| [ Summary ] |
Recent progress in our understanding of Klotho (KL) significantly advanced the field of mineral homeostasis. KL was originally identified in the mutant mouse with a phenotype resembling human aging. However, recent in vitro studies revealed that KL directly interacts with regulators of mineral homeostasis, including a calcium channel, transient receptor potential cation channel, subfamily V, member 5 (TRPV5) ; and a phosphaturic hormone, fibroblast growth factor 23 (FGF23). Involvement of KL in mineral metabolism is further supported by the identification of two disease-causing mutations in human KL. The first reported KL mutation was a homozygous loss-of-function mutation, which resulted in severe tumoral calcinosis with multiple abnormalities in mineral homeostasis. In contrast, a likely gain of function mutation caused by a chromosomal translocation resulted in hypophosphatemic rickets with hyperparathyroidism. Both KL mutations led to abnormal calcium, phosphate, and vitamin D metabolism, as well as elevated serum levels of parathyroid hormone （PTH） and FGF23. The opposing phenotypes due to defective KL functions provide in vivo evidence that KL acts primarily in PTH and FGF23-mediated mineral homeostasis. |