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

Leonardo D'Agruma, Michela Coco, Vito Guarnieri, Claudia Battista, Lucie Canaff, Antonio S. Salcuni, Sabrina Corbetta, Filomena Cetani, Salvatore Minisola, Iacopo Chiodini, Cristina Eller-Vainicher, Anna Spada, Claudio Marcocci, Giuseppe Guglielmi, Michele Zini, Rosanna Clemente, Betty Y L Wong, Danilo De Martino, Alfredo Scillitani, Geoffrey N. HendyDavid E C Cole

Research output: Contribution to journalArticle

Abstract

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 263-352). 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: 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. Results: 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). 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.

Original languageEnglish
Pages (from-to)E2794-E2798
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number12
DOIs
Publication statusPublished - Dec 1 2014

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Primary Hyperparathyroidism
Polymorphism
Neuroglia
Luciferases
Minerals
Assays
Creatinine
Bone
Transcriptional Activation
Carcinogenesis
Association reactions
Amino Acids
Parathyroid Glands
Organogenesis
HEK293 Cells
Gene Frequency
Bone Density
Italy
Confidence Intervals
Kidney

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Increased prevalence of the GCM2 polymorphism, Y282D, in primary hyperparathyroidism : Analysis of three Italian cohorts. / D'Agruma, Leonardo; Coco, Michela; Guarnieri, Vito; Battista, Claudia; Canaff, Lucie; Salcuni, Antonio S.; Corbetta, Sabrina; Cetani, Filomena; Minisola, Salvatore; Chiodini, Iacopo; Eller-Vainicher, Cristina; Spada, Anna; Marcocci, Claudio; Guglielmi, Giuseppe; Zini, Michele; Clemente, Rosanna; Wong, Betty Y L; De Martino, Danilo; Scillitani, Alfredo; Hendy, Geoffrey N.; Cole, David E C.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 99, No. 12, 01.12.2014, p. E2794-E2798.

Research output: Contribution to journalArticle

D'Agruma, Leonardo ; Coco, Michela ; Guarnieri, Vito ; Battista, Claudia ; Canaff, Lucie ; Salcuni, Antonio S. ; Corbetta, Sabrina ; Cetani, Filomena ; Minisola, Salvatore ; Chiodini, Iacopo ; Eller-Vainicher, Cristina ; Spada, Anna ; Marcocci, Claudio ; Guglielmi, Giuseppe ; Zini, Michele ; Clemente, Rosanna ; Wong, Betty Y L ; De Martino, Danilo ; Scillitani, Alfredo ; Hendy, Geoffrey N. ; Cole, David E C. / Increased prevalence of the GCM2 polymorphism, Y282D, in primary hyperparathyroidism : Analysis of three Italian cohorts. In: Journal of Clinical Endocrinology and Metabolism. 2014 ; Vol. 99, No. 12. pp. E2794-E2798.
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abstract = "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 263-352). 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: 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. Results: 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). 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.",
author = "Leonardo D'Agruma and Michela Coco and Vito Guarnieri and Claudia Battista and Lucie Canaff and Salcuni, {Antonio S.} and Sabrina Corbetta and Filomena Cetani and Salvatore Minisola and Iacopo Chiodini and Cristina Eller-Vainicher and Anna Spada and Claudio Marcocci and Giuseppe Guglielmi and Michele Zini and Rosanna Clemente and Wong, {Betty Y L} and {De Martino}, Danilo and Alfredo Scillitani and Hendy, {Geoffrey N.} and Cole, {David E C}",
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T1 - Increased prevalence of the GCM2 polymorphism, Y282D, in primary hyperparathyroidism

T2 - Analysis of three Italian cohorts

AU - D'Agruma, Leonardo

AU - Coco, Michela

AU - Guarnieri, Vito

AU - Battista, Claudia

AU - Canaff, Lucie

AU - Salcuni, Antonio S.

AU - Corbetta, Sabrina

AU - Cetani, Filomena

AU - Minisola, Salvatore

AU - Chiodini, Iacopo

AU - Eller-Vainicher, Cristina

AU - Spada, Anna

AU - Marcocci, Claudio

AU - Guglielmi, Giuseppe

AU - Zini, Michele

AU - Clemente, Rosanna

AU - Wong, Betty Y L

AU - De Martino, Danilo

AU - Scillitani, Alfredo

AU - Hendy, Geoffrey N.

AU - Cole, David E C

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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 263-352). 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: 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. Results: 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). 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.

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