Structure and Function of Disease-Related Allelozymes

Abstract

Genetic variation at structural loci encoding enzymes (or polypeptide subunits of oligomeric enzymes) can cause pathology (i.e. enzymopathies) by producing in the gene product either a quantitative change, or a qualitative change or both. Purely quantitative changes might result from a deletion, or from a mutation in a regulatory region of DNA, causing decreased transcription. Qualitative changes usually result from point mutations within the coding region. These may bring about impaired catalytic activity, decreased stability or altered glycosylation of the protein, thus producing enzyme deficiency by a translational or post- translational mechanism. The clinical manifestations of an enzymopathy will depend in the first place on whether the expression of the respective gene is tissue-specific (e.g. the gene encoding phenylalanine hydroxylase is expressed only or mainly in the liver), or universal, as is the case with so-called housekeeping genes (e.g. triose phosphate isomerase is distributed ubiquitously and its deficiency causes a multi-system disease). Secondly, the clinical phenotype will depend on the precise nature of the enzyme abnormality: for instance, on whether substrate affinity is modified or not. It is not yet entirely clear why genetic variations seem to be much more common at certain enzyme loci than others.