Hereditary Tubular Disorders of Mineral Handling

Inherited tubular transport disorders comprise a group of diseases that lead to profound derangements in the homeostasis of electrolytes, minerals, or organic solutes in the body. Over the past decade, remarkable progress has been made in our understanding of the molecular pathogenesis of hereditary tubulopathies and the fundamental molecular physiology of renal tubular transport processes. This review summarizes hereditary diseases caused by mutations in genes encoding various proteins operating along the renal tubule or modulating tubular function, which result in derangements in mineral homeostasis or bone disease. Review of the molecular basis of these hereditary tubulopathies reveals various loss-of-function or gain-of-function mutations in genes encoding co-transporters, exchangers, or channel proteins, which are located in the luminal, basolateral, or endosomal membranes of the tubular cell or in paracellular tight junctions. Some of these hereditary abnormalities in renal handling of minerals are caused by defects in receptors, enzymes or other biologically active proteins which are produced in or outside the renal tubular cell and normally modulate the activity of renal transport proteins. All these gene mutations result in a variety of functional defects in transporter/channel proteins, including decreased activity, impaired gating, defective trafficking, impaired endocytosis and defective degradation, all of which lead to derangements in mineral balance. Further molecular studies of inherited tubular transport disorders may shed more light on the molecular pathophysiology of these diseases and may significantly improve our understanding of the mechanisms underlying renal mineral homeostasis in health and disease. The identification of the molecular defects in these inherited tubulopathies may provide a basis for future design of targeted therapeutic interventions and, possibly, strategies for gene therapy of these complex disorders.