Hannan Fadil M, Babinsky Valerie N, Thakker Rajesh V
Academic Endocrine UnitRadcliffe Department of Medicine, University of Oxford, Oxford, UK Department of Musculoskeletal BiologyInstitute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
Academic Endocrine UnitRadcliffe Department of Medicine, University of Oxford, Oxford, UK.
J Mol Endocrinol. 2016 Oct;57(3):R127-42. doi: 10.1530/JME-16-0124.
The extracellular calcium (Ca(2+) o)-sensing receptor (CaSR) is a family C G protein-coupled receptor, which detects alterations in Ca(2+) o concentrations and modulates parathyroid hormone secretion and urinary calcium excretion. The central role of the CaSR in Ca(2+) o homeostasis has been highlighted by the identification of mutations affecting the CASR gene on chromosome 3q21.1. Loss-of-function CASR mutations cause familial hypocalciuric hypercalcaemia (FHH), whereas gain-of-function mutations lead to autosomal dominant hypocalcaemia (ADH). However, CASR mutations are only detected in ≤70% of FHH and ADH cases, referred to as FHH type 1 and ADH type 1, respectively, and studies in other FHH and ADH kindreds have revealed these disorders to be genetically heterogeneous. Thus, loss- and gain-of-function mutations of the GNA11 gene on chromosome 19p13.3, which encodes the G-protein α-11 (Gα11) subunit, lead to FHH type 2 and ADH type 2, respectively; whilst loss-of-function mutations of AP2S1 on chromosome 19q13.3, which encodes the adaptor-related protein complex 2 sigma (AP2σ) subunit, cause FHH type 3. These studies have demonstrated Gα11 to be a key mediator of downstream CaSR signal transduction, and also revealed a role for AP2σ, which is involved in clathrin-mediated endocytosis, in CaSR signalling and trafficking. Moreover, FHH type 3 has been demonstrated to represent a more severe FHH variant that may lead to symptomatic hypercalcaemia, low bone mineral density and cognitive dysfunction. In addition, calcimimetic and calcilytic drugs, which are positive and negative CaSR allosteric modulators, respectively, have been shown to be of potential benefit for these FHH and ADH disorders.
细胞外钙（Ca(2+)o）敏感受体（CaSR）是C家族G蛋白偶联受体，可检测Ca(2+)o浓度的变化，并调节甲状旁腺激素分泌和尿钙排泄。位于3号染色体q21.1上的影响CASR基因的突变已被鉴定出来，这突出了CaSR在Ca(2+)o稳态中的核心作用。功能丧失性CASR突变导致家族性低钙血症性高钙血症（FHH），而功能获得性突变则导致常染色体显性低钙血症（ADH）。然而，仅在≤70%的FHH和ADH病例中检测到CASR突变，分别称为1型FHH和1型ADH，对其他FHH和ADH家族的研究表明，这些疾病在遗传上是异质性的。因此，位于19号染色体p13.3上编码G蛋白α-11（Gα11）亚基的GNA11基因的功能丧失和功能获得性突变分别导致2型FHH和2型ADH；而位于19号染色体q13.3上编码衔接蛋白相关蛋白复合物2西格玛（AP2σ）亚基的AP2S1的功能丧失性突变导致3型FHH。这些研究表明Gα11是CaSR下游信号转导的关键介质，还揭示了参与网格蛋白介导的内吞作用的AP2σ在CaSR信号传导和转运中的作用。此外，3型FHH已被证明是一种更严重的FHH变体，可能导致症状性高钙血症、低骨矿物质密度和认知功能障碍。此外，拟钙剂和钙解剂药物，分别是CaSR的正性和负性变构调节剂，已被证明对这些FHH和ADH疾病具有潜在益处。
