Five patients with disorders of calcium metabolism presented with GCM2 gene variants

Alejandro García-Castaño,Ignacio Goicolea,Rosa Martínez,Pedro González,Luis Castaño,Alicia Martín,Inés Urrutia,Leire Madariaga,Sonia Gaztambide,María López-Iglesias,Laura Saso,Olaia Velasco,Yolanda Garcia-Fernández,Carmen Lourdes Rey Cordo,Aníbal Aguayo,Ana Belén De La Hoz,Sara Gómez-Conde,Idoia Martínez De Lapiscina,Gustavo Pérez De Nanclares

doi:10.1038/s41598-021-82661-y

Abstract

The GCM2 gene encodes a transcription factor predominantly expressed in parathyroid cells that is known to be critical for development, proliferation and maintenance of the parathyroid cells. A cohort of 127 Spanish patients with a disorder of calcium metabolism were screened for mutations by Next-Generation Sequencing (NGS). A targeted panel for disorders of calcium and phosphorus metabolism was designed to include 65 genes associated with these disorders. We observed two variants of uncertain significance (p.(Ser487Phe) and p.Asn315Asp), one likely pathogenic (p.Val382Met) and one benign variant (p.Ala393_Gln395dup) in the GCM2 gene in the heterozygous state in five families (two index cases had hypocalcemia and hypoparathyroidism, respectively, and three index cases had primary hyperparathyroidism). Our study shows the utility of NGS in unravelling the genetic origin of some disorders of the calcium and phosphorus metabolism, and confirms the GCM2 gene as an important element for the maintenance of calcium homeostasis. Importantly, a novel variant in the GCM2 gene (p.(Ser487Phe)) has been found in a patient with hypocalcemia.

Highlights

The GCM2 gene encodes a transcription factor predominantly expressed in parathyroid cells that is known to be critical for development, proliferation and maintenance of the parathyroid cells
The genetic study revealed other two variants located in the PTH1R and SLC34A1 genes, of uncertain significance and likely pathogenic respectively, both in the heterozygous state as well (Table 3)
According to the Human Gene Mutation Database, 14 variants in the GCM2 gene have been reported associated with hypoparathyroidism

Summary

Introduction

The GCM2 gene encodes a transcription factor predominantly expressed in parathyroid cells that is known to be critical for development, proliferation and maintenance of the parathyroid cells. A cohort of 127 Spanish patients with a disorder of calcium metabolism were screened for mutations by NextGeneration Sequencing (NGS). Parathyroid hormone (PTH), vitamin D and calcitonin regulate this balance by acting on their targets: intestine, bone and renal tubule. The GCM2 gene (glial cells missing transcription factor 2, MIM *603716) encodes a transcription factor predominantly expressed in parathyroid c ells[1,2]. This transcription factor is known to be critical for development of the parathyroid cells and plays a critical role in adult parathyroid cell proliferation and maintenance[3,4]. CIBERER, Endocrinology and Nutrition Department, Hospital Universitario Cruces, University of the Basque Country (UPV/EHU), Bizkaia, Spain. 11These authors contributed : Alejandro García-Castaño and Leire

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