New genetic link between magnesium balance and metabolism

In a recent publication in the Journal of the American Society of Nephrology, a multidisciplinary team integrated by Francisco Arjona, Jeroen de Baaij, Joost Hoenderop and René Bindels, Dept. of Physiology, theme Renal disorders, and collaborators from the Lausanne University Hospital and the University of Zürich mainly, has established novel genetic insights for the understanding of the regulation of the magnesium balance and its relation with metabolic phenotypes in the human population.

Disturbances in magnesium homeostasis lead to severe multi-systemic disorders. In the kidney, the urinary excretion of magnesium regulates plasma/systemic magnesium levels determining the homeostasis of magnesium. In order to identify new genes involved in renal magnesium handling, a meta-analysis of genome-wide association studies of urinary magnesium was performed combining seven European cohorts (9,099 people). Genetic variants of the gene ARL15 (coding a GTP-binding protein), linked to obesity and insulin biology but with no prior link to magnesium balance, were associated to urinary magnesium. Studies on gene and protein expression revealed that ARL15 localizes in the kidney tubule, where it regulates magnesium transport. In the zebrafish model, ARL15 dysfunction resulted in renal magnesium wasting and metabolic disturbances, phenotypes that were rescued by expressing human ARL15 in this model. Furthermore, the association between urinary magnesium and ARL15 genotypes was modified by metabolic phenotypes (fat mass and fasting insulin levels) in the human population. Our findings provided the genetic basis of urinary magnesium regulation uncovering ARL15 as a new key gene for renal magnesium handling, and established an unprecedented gene-environment interaction linking renal magnesium physiology and metabolism.

Link to the publication.

Francisco Arjona    Jeroen de Baaij     Joost Hoenderop   René Bindels