RESUMO
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.
Assuntos
Cálcio/metabolismo , Hiperparatireoidismo Primário/genética , Hipocalcemia/genética , Hipoparatireoidismo/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Cálcio/sangue , Sinalização do Cálcio/genética , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Mutação em Linhagem Germinativa , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hiperparatireoidismo Primário/sangue , Hiperparatireoidismo Primário/diagnóstico , Hipocalcemia/sangue , Hipocalcemia/diagnóstico , Hipoparatireoidismo/sangue , Hipoparatireoidismo/diagnóstico , Lactente , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Glândulas Paratireoides , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/metabolismo , Fatores de Transcrição/metabolismoRESUMO
The maintenance of magnesium (Mg2+) homeostasis is essential for human life. The Cystathionine-ß-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) have been described to be involved in maintaining Mg2+ homeostasis. Among these CNNMs, CNNM2 is expressed in the basolateral membrane of the kidney tubules where it is involved in Mg2+ reabsorption. A total of four patients, two of them with a suspected disorder of calcium metabolism, and two patients with a clinical diagnosis of primary tubulopathy were screened for mutations by Next-Generation Sequencing (NGS). We found one novel likely pathogenic variant in the heterozygous state (c.2384C>A; p.(Ser795*)) in the CNNM2 gene in a family with a suspected disorder of calcium metabolism. In this family, hypomagnesemia was indirectly discovered. Moreover, we observed three novel variants of uncertain significance in heterozygous state in the other three patients (c.557G>C; p.(Ser186Thr), c.778A>T; p.(Ile260Phe), and c.1003G>A; p.(Asp335Asn)). Our study shows the utility of Next-Generation Sequencing in unravelling the genetic origin of rare diseases. In clinical practice, serum Mg2+ should be determined in calcium and PTH-related disorders.
