More than 50% of patients with hereditary spastic paraplegia carry mutations in one of three genes: spastin (SPG4), receptor-expression-enhancing protein 1 (SPG31 or REEP1), or atlastin-1 (SPG3A). Spastin encodes an ATPase with a microtubule-severing activity that has different splice variants with different subcellular localizations, including the endosomes and the endoplasmic reticulum. Notably, spastin interacts with the other hereditary spastic paraplegia protein, REEP1. REEP proteins, and the structurally related reticulon proteins, have a major morphogenetic role at the endoplasmic reticulum45 because of a conserved domain of approximately 200 amino acids with two hydrophobic segments that form a hairpin in the membrane and have membrane-bending properties. Through this domain and its ability to oligomerize, the REEP and reticulon proteins can shape membranes of the endoplasmic reticulum into tubules.45 Intriguingly, spastin also interacts with the third major hereditary spastic paraplegia protein, atlastin. These collective observations led to the hypothesis that atlastin itself might have a role in the morphogenesis of the endoplasmic reticulum. This disease-inspired hypothesis turned out to be correct and revealed that atlastin is involved in the generation of the tubular endoplasmic-reticulum network, since it mediates homotypic fusion of tubules in the endoplasmic reticulum. Finally, in a further tightening of the relationships among atlastin-1, spastin, and REEP1, these three proteins have recently been reported to interact with one another.
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This emerging scenario supports a convergent mechanism of disease in the many forms of hereditary spastic paraplegia that involve a defect in the formation of the endoplasmic reticulum tubular network. This might be particularly detrimental for long spinal neurons, since the endoplasmic reticulum is a conduit for many important small molecules with signaling or structural roles (e.g., calcium and lipids). Thus, the pervasiveness and continuity of the endoplasmic-reticulum network might well be essential in these extremely elongated cells, whereas such a network may be at least partially dispensable in smaller cells.
As in such examples, other cases can be identified in which information that is gathered from genetic diseases might reasonably lead to the discovery of converging molecular pathways in the near future. One such case is inherited renal Fanconi’s syndrome, a common clinical manifestation of a heterogeneous group of genetic disorders that are characterized by dysfunction of renal proximal tubular cells. These cells reabsorb more than 90% of nutrients, vitamins, and low-molecular-weight proteins present in the ultrafiltrate. This reabsorption of nutrients and proteins relies on efficient endocytic recycling of the multiligand receptor megalin, which captures its ligands in the ultrafiltrate, internalizes them through clathrin-dependent endocytosis, delivers them to the endolysosomes, and then recycles back to the apical surface of the cell for another round of transport. The endocytic system of these cells is subjected to a very heavy burden, and a drop in its efficiency can cause low-molecular-weight proteinuria, one of the hallmarks of renal Fanconi’s syndrome. Such a decline in efficiency might arise from defects in this endocytic receptor, megalin; in its associated receptor, cubilin; or in the machinery associated with their endocytosis and recycling. For instance, impaired trafficking of megalin has been suggested to occur in Dent’s disease, a proximal renal tubulopathy characterized by low-molecular-weight proteinuria, nephrocalcinosis, and hypercalciuria. This disease is caused by mutations in CLCN5, which encodes the renal chloride–proton antiporter, which in turn controls the acidification and recycling activity of endosomal compartments. Moreover, it has been shown that some forms of Dent’s disease (Dent 2) appear to also derive from mutations in OCRL1, which encodes an endosome-associated phosphatidylinositol 4,5-bisphosphate 5-phosphatase. OCRL1 was originally discovered as the causative gene in Lowe’s syndrome, a more serious disease that is characterized by proximal renal tubular dysfunction and by congenital cataracts and mental retardation.