SAT-772 Investigating the in Vivo Role of an Activating GCM2 Variant, I383M, as a Potential Contributor to the Pathogenesis of Primary Hyperparathyroidism

Abstract Disclosure: M. Jakubowski: None. S. Yaqoob-Krzystofiak: None. C. Burke: None. J. Bellizzi: None. J. Costa: None. A. Arnold: None. Familial isolated primary hyperparathyroidism (FIHP) is a form of primary hyperparathyroidism (PHPT) in which there is familial clustering of individuals with tumors in the parathyroid glands, which secrete inappropriately elevated amounts of parathyroid hormone (PTH) leading to dysregulated calcium homeostasis. The genetic cause of FIHP in most kindreds is unknown. In vitro activating germline variants in GCM2, encoding an eponymous transcription factor critical for parathyroid gland development, were reported in a subset of FIHP kindreds, but their pathogenicity, penetrance, and implications for clinical management are uncertain. One such variant, I383M, was associated with a severe phenotype, including parathyroid carcinoma, in one kindred. We sought to evaluate the effects of GCM2 I383M on PHPT and parathyroid tumorigenesis in a mouse model. Genetically engineered mice with a Gcm2 I383M mutation were compared to wildtype littermate controls. Gcm2 I383M mutant mice were viable, developed normally and appeared healthy. Mice were followed to a terminal timepoint of 18 months, at which parathyroid tissue was excised and blood was collected. Mice were evaluated for biochemical hyperparathyroidism and parathyroid tumorigenesis. Serum calcium, PTH, parathyroid gland volume and parathyroid cell proliferation, as measured by Ki67 immunostaining, were indistinguishable between Gcm2 I383M mutant and wildtype littermates. Thus, our results demonstrate that Gcm2 I383M mutant mice do not develop PHPT or parathyroid tumors. However, as our laboratory has recently demonstrated, another Gcm2 activating variant (Y392S, equivalent to human Y394S) was similarly insufficient to drive PHPT on its own but could cooperatively enhance parathyroid tumorigenesis in a mouse model of PHPT driven by parathyroid-specific overexpression of cyclin D1, suggesting this variant might function as a mild-to-moderate predisposition allele, rather than a tumor driver. Whether GCM2 I383M might similarly serve as a predisposition allele for PHPT merits further investigation. Presentation: Saturday, July 12, 2025