ArticleEuropean journal of endocrinology2022
Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders.
Article in European journal of endocrinology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 23 citations in OpenAlex.
- Spatial transcriptomic analysis of mouse parathyroid gland cells expressing an activating variant ofJBMR plus · 2025Article
- Germline mutations of GCM2 cause a novel variant of hereditary primary hyperparathyroidism.Updates in surgery · 2025Article
- Heritable hyperparathyroidism: Genetic insights and clinical implications.Best practice & research. Clinical endocrinology & metabolism · 2025Review
- Progress report on multiple endocrine neoplasia type 1.Familial cancer · 2025Review
- Heterogeneous Transcriptional Landscapes in Human Sporadic Parathyroid Gland Tumors.International journal of molecular sciences · 2024Article
- Dicer-Mediated mTORC1 Signaling and Parathyroid Gland Integrity and Function.Journal of the American Society of Nephrology : JASN · 2024Article
- Familial states of primary hyperparathyroidism: an update.Journal of endocrinological investigation · 2024Review
- Identification of conserved skeletal enhancers associated with craniosynostosis risk genes.Human molecular genetics · 2024Article
- Molecular Genetic Aspects of Sporadic Multiglandular Primary Hyperparathyroidism.Physiological research · 2023Review
- A Knock-In Mouse Model of theJournal of the Endocrine Society · 2023Article
- Molecular and Clinical Spectrum of Primary Hyperparathyroidism.Endocrine reviews · 2023Article
- Parathyroid carcinoma: molecular therapeutic targets.Endocrine · 2023Review
- One half-century of advances in the evaluation and management of disorders of bone and mineral metabolism in children and adolescents.Journal of pediatric endocrinology & metabolism : JPEM · 2023Review
- Article
- Clinical and genetic analysis of atypical parathyroid adenoma compared with parathyroid carcinoma and benign lesions in a Chinese cohort.Frontiers in endocrinology · 2023Article
- Glial Cell Missing Homolog 2 Mutation Causing Severe Hypoparathyroidism: Report of Two Cases With Novel Mutations.Journal of the Endocrine Society · 2022Article
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Authors and funding
14 authors at 9 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveThe 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.
designWe characterized 2 families with hypoparathyroidism and 19 with FIHP in which we examined the mechanism of action of GCM2 variants.
methodsLeukocyte 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.
resultsA 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.
conclusionsWe 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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