Gene/Protein Disease Symptom Drug Enzyme Compound
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Duchenne and the less severe Becker form of muscular dystrophy (DMD,BMD) result from genetic deficiency in the level and/or activity of the protein dystrophin. The recent availability of cDNA based minigenes encoding recombinant dystrophin polypeptides has raised the possibility of somatic gene transfer as a therapeutic approach to treat dystrophin deficiency. In this respect, the mdx mouse provides a useful model of DMD exhibiting features characteristic of both the early myopathic and later fibrotic phases of the human disease. Using a mutated human cDNA, compatible in size with virus-based somatic gene transfer vectors, the pathophysiological consequences of restoring dystrophin expression have been examined in transgenic mdx mice. Transgene expression was correlated with a marked reduction of the skeletal myofibre necrosis and regeneration which is a major feature of the dystrophin-deficient phenotype in young mdx mice. The cDNA construct which is based on a very mild BMD phenotype thus encodes a highly functional dystrophin molecule whose reduced size renders it an attractive candidate for development as a therapeutic gene transfer reagent.
Hum Mol Genet 1992 Apr
PMID:Human dystrophin expression corrects the myopathic phenotype in transgenic mdx mice. 130 Nov 34

A combination of multiplex PCR with the single strand conformation polymorphism (SSCP) technique was employed to screen for point mutations in the human dystrophin gene. Co-amplification of 11 exons from genomic DNA of Duchenne and Becker muscular dystrophy (DMD/BMD) patients with no deletion or duplication was performed and the samples subjected to multiple SSCP analysis. We report the case of a nonsense mutation in a Duchenne patient identified by this approach. The mutation introduces a termination codon within exon 8 of the dystrophin gene. It is predicted to cause a very premature translational termination accounting for the severe phenotype observed. The patient inherited this mutation from his mother. In addition the analysis revealed 5 polymorphisms useful for internal control.
Hum Mol Genet 1992 Oct
PMID:Detection of a nonsense mutation in the dystrophin gene by multiple SSCP. 130 53

Genetic mapping has indicated that meiotic recombination occurs about 4 time more frequently in the dystrophin gene than expected on the basis of its length. To detect where recombinations occur within the gene, we have studied the CEPH families panel using highly polymorphic microsatellite markers located at the ends of the gene or flanking the major deletion hot spot in intron 44. We found a major hot spot of recombination between markers STR44 and STR50(1), i.e., between exons 44 and 51. Within this hot spot, a peak of recombination was located in the large intron 44. A second minor recombination prone region was found between DXS 206, (XJ, in the large intron 7) and the 5' end of the DMD gene. The distribution of the recombination events in the gene of healthy individuals was very similar to that of deletion breakpoints in DMD/BMD patients, suggesting that the two phenomenon may share a common mechanism. These results should also improve efficiency and accuracy of linkage analysis applied to carrier detection and prenatal diagnosis. In particular, if markers located at the very 3' end of the gene are not informative, the highly polymorphic ones located between exons 50 and 60 can be used instead of presently available extragenic markers, with a very low risk of diagnostic error due to recombination.
Hum Mol Genet 1992 Nov
PMID:Two hot spots of recombination in the DMD gene correlate with the deletion prone regions. 136 82

Both normal and pathological transcripts of tissue-specific genes may be detected by polymerase chain reaction (PCR) amplification in tissues not normally considered to express the gene product. The exploitation of constitutive basal mRNA levels ("ectopic" transcription) would be a major boon to diagnostic medicine since it promises both to simplify the analysis of complex genes and to avoid the requirement for an expressing tissue that is sometimes obtainable only by biopsy. We have demonstrated the feasibility of this novel strategy by characterizing a mutation in the X-chromosomal Duchenne (or Becker) muscular dystrophy (DMD/BMD) gene encoding dystrophin. The massive size of this gene has in the past often hindered carrier detection due to the high frequency of recombination and the high proportion of new mutations. In this study a deletion was identified in both a BMD patient and a heterozygous carrier using only a minimal volume of peripheral blood. Following specifically primed reverse transcription of lymphocyte RNA, the relevant region of the pathological cDNA was PCR-amplified. Sequence analysis indicated an in-frame deletion of exons 45 to 47.
Mol Biol Med 1990 Dec
PMID:Characterization of pathological dystrophin transcripts from the lymphocytes of a muscular dystrophy carrier. 170 53

The possibility of raising the expression level of a heterologous gene in Lactococcus lactis by exploiting the principle of translational coupling was investigated. For this purpose, the Escherichia coli lacZ gene was transcriptionally fused to a short open reading frame (ORF) of lactococcal origin. A Shine-Dalgarno (SD) sequence was introduced at the boundary of the two ORFs. In a series of otherwise identical plasmids, the relative positions of the translational stop codon of the upstream ORF and the translational start codon of the downstream ORF (lacZ) were varied. The expression of lacZ gradually increased as the stop and start codons were placed in closer proximity. A concomitant switch from translational interference to translational coupling was observed. Best results were obtained with partially overlapping stop and start codons. It is concluded that the principle of translational coupling offers good possibilities to increase the level of heterologous gene expression in L. lactis.
Mol Gen Genet 1991 May
PMID:Distance-dependent translational coupling and interference in Lactococcus lactis. 190 38

