Unstable genes

Demerec, M. (1941). Unstable genes in Drosophila. Cold Spring Harbor Symp. Quant. Biol. 9, 145-149. 

In the examples given, there is good evidence for the formation of an unstable epoxide intermediate in the production of monohydroxymetabolites. However, there is an ongoing debate about the possible operation of other mechanisms of primary oxidative attack that do not involve epoxide formation, for example, in the production of 2 OH 3,3, 4,4 -TCB (Figure 6.3). As mentioned earlier, P450s of gene family 1 (CYP 1) tend to be specific for planar substrates, including coplanar PCBs they do not appear to be involved in the metabolism of nonplanar PCBs. On the other hand. 

A naturally occurring animal model of PFK-M deficiency has been reported in English springer spaniels. Molecular analysis of this canine PFK-M deficiency disclosed that the enzyme deficiency was caused by a nonsense mutation in the penultimate exon of the PFK-M gene, leading to rapid degradation of a truncated (40 amino acid residues) and therefore unstable enzyme protein (SI8). 

ADA deficiency is most commonly associated with these mutations of the ADA structural gene that result in either unstable or inactive enzyme protein. Immune reconstitution would be achieved by enzyme replacement therapy with polyethylene glycol-modified bovine ADA (PEG-AD A), alone or in combination with gene therapy (H3). 

Friedreich s ataxia is caused by an intronic triplet repeat expansion. Friedreich s ataxia is an autosomal recessive disorder characterized by progressive ataxia, nystagmus, distal sensory polyneuropathy and corticospinal tract degeneration. It is caused by an unstable expanded GAA repeat in intron 1 of the frataxin gene on chromosome 9ql3. This diminishes expression of frataxin, a mitochondrial iron-storage protein that participates in free radical metabolism [71]. 

Huntington s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington s disease chromosomes. Cell 72 971-983,1993. 

David, G., Abbas, N., Stevanin, G. etal Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat. Genet. 17 65-70,1997. 

Arii T, Ohyanagi M, Shibuya J, Iwasaki T 1999 Increased function of the voltage-dependent calcium channels, without increase of Ca2+ release from the sarcoplasmic reticulum in the arterioles of spontaneous hypertensive rats. Am J Hypertens 12 1236-1242 Attree O, Olivos IM, Okabe I et al 1992 The Lowe s oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature 358 239-242 Brading AF, Turner WH 1994 The unstable bladder towards a common mechanism. Br J Urol 73 3-8... 

Regulation of expression may occur at both the transcriptional and post-transcriptional levels. The mRNA for GM-CSF contains (in common with those of some other cytokines) conserved regulatory sequences in the 3 untranslated region, which may affect its rate of translation. The gene is constitutively transcribed in monocytes, endothelial cells and fibroblasts, but the mRNA is unstable and so does not accumulate to levels sufficient to allow translation into significant amounts of protein. Activation of these cells results in the increased expression of GM-CSF protein, which arises from both an enhanced rate of transcription (as detected in nuclear runoff experiments) and also an increased stability of the mRNA, perhaps by mechanisms analogous to those described above during activation of G-CSF expression ( 2.2.3.1). 

Molecular models for circadian rhythms were initially proposed [107] for circadian oscillations of the PER protein and its mRNA in Drosophila, the first organism for which detailed information on the oscillatory mechanism became available [100]. The case of circadian rhythms in Drosophila illustrates how the need to incorporate experimental advances leads to a progressive increase in the complexity of theoretical models. A first model governed by a set of five kinetic equations is shown in Fig. 3A it is based on the negative control exerted by the PER protein on the expression of the per gene [107]. Numerical simulations show that for appropriate parameter values, the steady state becomes unstable and limit cycle oscillations appear (Fig. 1). 

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