Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transgenic mice were generated using a construct that encodes mouse polyoma virus large T antigen, one of three oncogenic products of the "early region" of the polyoma viral genome. Of 16 transgenic families developed, 1 was characterized by a neurologic disorder consisting of constant tremor and recurrent seizures. Morphologic analysis of the central nervous system (CNS) of affected transgenic mice included: classical light and electron microscopic examination; immunohistochemical assessment of the presence and localization of myelin-specific proteins, of the astrocyte marker glial fibrillary acidic protein, of the oligodendrocyte marker galactosyl cerebroside, and of large T; double immunolabeling of glial fibrillary acidic protein or galactosyl cerebroside and large T to identify the CNS cell type in which large T is expressed; and in situ hybridization to study myelin basic protein gene expression. Our results suggest that polyoma large T is expressed in astrocytes, possibly resulting in altered glial-glial interactions causing impaired oligodendroglial development and secondary dysmyelination. Transgenic oligodendrocytes exhibit features of immaturity, failing to myelinate axons properly and producing morphologic phenotypes of early stages of myelination, such as numerous mesaxonal profiles. Myelin proteins are markedly reduced in transgenic CNS, and myelin basic protein transcripts, while present, are generally decreased. We believe that expression of large T in astrocytes could influence the complex and dynamic interactions between astrocytes and oligodendrocytes, perhaps with regard to the molecular (trophic) signals in the local CNS environment, bringing about arrested oligodendroglial maturation and hypomyelination. This raises intriguing questions concerning the importance of glial-glial interactions in the CNS and the complex levels of control involved in biological expression of genetic information in glial cells.
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PMID:Transgenic mice expressing polyoma virus large T antigen in astrocytes develop severe dysmyelination of the central nervous system. 130 29

The mld mutation is a complex genetic lesion affecting the myelin basic protein (MBP) locus in the mouse. The mutation consists of a variety of DNA rearrangements including: tandem duplication of the MBP structural gene, partial inversion of the 3' end of the upstream gene copy, duplication of a region flanking the rearrangement junction in the upstream copy and insertion between the two gene copies of a segment of extraneous DNA not associated with the wild-type MBP locus. The net result of the mutation is a dysfunctional MBP locus. Homozygous mld/mld mice produce very little MBP and consequently very little myelin. They exhibit a clinical phenotype characteristic of hypomyelination (shaking, convulsions). We have discovered a revertant mld mouse which does not exhibit clinical symptoms of hypomyelination. Genetic analysis indicates that the reversion is allelic to mld. We have designated the revertant locus mldr. Restriction analysis of mldr genomic DNA indicates that there is a single intact MBP gene. Analysis of various junction regions using the polymerase chain reaction indicates that the single MBP gene in mldr is derived by recombination from the 5' end of the upstream gene and the 3' end of the downstream gene. Studies on MBP expression in mldr mice indicate that the developmental regulation, level of expression and pattern of post-transcriptional processing of MBP gene products in mldr are similar to wild type. These results indicate that the recombinant MBP gene in mldr is fully functional. From this we infer that the MBP-deficient phenotype of the original mld mutant is attributable to the complex rearrangements in the upstream gene copy which render the locus dysfunctional.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular genetic analysis of the mldr mouse: a spontaneous revertant at the mld locus containing a recombinant myelin basic protein gene. 137 58

Calcium-activated neutral protease (CANP) in normal and dysmyelinating mutant, paralytic tremor (PT) rabbit myelin and premyelin fractions was studied using immature (4-5 wk) or adult animals. The enzyme was estimated by determination of its catalytic activity as well as by using immunoblot analysis after SDS-PAGE separation. The presence of two forms of CANP--one activated by calcium in the micromolar concentration (mu CANP) range and the other exhibiting low calcium sensitivity in the millimolar concentration range (m-CANP)--was found in the myelin and premyelin fractions. The developmental pattern of the enzyme activity was different for each of these two enzyme isoforms depending on the fraction studied. The higher activity on CANP (both isoforms) found in PT myelin and premyelin could be related to delayed myelination and/or to the higher turnover rate of already formed myelin. These results suggest complex and specific roles for these isoenzymes during myelin formation as is discussed further in this article. Our results confirm the extensive degradation of myelin basic protein (MBP), proteolipid protein (PLP), and, to a lesser extent, the other myelin proteins by endo- and exogenous CANP. This degradation process was significantly elevated in PT rabbit myelin. Moreover as was shown by two-dimensional gel electrophoresis, calcium-controlled proteolysis in nonmutant rabbits affected the net-charge of MBP in a manner similar to that reported for PT myelin, suggesting the possible involvement of CANP in the generation of charge isomers of MBP.
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PMID:Calcium-activated neutral protease (CANP) in normal and dysmyelinating mutant paralytic tremor rabbit myelin. 141 20

