Bases moléculaires des maladies enzymatiques génétiques

Abstract

Summary An attempt has been made to precise the molecular mechanisms of human genetic enzymatic diseases. Starting from the data of bacterial genetics, predictions of the theory are compared to the actual facts. o 1. Controller gene abnormalities should now be discussed in the light of positive as well as negative control. Non-functioning of the regulator (regulator-negative mutation) would result in a recessive gain of function in a negative control system, in a recessive loss of function in a positive system. In both cases heterozygotes should show no change of enzymatic activity. A superrepressor mutation in a negative system would produce a dominant loss of function; a constitutive mutation in a positive system would in principle produce a dominant gain. The general case is actually that of a loss of function with a partial deficiency in heterozygotes and does not fit the predictions. Among recessive diseases the only good candidates are thalassemias, which could be explained by operator negative mutations in a negative system, or by regulator mutations in a positive system. Von Willebrand's disease (dominant vascular abnormalities with a deficiency of antihemophilic factor) could be due to a mutation of the superrepressor type. Hepatic porphyria (involving an increase in the enzyme amino-levulinic acid synthetase) would be best explained by a constitutive mutation of the activator in a positive regulatory system. 2. Structural gene abnormalities are increasingly being demonstrated despite many difficulties. Investigations are conducted along several lines: – Electrophoresis has been useful in only a few cases, an outstanding example being that of glucose-6-phosphate dehydrogenase. – A decreased affinity towards the substrate or a diminished reactivity with the coenzyme can in a good many examples explain the anomalies. In the latter case this affords a remarkable approach to therapy. – Immunological search for the molecule seems to be presently the best general tool to look for an enzymatically inactive protein. At least in six enzymatic deficiencies the molecule could be recognized showing in addition in each case a genetic heterogeneity. Only in two diseases attempts have been unsuccessful so far. In addition the molecule was found to be present in all six defects of clotting factors which have been investigated. 3. Other possible mechanisms are briefly discussed. One possibility is a non-sense mutation. An attempt to demonstrate the biosynthesis of an initial fragment of hemoglobin chain in some cases of thalassemia was unsuccessful. 4. In conclusion most of the simple genetic enzymatic deficiencies are probably due to missense mutations in the structural genes. The molecule is being found in an increasing number of diseases. The mechanisms which seem to be at work in most cases are the following: – Instability of the molecule: this is probably the most frequent case when the number of molecules is low in the diseased tissue. The best example is that of many types of red cell glucose-6-phosphate dehydrogenase deficiencies. – Modification of the active site or the overall structure of the molecule, which is probable when the molecule is present in normal amount. – Lack of transformation of a precursor molecule, which could be responsible for some clotting factor defects.