Human biochemical genetics / by H. Harris.

  • Harry Harris
Date:
1959
Catalogue details

Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

Credit: Human biochemical genetics / by H. Harris. Source: Wellcome Collection.

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    284 THE PROBLEM OF GENE ACTION Another common problem in these conditions concerns the inter¬ relationships between the metabolic disorder as expressed in bio¬ chemical terms and the other pathological and clinical features of the disease. The simple gene-enzyme hypothesis implies that all the diverse manifestations of each of these conditions should be attributable to the metabolic consequences of a single enzyme deficiency. The analysis of the precise causal sequence involved is of significance therefore in validating the general hypothesis. In hypophosphatasia, for example, there is a generalised deficiency of alkaline phosphatase activity, and this is associated with a characteristic disturbance in bone development. The causal connections are, however, quite obscure. Until this has been sorted out the possibility cannot be excluded that the abnormality in bone formation depends on a bio¬ chemical disturbance not directly resulting from the known enzyme deficiency but nevertheless a consequence of the presence of the abnormal gene. It has also to be remembered that the demonstration in vitro of a particular kind of enzymic activity by a protein does not necessarily mean that this corresponds to its normal metabolic function, or that the substrates used experimentally are those on which it acts under normal physiological conditions. In the same way the demonstration in vitro of the diminution or loss of a particular kind of enzymic activity in material from patients suffering from some inherited syndrome, does not necessarily imply that this loss of enzymic activity, as such, is the cause of the metabolic disorders present. These con¬ siderations are relevant, as an example, to the interpretation of the diminution of plasma oxidase activity in Wilson's disease. In this condition a characteristic finding is a marked reduction in the amounts of the copper-containing protein caeruloplasmin present in the plasma. Now caeruloplasmin has been shown to exhibit in vitro marked oxidase activity using a variety of different substrates such as /7-phenylene diamine, dopa, and adrenaline. The oxidase activity of plasma is closely correlated with its caeruloplasmin content, and in Wilson's disease the plasma oxidase activity and the caerulo¬ plasmin level are reduced in more or less proportionate amounts. But it is not known whether the oxidase activity of caeruloplasmin is of any significance physiologically, and one cannot assume that this activity is its main biological function. Furthermore, although it is possible that in Wilson's disease a defect in caeruloplasmin synthesis is the central lesion, there is nothing to suggest that the