Ramasamy Indra
Department of Chemical Pathology, Dumfries and Galloway District Hospital, Bankend Road, Dumfries, UK.
Clin Chim Acta. 2008 Aug;394(1-2):22-41. doi: 10.1016/j.cca.2008.04.011. Epub 2008 Apr 22.
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.
在哺乳动物中，一种复杂的稳态机制已经进化出来，以维持细胞外钙离子水平的近乎一致性。这种稳态机制涉及多种激素，其中包括甲状旁腺激素和维生素D。作为一个全球性的健康问题，近期维生素D缺乏症的再度出现增加了人们对这种激素的关注。除了维生素D缺乏外，佝偻病的其他病因还包括钙缺乏以及维生素D和磷代谢的遗传性疾病。维生素D抵抗综合征是由该激素代谢激活方面的遗传性缺陷或维生素D受体的突变所引起的，维生素D受体以高亲和力结合该激素，并通过锌指介导的DNA结合和蛋白质-蛋白质相互作用来调节基因的表达。当前的研究兴趣在于将导致维生素D代谢紊乱或维生素D受体功能障碍的突变类型/位置与可变的表型特征和临床表现联系起来。钙敏感受体在钙稳态中起关键作用。钙敏感受体的功能丧失性突变在杂合子时可导致家族性良性低钙血症性高钙血症，而当钙敏感受体发生纯合突变时可导致新生儿严重甲状旁腺功能亢进。功能获得性突变可导致相反的效应，引起常染色体显性低钙血症。使用靶向基因破坏策略的小鼠模型一直是研究突变对钙敏感受体或维生素D激活途径影响的有价值工具。具有功能改变突变的功能失调性钙敏感受体可能对钙敏感受体的变构调节剂治疗有反应。能在维生素D受体上诱导异常结构构象的维生素D类似物可能有多种治疗适应证。这篇综述总结了钙稳态遗传性疾病分子病理学知识方面的最新进展。
