Archibald Garrod recognized that alkaptonuria was a disorder reflecting Mendelian inheritance in the human population. In 1902, that was an observation with remarkable insight. Garrod called this and three other Mendelian disorders (cystinuria, pentosuria, and albanism) examples of human biochemical individuality. Another 50 years would elapse before our understanding of the inborn errors of metabolism would lead to a field of inquiry called “human biochemical genetics.” The growth of knowledge in this field, in the latter half of the 20th century, is reflected in the expansion of information in The Metabolic and Molecular Bases of Inherited Disease.
In the seventh edition of MMBID there is a table of 50 pages listing 469 entries perceived by the editors as inborn errors of metabolism, descendants of what Archibald Garrod described in 1909. The table consists of eight columns that itemize the qualities of each inborn error. One of these, headed “Mutant gene product,” lists the names of the variant proteins that lie at the root of the pathogenesis of each disease. These proteins comprehend principally enzymes, but there are also receptors, transporting and structural proteins, hormones, clotting factors, immunoproteins, hemoglobins, and the like. Other columns lodge the variant in its homeostatic system and allude to its phenotype, while still others reveal the chromosomal locus occupied by the gene of its origin.
So the data comprise gene, gene locus, gene product, homeostatic system, and the results of dysfunction. Naturally the data are not complete. Of the total, the crucial variant protein is missing for 71, and for even more, chromosomal localization and other properties are missing. Why are those incomplete entries included? Because the disease phenotypes segregate and biochemical and other attributes predict that gene and gene product will soon be manifest. Such is the power of segregation!
Of course, the list was out of date when the seventh edition emerged in 1994, and the list in the present edition, despite the addition of many more entries, will also be out of date; the rate of increase is exponential. Even so, we may be confident that although the new list embraces new kinds of protein variants and new homeostatic systems, it does not deviate in principle from the old. But the significance for medicine of this expanding list of proteins and homeostatic devices lies not in their number or rate of increase but in the hypothesis that no homeostatic element is invulnerable, so that, as defined by the editors of MMBID, the list of inborn errors must expand until all variants of all protein components of all homeostatic systems have been included.
There is a further hypothesis, more embracing, more profound. It is that the protein variants of homeostasis, each a unit step in a physiological mechanism, are the points of origin of all disease. Descriptions of pathogenesis focus on cellular dysfunction as it originates in the protein ...