Schematic highlighting molecular components associated with monogenic disorders of calcium and bone metabolism. Alterations in extracellular calcium are detected by the calcium-sensing receptor (CaSR), which is expressed in parathyroid, kidney, and bone cells. The CaSR signals via the Gq/11 proteins to stimulate phospholipase C (PLC), which catalyses the hydrolysis of phosphoinositide (PIP2) to inositol triphosphate (IP3), thereby increasing intracellular calcium (Ca2+i), and diacylglycerol (DAG). Expression of CaSR is also regulated by the AP2 adaptor complex (AP2) which is involved in clathrin-mediated endocytosis. In parathyroid cells, CaSR activation decreases PTH secretion. Parathyroid gland development and function are regulated by genes encoding: transcription factors (e.g., GCM2, GATA3, TBX1), members of epigenetic regulatory complexes (e.g., MEN1, CDC73), and mitochondrial and cytoskeletal proteins. Parathyroid cells express other receptors (e.g., RET) that may influence their proliferation/behaviour. The PTH1 receptor is abundantly expressed in kidney and bone where it regulates calcium and phosphate homeostasis. Binding of PTH to the PTH1 receptor results in activation of two second messenger pathways: Gs-dependent cyclic adenosine monophosphate (cAMP)/Protein Kinase A (PKA) and Gq/11-dependent IP3/Protein Kinase C (PKC). The generation of cAMP results in binding to the PKA regulatory subunits (R) and release of catalytic subunits (C), facilitating serine-threonine phosphorylation of downstream target proteins. cAMP levels are also regulated by degradation, mediated by phosphodiesterase enzymes (e.g., PDE4D). Renal phosphate homeostasis is predominantly regulated in the proximal renal tubule by two apically expressed Na/Pi cotransporters. Activation of the PTH1 receptor and FGF receptor inhibit phosphate reabsorption. In the latter setting, the ligand FGF23, whose expression is regulated by the endopeptidase PHEX, binds to the FGF receptor in the presence of the membrane bound klotho (K) coreceptor, to activate MAPK and downstream phosphorylation of the Na+-H+ exchanger regulatory factor 1 (NHERF1) and internalisation of the NPT2a and NPT2c proteins. Mutations in several genes involved in parathyroid gland development and function, and/or those involved in the activities of PTH-dependent target tissues (e.g., kidney and bone) are associated with monogenic disorders of calcium and bone metabolism. In this schematic, disorders manifesting HP/hypocalcaemia are highlighted in bold red font to the right of the figure, those associated with PHPT/hypercalcaemia are shown in bold blue font to the left of the figure, while relevant disorders of bone/mineral metabolism not typically associated with hypo- or hypercalcaemia calcium are shown in italic green font (both sides of schematic). Additional details of each of these disorders is provided in Tables 1–3 [Color figure can be viewed at wileyonlinelibrary.com]