Housekeeping Proteins and Specialty Proteins in Genetic Disease
Proteins can be separated into two general classes on the basis of their pattern of expression: housekeeping proteins, which are present in virtually every cell and have fundamental roles in the maintenance of cell structure and function; and tissue-specific specialty proteins, which are produced in only one or a limited number of cell types and have unique functions that contribute to the individuality of the cells in which they are expressed. Most cell types in humans express 10,000 to 15,000 protein-coding genes. Knowledge of the tissues in which a protein is expressed, particularly at high levels, is often useful in understanding the pathogenesis of a disease.
Two broad generalizations can be made about the relationship between the site of a protein’s expression and the site of disease.
• First (and somewhat intuitively), mutation in a tissue-specific protein most often produces a disease restricted to that tissue. However, there may be secondary effects on other tissues, and in some cases mutations in tissue-specific proteins may cause abnormalities primarily in organs that do not express the protein at all; ironically, the tissue expressing the mutant protein may be left entirely unaffected by the pathological process. This situation is exemplified by phenylketonuria, discussed in depth in the next section. Phenylketonuria is due to the absence of phenylalanine hydroxylase (PAH) activity in the liver, but it is the brain (which expresses very little of this enzyme), and not the liver, that is damaged by the high blood levels of phenylalanine resulting from the lack of hepatic PAH. Consequently, one cannot necessarily infer that disease in an organ results from mutation in a gene expressed principally or only in that organ, or in that organ at all.
• Second, although housekeeping proteins are expressed in most or all tissues, the clinical effects of mutations in housekeeping proteins are frequently limited to one or just a few tissues, for at least two reasons. In most such instances, a single or a few tissue(s) may be affected because the housekeeping protein in question is normally expressed abundantly there and serves a specialty function in that tissue. This situation is illustrated by Tay-Sachs disease, as discussed later; the mutant enzyme in this disorder is hexosaminidase A, which is expressed in virtually all cells, but its absence leads to a fatal neurodegeneration, leaving non-neuronal cell types unscathed. In other instances, another protein with overlapping biological activity may also be expressed in the unaffected tissue, thereby lessening the impact of the loss of function of the mutant gene, a situation known as genetic redundancy. Unexpectedly, even mutations in genes that one might consider as essential to every cell, such as actin, can result in viable offspring.