The calcium-sensing receptor in hereditary disordersof calcium homeostasis
2006
Inherited diseases of calcium homeostasis were described
more than 30 years ago. Consecutively, the discovery of the
calcium receptor (CaR) more than a decade ago, followed by
the demonstration that familial diseases of hyper- and hypocalcemia,
in some cases were caused by functionally important
mutations in the CaR, highlighted the receptor's pivotal role in
the maintenance of systemic calcium homeostasis. Mutations
that change the receptor’s affinity toward calcium induce illnesses
of calcium homeostasis by changing the set-point for
calcium-regulated PTH release as well as the renal handling of
calcium. Gain-of-function mutations cause a form of autosomal
dominant hypoparathyroidism (ADH); this rare disease exhibits
a clinical spectrum from mild to much more severe and
symptomatic hypocalcemia with relative or absolute hypercalciuria.
Loss-of-function mutations produce PTH-dependent
forms of hypercalcemia called familial hypocalciuric hypercalcemia
(FHH) in their heterozygous state (one mutated allele)
and neonatal severe primary hyperparathyroidism (NSPHT) in
their homozygous or compound heterozygous forms (two mutated
alleles). FHH is thought to occur with about 1% of the
prevalence of primary hyperparathyroidism and is often a benign
state of hypercalcemia with relatively low urinary calcium
output. NSPHT, on the other hand, is a considerably more rare
but severe form of hypercalcemia presenting in most cases
during the first 6 months of life. Affected children become
symptomatic early on in life with failure to thrive and severe
hyperparathyroid bone disease and may even die if left untreated.
Until recently treatment of this condition involved total
or subtotal parathyroidectomy. Similar to the inherited diseases
with mutations in the calcium-sensing receptor, autoimmune
diseases with antibodies targeting the CaR have been
recognized. This review will focus on the calcium-sensing receptor,
including its molecular physiology, as well as its role
in various diseases of calcium homeostasis that illuminate the
receptor’s role not only in pathophysiology but also in normal
physiology. Lastly, we shall describe the CaR as a drug target
with proven and potential applications
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