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The study of the disorders of membrane transport has contributed as much or more to our understanding of cell biology and metabolism as any other group of disorders discussed in this book. Indeed, one might make the cogent argument that one of these disorders defined the term inborn errors of metabolism when Dr. Archibald Garrod introduced the phrase in 1908. In his Croonian Lecture to the members of the Royal Academy, Garrod proposed that there is a group of disorders, each one familial in nature, deriving from a specific abnormality of metabolism of a particular compound. As proof of his hypothesis, he offered examples of four distinct disorders, of which one was the membrane-transport disorder cystinuria.

The field of pharmacology is greatly beholden to the study of disorders of membrane transport, which helped to shape the design of drugs such as calcium channel blockers, proton pump inhibitors, and receptor-blocking agents. Also, the increased understanding of the biochemical composition and topology of cell membranes deriving from studies of these diseases greatly informed investigations of acquired immune-deficiency syndrome, as well as the development of antibiotic and antiviral agents. Our understanding of the pathophysiology of many diseases of the central nervous system was furthered by knowledge of membrane biology that had its origins in investigations of transport disorders. A recently burgeoning field of investigation includes exploration of linkages between psychiatric conditions and mutations in neurotransmitter membrane carriers.1,2,3 Thus far, however, the data are merely associative and do not establish a clear causality. Therefore, discussion of this area remains outside the purview of this chapter. Out of all these studies, two fundamental principles of membrane transport emerged: membrane transport carriers have a substrate-binding specificity very much like enzymes, and in order to operate against a concentration gradient, there must be an energy source to drive the system.

Each of the disorders in this family is substrate-specific and usually is manifested by abnormally high levels of excretion in urine and/or stool of particular biological materials. This specificity gives the first clue to the underlying genetic nature of these disorders because biological specificity typically is based on the tertiary–quaternary structure of proteins, whose synthesis is genetically directed. The proteins involved in the group of transport disorders normally function to convey substrate either into or out of the cell or cellular organelles and thus must be located physically at or within the membrane. In fact, these proteins have different “domains,” some located at cell surfaces, either inner or outer, and others embedded within the bilayer structure. As a group, membrane-transport disorders generally are monogenetic with a pattern of autosomal recessive transmission. Some (eg, cystic fibrosis) exhibit devastating consequences for the affected individual, whereas others, such as renal tubular glycosuria, are harmless variations of normal, generally discovered by accident.


Disorders of renal hydrogen ion ...

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