KL

The KL gene provides instructions for making the protein alpha-klotho, which is found primarily in kidney cells. This protein plays a major role in regulating the phosphate levels within the body (phosphate homeostasis). Among its many functions, phosphate plays a critical role in the formation and growth of bones in childhood and helps maintain bone strength in adults. Phosphate levels are controlled in large part by the kidneys. The kidneys normally rid the body of excess phosphate by excreting it in urine, and they reabsorb this mineral into the bloodstream when more is needed.

Alpha-klotho attaches (binds) to and turns on (activates) a protein called FGF receptor 1 that spans the membrane of many types of cells, including kidney cells. Once the receptor is active, another protein called fibroblast growth factor 23 can also bind to it. Binding of fibroblast growth factor 23 to its receptor stimulates signaling that stops phosphate reabsorption into the bloodstream.

hyperphosphatemic familial tumoral calcinosis - caused by mutations in the KL gene

At least one mutation in the KL gene has been found to cause hyperphosphatemic familial tumoral calcinosis (HFTC), a condition characterized by an increase in the levels of phosphate in the blood (hyperphosphatemia) and abnormal deposits of phosphate and calcium (calcinosis) in the body's tissues. The KL gene mutation that causes HFTC replaces the protein building block (amino acid) histidine with the amino acid arginine at position 193 in the protein sequence (written as His193Arg or H193R). This mutation results in a shortage of functional alpha-klotho. As a result, FGF receptor 1 is not activated, making it unavailable for fibroblast growth factor 23 binding. The fibroblast growth factor 23 protein is normal, but it cannot bind to its receptor and cannot send out signals to stop phosphate reabsorption. As a result, too much phosphate is reabsorbed into the bloodstream, leading to hyperphosphatemia and subsequent calcinosis.