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J Clin Endocrinol Metab. 2014 Dec;99(12):E2794-8. doi: 10.1210/jc.2014-2857.

Increased prevalence of the GCM2 polymorphism, Y282D, in primary hyperparathyroidism: analysis of three Italian cohorts.

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Medical Genetics, Endocrinology, Pathology and Radiology (L.D., M.C., V.G., C.B., A.S.S. G.G., R.C., D.d.M., A.Sc.), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) "Casa Sollievo della Sofferenza," 71013 San Giovanni Rotondo (FG), Italy; Endocrine and Diabetology Unit (I.C., C.E.-V., A.Sp.) Department of Medical Sciences, University of Milan and IRCCS Policlinico San Donato (S.C.), San Donato Milanese, Milan, Italy; Departments of Endocrinology and Metabolism (F.C., C.M.), University of Pisa, Pisa, Italy; Department of Internal Medicine and Medical Disciplines (S.M.), "Sapienza" Rome University, Rome, Italy; Endocrine Unit (M.Z.), Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy; Departments of Medicine, Physiology and Human Genetics (L.C., G.N.H.), McGill University, and Calcium Research Laboratory, and Hormones and Cancer Research Unit, Royal Victoria Hospital, Montreal, Quebec, H3A 1A1 Canada; and Departments of Laboratory Medicine and Pathobiology, Medicine and Genetics (B.Y.L.W., D.E.C.C.), University of Toronto, Ontario, M4N 3M5 Canada.



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 263-352).


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 included a large southern Italian cohort (310 PHPT and 433 C) and 2 replication cohorts from northern Italy. Association of 282D with PHPT was tested in all cohorts and with phenotypic features in the larger PHPT cohort. An in vitro GCM promoter-luciferase reporter assay was conducted in HEK293 cells.


282D was significantly increased in the PHPT group, with a minor allele frequency of 0.066 compared with 0.029 in the C group (P = .0008), in the discovery cohort and was more prevalent in the replication cohorts. Combined analysis (510 PHPT and 665 C) yielded a likelihood ratio of 2.27 (95% confidence interval = 1.50-3.42; P < .0001). The 282D variant was not associated with serum calcium, phosphate, creatinine, or PTH levels or with bone mineral density, fractures, or renal stones in the PHPT group. The 282D variant had significantly greater transcriptional activity than the wild-type Y282 (17× basal vs 12× basal; P < 0.05).


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.

[Indexed for MEDLINE]

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