The crystal structure of the complex between adenylate kinase from bovine mitochondrial matrix and its substrate AMP has been refined at 1.85 A resolution (1 A = 0.1 nm). Based on 42,519 independent reflections of better than 10 A resolution, a final R-factor of 18.9% was obtained with a model obeying standard geometry within 0.016 A in bond lengths and 3.2 degrees in bond angles. There are two enzyme: substrate complexes in the asymmetric unit, each consisting of 226 amino acid residues, one AMP and one sulfate ion. A superposition of the two full-length polypeptides revealed deviations that can be described as small relative movements of three domains. Best superpositions of individual domains yielded a residual overall root-mean-square deviation of 0.3 A for the backbone atoms and 0.5 A for the sidechains. The final model contains 381 solvent molecules in the asymmetric unit, 2 x 72 = 144 of which occupy corresponding positions in both complexes.
J Mol Biol 1991 Feb 05
PMID:The refined structure of the complex between adenylate kinase from beef heart mitochondrial matrix and its substrate AMP at 1.85 A resolution. 199 37

Techniques are described for visualizing intracellular tropoelastin at the light level using immunofluorescence and immunogold techniques. Best results were obtained with B5 fixative on cells permeabilized with acetone. Using either formaldehyde or paraformaldehyde for fixation (instead of B5) resulted in both less reproducible and less intense intracellular staining, and permeabilization of the cells with ethanol resulted in relatively high background staining compared with that obtained with cold (-20 degrees C) acetone. Intracellular tropoelastin was seen most prominently in the perinuclear region, and the intensity of staining agreed with the reported rate of tropoelastin synthesis as assayed by enzyme-linked immunosorbent assay (ELISA) and RNA hybridization studies. The applicability of the intracellular staining technique for studying the elastin phenotype was tested by demonstrating increases in both the number of positive cells and in the intensity of elastin staining in cells treated with smooth muscle elastogenic factor (SMEF), an elastogenic factor known to stimulate elastin production.
Am J Respir Cell Mol Biol 1990 Jul
PMID:Immunohistochemical detection of intracellular tropoelastin: an assay for elastin production and its use in the detection and assessment of elastogenic factors. 219 20

Recombinant cutinase from Fusarium solani pisi is expressed and excreted with very high yields in Escherichia coli cultures. Cutinase was crystallized at 20 degrees C using the vapour diffusion technique, with polyethylene glycol 6000 as precipitant. Best crystals were obtained at pH 7.0 with polyethylene glycol 6000 as precipitant. Best crystals were obtained at pH 7.0 with polyethylene glycol at 15 to 20%. They are monoclinic, with space group P2(1) and cell dimensions a = 35.1 A, b = 67.4 A, c = 37.05 A and beta = 94.0 degrees; they diffract beyond 1.5 A resolution. The asymmetric unit contains one molecule of 22,000 Da (Vm = 1.98 A3/Da; 38% water).
J Mol Biol 1990 Sep 20
PMID:Crystallization and preliminary X-ray study of a recombinant cutinase from Fusarium solani pisi. 221 80

The investigation of the inherited matrix disorders has been an example of progress on two parallel fronts. Two decades of protein chemistry have provided detailed background information on the structure, if not the function, of collagen. This has been used to identify the likely candidate genes for analysis using DNA markers. Segregation analysis has in turn sorted out which diseases are caused by collagen gene mutations and which are not. This information is now concentrating effort on defining the mutations in the linked diseases and establishing linkages to other genes in the rest. Using the background structural information, efficient and specific strategies for rapidly identifying individual mutants are being designed. Best of all, prenatal diagnosis is now a reality for many parents faced with the prospect of having a severely crippled child.
Mol Biol Med 1989 Feb
PMID:Inherited collagen disorders. 266 15

We report the visualization of calcitonin gene expression products at the mRNA and peptide levels on the same section of a medullary thyroid carcinoma by combined in situ hybridization and immunohistochemistry. mRNA detection was accomplished by hybridization with radioactively labeled antisense RNA probes followed by autoradiography and immunohistochemically using the avidin-biotin complex method. Best results were obtained when in situ hybridization preceded immunohistochemistry, as determined by quantitative analysis of the autoradiographs. When immunohistochemistry was performed prior to in situ hybridization, the RNase inhibitor heparin had to be added to the antibodies to retain hybridizable mRNA. The intensity of the two reactions varied in individual cells, indicating a functional heterogeneity of tumor cells with regard to calcitonin mRNA content and storage of the related immunoreactive peptide. These results, in combination with elevated serum calcitonin levels, suggest significant differences in the rate of secretion of individual tumor cells. Simultaneous localization of mRNA and its peptide within the same cell may, therefore, provide further insight into gene expression and secretory activity at the single cell level.
Virchows Arch B Cell Pathol Incl Mol Pathol 1987
PMID:Simultaneous localization of calcitonin mRNA and peptide in a medullary thyroid carcinoma. 289 88


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