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Clin Chim Acta. 2008 Aug;394(1-2):22-41. doi: 10.1016/j.cca.2008.04.011. Epub 2008 Apr 22.

Inherited disorders of calcium homeostasis.

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Department of Chemical Pathology, Dumfries and Galloway District Hospital, Bankend Road, Dumfries, UK.


In mammals a complicated homeostatic mechanism has evolved to maintain near consistency of extracellular calcium ion levels. The homeostatic mechanism involves several hormones, which comprise among others, parathyroid hormone and vitamin D. The recent resurge in vitamin D deficiency, as a global health issue, has increased interest in the hormone. In addition to vitamin D deficiency, other causes of rickets are calcium deficiency and inherited disorders of vitamin D and phosphorus metabolism. Vitamin D-resistant syndromes are caused by hereditary defects in metabolic activation of the hormone or by mutations in the vitamin D receptor, which binds the hormone with high affinity and regulates the expression of genes through zinc finger mediated DNA binding and protein-protein interaction. Current interest is to correlate the type/position of mutations that result in disorders of vitamin D metabolism or in vitamin D receptor function with the variable phenotypic features and clinical presentation. The calcium sensing receptor plays a key role in calcium homeostasis. Loss of function mutations in the calcium sensing receptor can cause familial benign hypocalciuric hypercalcemia in heterozygotes and neonatal severe hyperparathyroidism when homozygous mutations occur in the calcium sensing receptor. Gain of function mutation can cause the opposite effect causing autosomal dominant hypocalcemia. Mouse models using targeted gene disruption strategies have been valuable tools to study the effect of mutations on the calcium sensing receptor or in the vitamin D activation pathway. Dysfunctional calcium sensing receptors with function altering mutations may be responsive to treatment with allosteric modulators of the calcium sensing receptor. Vitamin D analogs which induce unusual structural conformations on the vitamin D receptor may have a variety of therapeutic indications. This review summarises recent advances in knowledge of the molecular pathology of inherited disorders of calcium homeostasis.

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