When calcium goes wrong: genetic alterations of a ubiquitous signaling route

In all eukaryotic cells, the cytosolic concentration of calcium ions ([Ca2+](c)) is tightly controlled by complex interactions among transporters, pumps, channels and binding proteins. Finely tuned changes in [Ca2+](c) modulate a variety of intracellular functions, and disruption of Ca2+ handling leads to cell death. Here we review the human genetic diseases associated with perturbations in the Ca2+ signaling machinery. Despite the importance of Ca2+ in physiology and pathology, the number of known genetic diseases that can be attributed to defects in proteins directly involved in Ca2+ homeostasis is limited to few examples, which will be discussed. This paucity in contrast with the wide molecular repertoire may depend on the extreme severity of the phenotype (leading to death in utero) or, conversely, on functional compensation due to redundancy. In the latter case, it stands to reason that other genetic defects in calcium signaling have yet to be identified owing to their subtle phenotype.