Oxford University Press (OUP), The Journal of Clinical Endocrinology & Metabolism, 12(99), p. E2794-E2798
DOI: 10.1210/jc.2014-2857
Full text: Download
Context: Glial cells missing-2 (GCM2) is key for parathyroid gland organogenesis. Its persistent expression in the adult parathyroid raises the possibility that overactive forms play a role in the evolution of parathyroid hyperactivity or tumorigenesis. A GCM2 c.844T>G; p.Y282D missense variant has been described within a transactivation inhibitory domain (amino acids 263 to 352). Objective: The aims of the study were to: 1) assess the frequency of Y282D in Italian primary hyperparathyroidism (PHPT) and control (C) populations, 2) test for association of 282D with PHPT and its phenotypic features, and 3) compare the transactivation potency of GCM2 282D relative to wild-type Y282. Subjects and Methods: A large southern Italian cohort (PHPT=310, C=433) and two replication cohorts from northern Italy. Association of 282D with PHPT was tested in all cohorts and with phenotypic features in the larger PHPT cohort. In vitro GCM promoter-luciferase reporter assay was conducted in HEK293 cells. Results: 282D was significantly increased in PHPT group [minor allele frequency (MAF)=0.066] compared to C (MAF=0.029, p=.0008) in the discovery cohort and was more prevalent in the replication cohorts. Combined analysis (PHPT=510, C=665) yielded a likelihood ratio of 2.27 (95% CI 1.50 - 3.42; p<0.0001). The 282D variant was not associated with serum calcium, phosphate, creatinine and PTH levels, nor bone mineral density (BMD), fractures or renal stones in the PHPT group. The 282D variant had significantly greater transcriptional activity than the wild-type Y282 (17x basal versus 12x basal; p<0.05). Conclusion: The higher frequency of GCM2 282D in PHPT and enhanced transcriptional activity of this variant supports the notion that it could contribute causally to parathyroid tumorigenesis.