Structural gene defects

The discovery of X-linked agammaglobulinaemia in 1952 was only a prelude to the discovery of a large number of deficiency states in the immunological systems. At present, almost all the well-defined immunodeficiencies in man and animals have a genetic basis. Despite this fact, it is curious that very few examples of structural gene defects have come to light. Most of the immunodeficiency diseases appear to result from the failure of some regulatory process, and a disproportionate number of them are X linked. 

Many of the speculative possibilities could give rise to less drastic clinical abnormalities than are seen with structural gene defects. These conditions are difficult to study because there is no defect in protein structure, and in some cases a normal amount of protein may be produced. The adaptive defect is expressed mainly as a failure of protein synthesis to undergo a change in response to a stimulus. 

Electrophoretic and kinetic studies of the patient s enzyme have been reported in several cases (F10). Most of them showed decreased substrate affinity and abnormal electrophoretic mobility. The main cause of P5N deficiency is considered to be an abnormality of P5N-I, probably arising from a structural gene mutation (H6). The precise molecular defect has not been clarified, because the normal gene for P5N-I has not been isolated. 

A closely related disease is caused by a deficiency of propionyl-CoA carboxylase.3 This may be a result of a defective structural gene for one of the two subunits of the enzyme, of a defect in the enzyme that attaches biotin to carboxylases, or of biotinitase, the enzyme that hydrolytically releases biotin from linkage with lysine (Chapter 14). The latter two defects lead to a multiple carboxylase deficiency and to methylmalonyl aciduria as well as ketoacidosis and propionic acidemia. ... 

Not all patients who present the same clinical picture respond to vitamin therapy. Thus, if the structural gene for an apoenzyme or transport molecule is completely absent because of a gene deletion, no amount of vitamin or cofactor will correct the defect. If the mutation affects substrate rather than cofactor binding, the pathway is blocked just as effectively and cannot be relieved by increased concentration of cofactor. Thus, six mutations have been identified that cause methylmalonic aciduria. 

E2. Epstein, C. J., Structural and control gene defects in hereditary diseases in man. Lancet U, 1066-1067 (1964). 

We devised a screen for isolating mutants defective in iron-dependent regulation of heme biosynthesis that did not require prior knowledge of the mechanism or of the rate-limiting steps [83]. We speculated that if the pathway as a whole were regulated by iron, a mutant defective in that control would accumulate protoporphyrin under iron limitation. Mutants defective in the heme synthesis enzymes ferrochelatase [75] or protoporphyrinogen oxidase would likely have a similar phenotype, but porphyrin accumulation would likely be independent of iron in the structural gene mutants, and those strains would also be expected to be heme auxotrophs. 

Several types of human mutants with hypoxanthine uanine phospho-ribosyltransferase defects have recently been identified (8, 41, 42). Cells from patients with the so-called Lesch-Nyhan syndrome have very low i4S) or undetectable activities of this enzyme, but immunological studies have demonstrated that the enzyme protein is made even when it is cata-lytically inactive 44)- In some patients with gout, 0.05 to 10% of normal activity remains isozymes (45) and other mutants (46) have also been detected. The structural gene for hypoxanthine-guanine phosphoribo-syltransferase is on the X chromosome, and mutations at this locus are, therefore, only fully expressed in males. 

Probably due to a defective operator in the nucleus which controls the structural gene for ALA-synthetase... 

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