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Recent data suggest an increase in the overall incidence of parathyroid disorders, with primary hyperparathyroidism (PHPT) being the most prevalent parathyroid disorder. PHPT is associated with morbidities (fractures, kidney stones, chronic kidney disease) and increased risk of death. The symptoms of PHPT can be nonspecific, potentially delaying the diagnosis. Approximately 15% of patients with PHPT have an underlying heritable form of PHPT that may be associated with extraparathyroidal manifestations, requiring active surveillance for these manifestations as seen in multiple endocrine neoplasia type 1 and 2A. Genetic testing for heritable forms should be offered to patients with multiglandular disease, recurrent PHPT, young onset PHPT (age ≤40 years), and those with a family history of parathyroid tumors. However, the underlying genetic cause for the majority of patients with heritable forms of PHPT remains unknown. Distinction between sporadic and heritable forms of PHPT is useful in surgical planning for parathyroidectomy and has implications for the family. The genes currently known to be associated with heritable forms of PHPT account for approximately half of sporadic parathyroid tumors. But the genetic cause in approximately half of the sporadic parathyroid tumors remains unknown. Furthermore, there is no systemic therapy for parathyroid carcinoma, a rare but potentially fatal cause of PHPT. Improved understanding of the molecular characteristics of parathyroid tumors will allow us to identify biomarkers for diagnosis and novel targets for therapy., (Published by Oxford University Press on behalf of the Endocrine Society 2023.)

Hereditary origin of a tumor helps toward early discovery of its mutated gene; for example, it supports the compilation of a DNA panel from index cases to identify that gene by finding mutations in it. The gene for a hereditary tumor may contribute also to common tumors. For some syndromes, such as hereditary paraganglioma, several genes can cause a similar syndrome. For other syndromes, such as multiple endocrine neoplasia 2, one gene supports variants of a syndrome. Onset usually begins earlier and in more locations with hereditary than sporadic tumors. Mono- or oligoclonal ("clonal") tumor usually implies a postnatal delay, albeit less delay than for sporadic tumor, to onset and potential for cancer. Hormone excess from a polyclonal tissue shows onset at birth and no benefit from subtotal ablation of the secreting organ. Genes can cause neoplasms through stepwise loss of function, gain of function, or combinations of these. Polyclonal hormonal excess reflects abnormal gene dosage or effect, such as activation or haploinsufficiency. Polyclonal hyperplasia can cause the main endpoint of clinical expression in some syndromes or can be a precursor to clonal progression in others. Gene discovery is usually the first step toward clarifying the molecule and pathway mutated in a syndrome. Most mutated pathways in hormone excess states are only partly understood. The bases for tissue specificity of hormone excess syndromes are usually uncertain. In a few syndromes, tissue selectivity arises from mutation in the open reading frame of a regulatory gene (CASR, TSHR) with selective expression driven by its promoter. Polyclonal excess of a hormone is usually from a defect in the sensor system for an extracellular ligand (e.g., calcium, glucose, TSH). The final connections of any of these polyclonal or clonal pathways to hormone secretion have not been identified. In many cases, monoclonal proliferation causes hormone excess, probably as a secondary consequence of accumulation of cells with coincidental hormone-secretory ability.

An extensive body of pharmacological data demonstrates the existence of at least three opioid receptor subtypes mediating the diverse effects of opioids. Distinct binding and activity profiles of highly selective ligands, variable sensitivity to naloxone antagonisms, and selective protection and inactivation experiments strongly suggest that mu-, delta-, and kappa-opioid receptors represent recent discrete molecular entities. Purification and affinity labeling of receptor subunits are beginning to provide confirmation of this concept. The delta-opioid receptor affinity labeled and purified to homogeneity from NG108-15 cells comprises a glycoprotein subunit of Mr58,000 with one mol ligand bound/mol protein. Antibodies to this protein recognize native receptor in detergent solution and selectively bind to the Mr58,000 protein on immunoblots of partially purified preparations. Purification of the mu-opioid receptor from bovine striatum reveals a glycoprotein of Mr 65,000 which demonstrates opioid binding activity. Purification and affinity-labeling studies from other laboratories suggest a smaller size of Mr 58,000 for the mu-receptor however. The kappa-opioid receptor from guinea pig brain exhibits a unique mobility on sucrose density gradient centrifugation but has not been characterized in purified form. The primary structure of the opioid receptors, although unknown at present, will most likely reflect structural features of other inhibitory receptors coupled to G-proteins, with seven transmembrane helices and a large third cytoplasmic loop. Biochemical evidence clearly demonstrates the coupling of opioid receptors to Gi, accounting for opioid inhibition of adenylyl cyclase in neuronal cell culture and brain. Opioid inhibition of adenylyl cyclase has been reconstituted in IAP-treated NG108-15 cell membranes with a Gi preparation from brain. Electrophysiological evidence suggests that mu- and delta-opioid receptors can couple to a G-protein which mediates activation of inwardly rectifying potassium channels, perhaps to the same Gk mediating muscarinic potassium channel activation in heart. kappa-Opioid receptors are coupled to inhibition of voltage-dependent calcium channels in several neuronal systems. In NG108-15 cells opioid inhibition of calcium conductance is IAP sensitive and can be reconstituted with G-proteins purified from brain. Differences in the primary structure of mu-, delta-, and kappa-opioid receptors, as well as possible novel opioid receptor subtypes, will be defined by molecular cloning of recombinant DNA.(ABSTRACT TRUNCATED AT 400 WORDS)