We report a mother and son with a deletion at 18q22.3. Both have the typical manifestations of the 18q- syndrome. In addition, both have an action tremor which became apparent in childhood. The mother subsequently developed chorea and dysmetria in late adolescence. Magnetic resonance imaging of their brains showed poor myelination of the central white matter tracts with relatively normal myelination of the corpus callosum. We propose that these neurologic findings are most likely due to a failure of expression of the myelin basic protein gene.
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PMID:Neurologic manifestations in 18q- syndrome. 170 Jun 7

1. Myelin is an important structure for facilitating the conduction of impulses along the axons both in the central nervous system (CNS) and peripheral nervous system (PNS). 2. Myelin basic protein (MBP) is a major protein in CNS myelin. 3. MBP is expressed specifically in the nervous system. 4. The MBP gene has been cloned and characterized. 5. Two mutant mice, Shiverer (shi) and myelin-deficient (mld. shimid), are autosomal recessive mutants that show severe symptoms such as intentional tremor. They have been found to have a mutation in the MBP gene that results in poor myelination in the central nervous system. 6. It was found that rearrangement within the MBP gene results in low expression of the gene. 7. In Shiverer, the MBP gene is partially deleted (from exons 3 to 7), and in mld, the gene is duplicated tandemly and a large portion of the duplication is inverted upstream of the intact copy. 8. In mld, anti-sense RNA complementary to exons 3-7, which correspond to the inverted segment, was detected by RNase protection studies, and presumed to be responsible for the reduced expressions of MBP. 9. The mechanism of gene rearrangement in MBP was also characterized. 10. This article reviews the recent progress in the study of the MBP gene, especially the rearrangement of the gene and its expression in mutant mice.
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PMID:Molecular biology of myelin basic protein: gene rearrangement and expression of anti-sense RNA in myelin-deficient mutants. 170 79

Several mouse mutations cause unstable locomotion, tremor, seizures, and a reduced lifespan because of deficient myelin formation in the central nervous system. Mutant alleles at the shiverer (shi) locus are the only ones in this series with a selective molecular defect, namely, in myelin basic proteins (MBPs), which are virtually absent in shi homozygotes and 50% reduced in heterozygotes. In the present study, backcross and intercross matings indicate recombination of 21.2 +/- 3.3% between myelin deficient, shimld, and fused phalanges, syfp, a marker near the middle of chromosome 18. Recombination of shimld with twirler (Tw), a marker near the centromere, is 45.7 +/- 4.9%. Thus, the shi locus maps near the distal end of mouse chromosome 18 and is the first available marker for this region. Given the evidence of other workers that an MBP locus maps to the same mouse chromosome, and that part of this chromosome may be syntenic with an MBP-PEPA region on human chromosome 18, it is likely that shi is in or near an MBP gene.
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PMID:Shiverer gene maps near the distal end of chromosome 18 in the house mouse. 241 73

Myelin deficiency (mld) is an autosomal recessive mutation in mice and is considered to be allelic to the shiverer (shi) mutation. Mld mice are characterized by hypomyelination of the central nervous system (CNS). They show typical symptoms such as tremor, tonic convulsion and ataxic movement. Subcellular fractionation of the CNS revealed that the MBP bands were greatly decreased in the P2A (myelin) fraction and the total content of myelin basic protein (MBP) was much lower than that in the control in all parts of the CNS. Sections from mld mice were examined by immunohistochemical tests with MBP antiserum, and a mosaic expression of MBP was found in the myelin of the mld mice. Since the major dense line is considered to be composed mainly of MBP, we investigated the myelin of mld mice by electron microscopy and found that there were 3 types of myelin: (1) a normal type compact myelin with a major dense line, (2) a shiverer-type myelin with no major dense line, and (3) a mixed-type myelin, in which within a myelin lamella the major dense line abruptly changes to cytoplasm of oligodendrocytes.
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PMID:Immunohistochemical, biochemical and electron microscopic analysis of myelin formation in the central nervous system of myelin deficient (mld) mutant mice. 244 19

