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When calcium goes wrong: genetic alterations of a ubiquitous signaling route
Rosario Rizzuto1, Tullio Pozzan
1Department of Experimental and Diagnostic Medicine and Interdisciplinary Centre for the Study of Inflammation, University of Ferrara, Section of General Pathology, Via Borsari 46, 44100 Ferrara, Italy. rosario.rizzuto@unife.it
Abstract:
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.
Insights
Genetic defects in calcium signaling proteins cause severe diseases. Few human genetic diseases linked to calcium ion (Ca2+) homeostasis proteins are known, possibly due to severe phenotypes or functional redundancy.
Area of Science:
- Cellular Biology
- Genetics
- Physiology
Background:
- Cytosolic calcium ions ([Ca2+]c) are critical for eukaryotic cell function.
- Tight regulation of [Ca2+]c involves transporters, pumps, channels, and binding proteins.
- Disruptions in calcium handling can lead to cell death.
Purpose of the Study:
- To review human genetic diseases linked to calcium signaling machinery defects.
- To discuss the limited known genetic diseases associated with calcium homeostasis proteins.
- To explore reasons for the paucity of identified genetic defects.
Main Methods:
- Literature review of human genetic diseases.
- Analysis of proteins involved in calcium homeostasis.
- Discussion of calcium signaling perturbations.
Main Results:
- A limited number of human genetic diseases are directly attributed to defects in calcium homeostasis proteins.
- Potential reasons for this paucity include extreme in utero lethality or functional redundancy.
- Subtle phenotypes may mask other genetic defects in calcium signaling.
Conclusions:
- Despite the wide array of calcium-handling proteins, known genetic diseases are few.
- Further research may uncover additional genetic defects with subtle phenotypes.
- Understanding calcium signaling is crucial for identifying and treating genetic disorders.