retardation in DMD patients. 828 Nov 50

Transcriptional and translational fusions were made between the reading frame coding for beta-D-glucuronidase and sequences of either a constitutively expressed rice gene (GOS2) involved in initiation of translation or a light-inducible rice gene (GOS5). The transient expression of the fusions was studied via particle bombardment of seedling tissues of rice, perennial ryegrass and barley. Furthermore, the results of transient and stable expression were compared for cell suspensions of four rice varieties, one barley variety and one perennial ryegrass variety. The GOS2-gusA fusions were active in all three monocots studied. Best results were obtained for a construct having both a transcriptional and a translational fusion as well as intron and exon sequences (PORCEHyg). The level of GUS activity was in the range of activities as obtained by the 35S CaMV promoter transcriptionally fused to gusA. The gusA fusion with the light-inducible gene (GOS5) was active in green seedling tissues of all monocots studied. Also a weak expression compared to the GOS2 constructs was found in stably transformed rice callus. The gusA fusions with the mannopine synthase promoters 1' and 2' of the TR-DNA were transiently expressed at lower levels in cell suspensions than PORCEHyg. For stably transformed rice callus the expression of the GOS2-gusA fusion often decreased during prolonged subculture. This decrease in GUS activity and the various GUS-staining phenotypes of transgenic calli are explained by the presence of different cell types in the suspensions used and in the calli. It is presumed that the nature of the cells and their relative contribution in the calli change drastically upon further subculture.
Plant Mol Biol 1993 Sep
PMID:Transient and stable expression of gusA fusions with rice genes in rice, barley and perennial ryegrass. 840 Jan 27

The severe Duchenne muscular dystrophy (DMD) and the more benign Becker type (BMD) are allelic conditions, controlled by a defective gene at Xp21, caused by the absence (DMD) or a defect in quantity or quality (BMD) of the protein dystrophin. It has been suggested that the C-terminus domain of dystrophin is fundamental to ensure the proper protein sub-cellular localization and function. We wish to report our dystrophin findings in 4 among 142 DMD patients studied for DNA deletions and dystrophin analysis. Although they have a severe clinical course, a positive dystrophin immunofluorescence pattern was seen using C-terminal antibody, and a dystrophin band of reduced molecular weight (corresponding to their DNA deletions), but which maintained the C-terminus was seen through Western blot (WB). Based on these findings, we suggest that in order to partially maintain its function, resulting in a milder phenotype, dystrophin may carry large internal deletions but in addition to the C-terminus, the region encompassing both the N-terminus and the proximal region of the rod domain cannot be absent. Therefore, the prognosis of a Becker phenotype in a young patient should be done with caution if based only on the presence or not of dystrophin.
Hum Mol Genet 1993 Jan
PMID:Is the maintainance of the C-terminus domain of dystrophin enough to ensure a milder Becker muscular dystrophy phenotype? 849 Jun 21


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