A disorder of CNS myelination was found in paralytic tremor ("pt") rabbits. The condition is inherited in a sex-linked recessive mode. Ultrastructurally, an obvious myelin deficiency with aberration of myelin sheath formation is observed. The yield of myelin isolation was reduced to 20-30% of control. Myelin isolated from 4-week-old "pt" rabbits contained reduced amounts of galactosphingolipids and of several myelin protein markers. Moreover, myelin basic protein, analyzed by two-dimensional gel electrophoresis, showed a deficit in its more basic components. All these facts suggest a delay in myelin maturation. Ganglioside content was increased as well as Na+,K+-ATPase specific activity. 2',3'-Cyclic nucleotide phosphodiesterase (CNPase) specific activity was the same in "pt" as in control myelin but differed by having greater sensitivity to detergent activation.
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PMID:Myelin composition and activities of CNPase and Na+,K+-ATPase in hypomyelinated "pt" mutant rabbit. 282 82

Myelin proteins were quantitated in whole tissue and isolated 'myelin fractions' from spinal cord, brainstem and hemispheres of 'shaking pups', a mutation in Springer-Spaniel dogs characterized by hypomyelination of the CNS. The amount of myelin basic protein (MBP) in the brainstem of affected 4-week-old pups was 2.6% of that in age-matched controls, while the levels of 2'3'-cyclic nucleotide phosphodiesterase (CNP) and myelin-associated glycoprotein (MAG) were 10% and 15% of the control levels, respectively. Similar results were obtained in the spinal cord and hemispheres, and the amounts of these proteins in the mutant pups did not change substantially between 4 and 16 weeks of age. The amount of the 21 kDa MBP compared to the 18 kDa MBP was relatively increased in the shaking pups, suggesting that the small amount of myelin formed was immature. The yields of myelin fractions from the mutant pups were very low; e.g., the yield from the brainstems of 4-week-old mutants was only 2.4% of that from age-matched controls and the yield did not increase by 16 weeks. The isolated myelin fractions contained very little MBP (less than 0.5% of total protein) or proteolipid protein, indicating that they were a very immature form of myelin or consisted largely of non-myelin contaminants. MAG in the 'myelin fractions' from the mutant brainstems were 9-15 fold higher and CNP levels were 2-3 fold higher than those in whole homogenates, suggesting that the isolated fractions were enriched in oligodendroglia-derived membranes. Overall, the biochemical results are consistent with a severe hypomyelination of the CNS in which a small amount of immature myelin is formed.
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PMID:Myelin proteins in the CNS of 'shaking pups'. 370 84

Comparisons have been made of myelinogenic activities in fetal rat brain mixed primary cultures and cultures of isolated oligodendrocytes of comparable age. The specific activities of the sulfatide synthesis, 2',3'-cyclic-nucleotide 3'-phosphohydrolase (2',3'-cyclic-nucleotide 3'-phosphodiesterase, EC 3.1.4.37), and accumulation of myelin basic protein, when expressed per mg of protein, were as high (or generally higher) in isolated oligodendrocyte cultures as in comparable mixed primary cultures at 29 days. However, when these data were analyzed per oligodendrocyte, it became apparent that the isolated oligodendrocytes were substantially less active than their mixed culture counterparts. The results suggest the necessity of nonologodendrocyte positive signals for the optimal expression by oligodendrocytes of myelin-related differentiated functions. The isolation method involves the selection of oligodendrocytes by shaking them from primary cultures of rat brain, followed by the lysis of other contaminating cells in a balanced salt solution at pH 7.2. More than 99% of the isolated cells are viable, at least initially divide, and can be cultured for at least 60 days. The oligodendrocytes selected in this way were characterized by: (i) morphology, (ii) immunofluorescence labeling by antibodies to myelin basic protein and galactosylceramide, and (iii) biochemical analyses for myelin basic protein, activity of 2',3'-cyclic-nucleotide 3'-phosphohydrolase, and sulfogalactosylceramide synthesis.
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PMID:Requirement for nonoligodendrocyte cell signals for enhanced myelinogenic gene expression in long-term cultures of purified rat oligodendrocytes. 616 9


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