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A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism
1Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
Mice lacking the calcium-sensing receptor (Casr) were created to examine the receptor's role in calcium homeostasis and to elucidate the mechanism by which inherited human Casr gene defects cause diseases. Casr+/- mice, analogous to humans with familial hypocalciuric hypercalcemia, had benign and modest elevations of serum calcium, magnesium and parathyroid hormone levels as well as hypocalciuria. In contrast, Casr-/- mice, like humans with neonatal severe hyperparathyroidism, had markedly elevated serum calcium and parathyroid hormone levels, parathyroid hyperplasia, bone abnormalities, retarded growth and premature death. Our findings suggest that Casr mutations cause these human disorders by reducing the number of functional receptor molecules on the cell surface.
Insights
Mice lacking the calcium-sensing receptor (Casr) showed that Casr is crucial for maintaining calcium balance. Loss of Casr function in mice and humans leads to severe hypercalcemia and related health issues.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- The calcium-sensing receptor (Casr) plays a vital role in regulating calcium homeostasis.
- Inherited defects in the Casr gene are linked to human disorders characterized by abnormal calcium levels.
Purpose of the Study:
- To investigate the function of the calcium-sensing receptor (Casr) in vivo.
- To understand the mechanisms underlying human diseases caused by Casr gene mutations.
Main Methods:
- Generation and analysis of Casr-deficient mouse models (Casr+/- and Casr-/-).
- Measurement of serum calcium, magnesium, and parathyroid hormone levels.
- Assessment of urinary calcium excretion and parathyroid gland morphology.
Main Results:
- Casr+/- mice exhibited mild hypercalcemia, hypermagnesemia, elevated parathyroid hormone, and hypocalciuria, mirroring familial hypocalciuric hypercalcemia.
- Casr-/- mice displayed severe hypercalcemia, marked parathyroid hyperplasia, bone abnormalities, growth retardation, and premature death, similar to neonatal severe hyperparathyroidism.
- A reduction in functional cell surface Casr molecules was implicated in disease pathogenesis.
Conclusions:
- The calcium-sensing receptor is essential for maintaining calcium and magnesium homeostasis.
- Casr gene mutations causing loss of functional receptor molecules lead to severe human hypercalcemic disorders.
- Casr deficiency in mice serves as a relevant model for studying these human genetic diseases.