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Molecular biology and clinical importance of the Ca(2+)-sensing receptor
1National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1862, USA.
Abstract:
The Ca(2+)-sensing receptor (CaR) is a member of the seven-transmembrane domain, G protein-coupled receptor super-family. In the parathyroid gland, it mediates the inhibitory effects of extracellular Ca2+ on the secretion of parathyroid hormone. In the kidney, activation of the CaR causes decreased reabsorption of Ca2+ from the tubular lumen. Mutations in the CaR gene produce abnormalities of Ca2+ homeostasis. Heterozygous loss-of-function mutations cause familial hypocalciuric hypercalcemia. Homozygous loss-of-function mutations cause neonatal severe hyperparathyroidism. In contrast, gain-of-function CaR mutations result in autosomal dominant and sporadic hypoparathyroidism. The resulting hypoparathyroidism and hypocalcemia can range from asymptomatic to life-threatening. Patients with hypocalcemia due to CaR mutations also show disproportionate hypercalciuria that may increase the risk of nephrocalcinosis, nephrolithiasis, and renal insufficiency.
Insights
The calcium-sensing receptor (CaR) regulates calcium levels. CaR gene mutations disrupt calcium balance, leading to various hypercalcemic or hypocalcemic disorders and potential kidney complications.
Area of Science:
- Endocrinology
- Molecular Biology
- Nephrology
Background:
- The calcium-sensing receptor (CaR), a G protein-coupled receptor, plays a critical role in calcium homeostasis.
- It regulates parathyroid hormone secretion and renal calcium reabsorption.
Purpose of the Study:
- To elucidate the impact of CaR gene mutations on calcium homeostasis and associated clinical manifestations.
- To understand the spectrum of disorders caused by CaR dysfunction.
Main Methods:
- Analysis of CaR gene mutations and their effects on receptor function.
- Clinical correlation of genotype with calcium metabolism abnormalities.
Main Results:
- Loss-of-function mutations cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.
- Gain-of-function mutations lead to autosomal dominant hypoparathyroidism with hypocalcemia and hypercalciuria.
- CaR mutations can result in significant renal complications like nephrocalcinosis and nephrolithiasis.
Conclusions:
- CaR mutations are a significant cause of calcium-related endocrine and renal disorders.
- Understanding CaR function is crucial for diagnosing and managing these conditions.
- CaR dysfunction highlights the intricate regulation of calcium balance in the human body.