Novel Glial Cells Missing-2 ( <i>GCM2</i>) variants in parathyroid disorders

Canaff, Lucie; Guarnieri, Vito; Kim, Yoojung; Wong, Betty Y L; Nolin-Lapalme, Alexis; Cole, David E C; Minisola, Salvatore; Eller-Vainicher, Cristina; Cetani, Filomena; Repaci, Andrea; Turchetti, Daniela; Corbetta, Sabrina; Scillitani, Alfredo; Goltzman, David

doi:10.1530/EJE-21-0433

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Novel Glial Cells Missing-2 ( GCM2) variants in parathyroid disorders

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Author(s): Lucie Canaff ¹ ^, *, Vito Guarnieri ² ^, *, Yoojung Kim ¹ , Betty Y L Wong ³ , Alexis Nolin-Lapalme ¹ , David E C Cole ³ , Salvatore Minisola ⁴ , Cristina Eller-Vainicher ⁵ , Filomena Cetani ⁶ , Andrea Repaci ⁷ , Daniela Turchetti ⁸ , Sabrina Corbetta ⁹ ^, ¹⁰ , Alfredo Scillitani ² , David Goltzman ¹ ^,

Publication date (Electronic): 13 January 2022

Journal: European Journal of Endocrinology

Publisher: Bioscientifica Ltd

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Abstract

Objective

The aim of this study was to analyze variants of the gene glial cells missing-2 ( GCM2), encoding a parathyroid cell-specific transcription factor, in familial hypoparathyroidism and in familial isolated hyperparathyroidism (FIHP) without and with parathyroid carcinoma.

Design

We characterized 2 families with hypoparathyroidism and 19 with FIHP in which we examined the mechanism of action of GCM2 variants.

Methods

Leukocyte DNA of hypoparathyroid individuals was Sanger sequenced for CASR, PTH, GNA11 and GCM2 mutations. DNA of hyperparathyroid individuals underwent MEN1, CDKN1B, CDC73, CASR, RET and GCM2 sequencing. The actions of identified GCM2 variants were evaluated by in vitro functional analyses.

Results

A novel homozygous p.R67C GCM2 mutation which failed to stimulate transcriptional activity in a luciferase assay was identified in affected members of two hypoparathyroid families. Oligonucleotide pull-down assay and in silico structural modeling indicated that this mutant had lost the ability to bind the consensus GCM recognition sequence of DNA. Two novel (p.I383M and p.T386S) and one previously reported (p.Y394S) heterozygous GCM2 variants that lie within a C-terminal conserved inhibitory domain were identified in three affected individuals of the hyperparathyroid families. One family member, heterozygous for p.I138M, had parathyroid carcinoma (PC), and a heterozygous p.V382M variant was found in another patient affected by sporadic PC. These variants exerted significantly enhanced in vitrotranscriptional activity, including increased stimulation of the PTH promoter.

Conclusions

We provide evidence that two novel GCM2 R67C inactivating mutations with an inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter in vitro and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease.

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Most cited references 73

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Michael W Yeh, Philip Ituarte, Hui Cynthia Zhou … (2013)

The epidemiology of primary hyperparathyroidism (PHPT) has generally been studied in Caucasian populations. The aim was to examine the incidence and prevalence of PHPT within a racially mixed population. A descriptive epidemiologic study was performed. The study population included 3.5 million enrollees within Kaiser Permanente Southern California. All patients with at least one elevated serum calcium level (>10.5 mg/dL, 2.6 mmol/L) between 1995 and 2010 were included. Cases of PHPT were identified by electronic query of laboratory values using biochemical criteria, after exclusion of secondary or renal and tertiary hyperparathyroidism cases. The incidence and prevalence rates of PHPT were calculated according to sex, race, age group by decade, and year. Initial case finding identified 15,234 patients with chronic hypercalcemia, 13,327 (87%) of which had PHPT as defined by elevated or inappropriately normal parathyroid hormone levels. The incidence of PHPT fluctuated from 34 to 120 per 100,000 person-years (mean 66) among women, and from 13 to 36 (mean 25) among men. With advancing age, incidence increased and sex differences became pronounced (incidence 12-24 per 100,000 for both sexes younger than 50 y; 80 and 36 per 100,000 for women and men aged 50-59 y, respectively; and 196 and 95 for women and men aged 70-79 y, respectively). The incidence of PHPT was highest among blacks (92 women; 46 men, P < .0001), followed by whites (81 women; 29 men), with rates for Asians (52 women, 28 men), Hispanics (49 women, 17 men), and other races (25 women, 6 men) being lower than that for whites (P < .0001). The prevalence of PHPT tripled during the study period, increasing from 76 to 233 per 100,000 women and from 30 to 85 per 100 000 men. Racial differences in prevalence mirrored those found in incidence. PHPT is the predominant cause of hypercalcemia and is increasingly prevalent. Substantial differences are found in the incidence and prevalence of PHPT between races.

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Author and article information

Journal

Journal ID (nlm-ta): Eur J Endocrinol

Journal ID (iso-abbrev): Eur J Endocrinol

Journal ID (hwp): EJE

Title: European Journal of Endocrinology

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Print): 0804-4643

ISSN (Electronic): 1479-683X

Publication date (Electronic): 13 January 2022

Publication date Collection: 01 March 2022

Volume: 186

Issue: 3

Pages: 351-366

Affiliations

[1 ]Metabolic Complications and Disorders, Research Institute-McGill University Health Centre , Montreal, Quebec, Canada

[2 ]Division of Medical Genetics and Unit of Endocrinology , Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

[3 ]Department of Laboratory Medicine and Pathobiology , University of Toronto, Toronto, Ontario, Canada

[4 ]Department of Internal Medicine and Medical Disciplines , ‘Sapienza’ Rome University, Rome, Italy

[5 ]Department of Medical Sciences and Community , Fondazione Ca’Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy

[6 ]University Hospital of Pisa , Pisa, Italy

[7 ]Unit of Endocrinology , S. Orsola Malpighi Hospital, Bologna, Italy

[8 ]Center for the Studies of Hereditary Cancers , Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

[9 ]Endocrinology and Diabetology Service , IRCCS Istituto Ortopedico Galeazzi, Milan, Italy

[10 ]Department of Biomedical , Surgical and Dental Sciences, University of Milan, Milan, Italy

Author notes

Correspondence should be addressed to D Goltzman; Email: david.goltzman@ 123456mcgill.ca

^*(L Canaff and V Guarnieri contributed equally to this work)

Author information

Alexis Nolin-Lapalme http://orcid.org/0000-0001-7919-2508

Salvatore Minisola http://orcid.org/0000-0001-6525-0439

Sabrina Corbetta http://orcid.org/0000-0001-8140-3175

Article

Publisher ID: EJE-21-0433

DOI: 10.1530/EJE-21-0433

PMC ID: 8859918

PubMed ID: 35038313

SO-VID: d2a299ab-242d-4c43-b9ed-0df764be1956

License:

This work is licensed under a Creative Commons Attribution 4.0 International License.