Genetic errors

If enzymes responsible for DNA repair are unable to remove the DNA adduct, or if an error takes place in the repair, then the error in the genetic code remains when the cell divides. Thus, cellular proliferation is also required, in addition to a mutation, for there to be a permanent effect of a chemical compound. Accumulation of genetic errors, i.e., mutations, has been suspected to be an important factor in chemical carcinogenesis. ... 

Mitochondria are unique organelles in that they contain their own DNA (mtDNA), which, in addition to ribosomal RN A (rRNA) and transfer RN A (tRNA)-coding sequences, also encodes 13 polypeptides which are components of complexes I, III, IV, and V (Anderson et al., 1981). This fact has important implications for both the genetics and the etiology of the respiratory chain disorders. Since mtDNA is maternally-inherited, a defect of a respiratory complex due to a mtDNA deletion would be expected to show a pattern of maternal transmission. However the situation is complicated by the fact that the majority of the polypeptide subunits of complexes I, III, IV, and V, and all subunits of complex II, are encoded by nuclear DNA. A defect in a nuclear-coded subunit of one of the respiratory complexes would be expected to show classic Mendelian inheritance. A further complication exists in that it is now established that some respiratory chain disorders result from defects of communication between nuclear and mitochondrial genomes (Zeviani et al., 1989). Since many mitochondrial proteins are synthesized in the cytosol and require a sophisticated system of posttranslational processing for transport and assembly, it is apparent that a diversity of genetic errors is to be expected. 

Incidence of inherited diseases of amino acid metabolism. [Note Cystinuria is the most common genetic error of amino acid transport.]... 

Oxidation of fatty acids with an odd number of carbons proceeds two carbons at a time (pro ducing acetyl CoA) until the last three carbons (propionyl CoA). This compound is con verted to methylmalonyl CoA (a reaction requiring biotin), which is then converted to succinyl CoA by methylmalonyl CoA mutase (requiring vitamin B )- A genetic error in the mutase or vitamin B12 deficiency causes methylmalonic acidemia and aciduria. 

Genetic errors in or damage to cytoskeletal components can play a central role in disease including many forms of hemolytic anemia and the Duchenne and Becker muscular dystrophies. Appropriate cell-cell contact (regulated through the cytoskeleton) appears to be critical in preventing cells from becoming cancerous and, indeed, many types of cancerous cell exhibit abnormal cytoskeletons. 

A well-balanced system of enzymes involved in the degradation of sialoglycoconjugates is required for the normal functions of cells and tissues. A lack of catabolic enzymes, often due to genetic errors, may lead to severe diseases, as may a surplus of such enzymes, e.g. due to infections by microorganisms. These problems will be addressed in section 10.5. 

Influential model of Jacob and Monod ( ) shown in Figure 1. that control Is exercised by a repressor protein that affects the Initiation of transcription. For many years this was the favorite paradigm of biologists concerned with the normal processes of homeostasis, growth and differentiation, as well as their pathological manifestations—Infectious diseases. Inborn genetic errors and cancer. By almost any criterion this has been one of the most fruitful Ideas in modern biology. 

However, encephalopathies with a metabohc basis tend to be the most problanatic for infants or children, with functional outcomes dependent upon timely and pradent interventions. Three varieties of metabolic encephalopathy in children are discussed here. The first two are closely related. Inborn (genetic) errors of metabolism can present in the newborn as severe encephalopathy from hyperammonemia alone. When a metabolic error presents months to years later, a degree of hepatic insufficiency may complicate the metabolic derangement. In acute or fulminant hepatic failure of any etiology (i.e., infections, drug-induced, toxin-related), the rise in serum ammonia may be only moderate but other factors contribute to the ensuing encephalopathy, which may be devastating within days. 

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