Cargando…

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

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 characte...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bioscientifica Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859918/
https://www.ncbi.nlm.nih.gov/pubmed/35038313
http://dx.doi.org/10.1530/EJE-21-0433
_version_ 1784654558610325504
author 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
author_facet 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
author_sort Canaff, Lucie
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8859918
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Bioscientifica Ltd
record_format MEDLINE/PubMed
spelling pubmed-88599182022-02-23 Novel Glial Cells Missing-2 (GCM2) 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 Eur J Endocrinol Clinical Study 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. Bioscientifica Ltd 2022-01-13 /pmc/articles/PMC8859918/ /pubmed/35038313 http://dx.doi.org/10.1530/EJE-21-0433 Text en © The authors https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. (https://creativecommons.org/licenses/by/4.0/)
spellingShingle Clinical Study
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
Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders
title Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders
title_full Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders
title_fullStr Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders
title_full_unstemmed Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders
title_short Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders
title_sort novel glial cells missing-2 (gcm2) variants in parathyroid disorders
topic Clinical Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859918/
https://www.ncbi.nlm.nih.gov/pubmed/35038313
http://dx.doi.org/10.1530/EJE-21-0433
work_keys_str_mv AT canafflucie novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT guarnierivito novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT kimyoojung novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT wongbettyyl novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT nolinlapalmealexis novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT coledavidec novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT minisolasalvatore novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT ellervainichercristina novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT cetanifilomena novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT repaciandrea novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT turchettidaniela novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT corbettasabrina novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT scillitanialfredo novelglialcellsmissing2gcm2variantsinparathyroiddisorders
AT goltzmandavid novelglialcellsmissing2gcm2variantsinparathyroiddisorders