Another reason for the tissue specificity of symptoms relates to a requirement for very efficient trafficking in tissues that require high transport rates for their function. Here, a defect without consequence for other cells might result in functional collapse, as can be seen in a number of cases: for cells that transport very large amounts of cargo at some stage of their life cycle, such as Schwann cells during myelination, which can selectively express genetic defects of ubiquitous trafficking components, such as MTMR2, MTMR13, FIG4, and SH3TC2, resulting in the demyelinating forms of Charcot–Marie–Tooth disease (CMT4). Also included are cells that require very high rates of internalization and recycling of plasma-membrane components, such as proximal tubular cells in the kidney, which must reabsorb essential components from the ultrafiltrate and which suffer from genetic defects of components of the endosomal system (as in many inherited forms of renal Fanconi’s syndrome, including Lowe’s syndrome), and cells that require very efficient long-range transport and communication, such as motor neurons, which are particularly sensitive to defects in proteins involved in different steps of membrane trafficking (as is the case in hereditary spastic paraplegias).

Lessons on the Role of Transport Proteins

Our understanding of mendelian diseases can benefit from knowledge of the transport machinery. However, the reverse is also true: important lessons on the physiological functions of transport proteins can be derived from the study of disease genes. Classic examples are the combined deficiency of coagulation factors V and VIII and mucolipidosis II (also called inclusion-cell disease). Here, studies of the factors V and VIII combined deficiency helped to reveal the physiological role in transport of the protein ERGIC53 (also called lectin mannose-binding 1). After it was discovered that a mutation in this protein is the cause of factors V and VIII deficiency, a series of studies revealed that ERGIC53 functions as a chaperone in protein transport from the endoplasmic reticulum to the Golgi complex for a specific subgroup of secreted proteins that includes these two coagulation factors. As for mucolipidosis II, Hickman and Neufeld observed in 1972 that lysosomal enzymes from patients with inclusion-cell disease “failed to reach their lysosomal destination.” Subsequent studies indicated that this disorder is caused by a defect in the Golgi enzyme that phosphorylates a specific mannose on lysosomal hydrolases. These observations helped in gaining an understanding of the key role of the mannose-6-phosphate receptor in the transport of these hydrolases from the Golgi complex to the lysosomes.