Novel variant in the CNNM2 gene associated with dominant hypomagnesemia

• Published in: PloS one 2020-09, Vol.15 (9), p.e0239965-e0239965
• Main Authors: García-Castaño, Alejandro, Madariaga, Leire, Antón-Gamero, Montserrat, Mejia, Natalia, Ponce, Jenny, Gómez-Conde, Sara, Pérez de Nanclares, Gustavo, De la Hoz, Ana Belén, Martínez, Rosa, Saso, Laura, Martínez de LaPiscina, Idoia, Urrutia, Inés, Velasco, Olaia, Aguayo, Aníbal, Castaño, Luis, Gaztambide, Sonia
• Format: Article
• Language: English
• Subjects: Adenosine triphosphate; Adolescent; Adult; Amino acids; Binding sites; Biology and Life Sciences; Calcium; Calcium metabolism; Cation Transport Proteins - chemistry; Cation Transport Proteins - genetics; Codon, Nonsense; Deoxyribonucleic acid; DNA; Endocrinology; Female; Genes; Genetic aspects; Genetic variation; Genomes; Health aspects; Heterozygote; High-Throughput Nucleotide Sequencing; Homeostasis; Hospitals; Humans; Hypomagnesemia; Infant; Intellectual disabilities; Laboratories; Magnesium; Magnesium - blood; Magnesium deficiency; Male; Medical research; Medicine and Health Sciences; Membrane proteins; Metabolism; Metal ions; Mutation; Nephrology; Next-generation sequencing; Parathyroid hormone; Patients; Pediatrics; Physical Sciences; Physiological aspects; Polymorphism, Single Nucleotide; Proteins; Rare diseases; Reabsorption; Renal Tubular Transport, Inborn Errors - diagnosis; Renal Tubular Transport, Inborn Errors - genetics; Research and analysis methods; Sequence Analysis, DNA; Software; Tubules
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0239965

The maintenance of magnesium (Mg2+) homeostasis is essential for human life. The Cystathionine-β-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.