Genetic mutations cause severe magnesium deficiency

Severe magnesium deficiency is a rare condition caused by genetic mutations. But in about a fifth of cases, doctors have so far found no explanation in the DNA. Researchers led by Jeroen de Baaij, together with an international team, tracked down new genetic errors that cause magnesium deficiency. This finding has implications for both treatment and diagnostics. The results are described in two publications in the Journal of the American Society of Nephrology.

The kidneys provide a balance of fluids, salts and minerals in the body, including magnesium. Sometimes a genetic error causes a problem in the kidneys that results in a magnesium deficiency. Patients then excrete too much magnesium and suffer from symptoms such as muscle cramps and fatigue, but in severe cases also seizures. Administering extra magnesium does not help, because the body simply does not absorb the substance. Sometimes doctors find a genetic explanation for the magnesium deficiency, but not always.

Physiologist Jeroen de Baaij from Radboudumc started his search for new causes for magnesium deficiency already ten years ago. The condition is rare, so he sought cooperation with researchers from several European countries, so he could find more patients. Using a device for DNA sequencing, which maps out a patient's entire DNA, the team analyzed 23 families. In this way, the researchers uncovered important new genetic abnormalities.

Preventing heart transplantation

In the first article, the researchers describe mutations in the RRAGD gene. Jeroen de Baaij explains: "Children with this mutation suffer from calcification of the kidneys and develop severe heart failure. Sometimes even a heart transplant is necessary. Mutations in this gene usually occur spontaneously, so they are not passed on by the parents. This is mainly because people with such a mutation used to not have a high life expectancy, and therefore often did not have children. Meanwhile, care has improved."

The finding of errors in the RRAGD gene offers a starting point for treatment. "We know that mutations in this gene lead to activation of the so-called mTOR protein, which then causes the problems in the heart and kidneys. There are already drugs for this, the mTOR inhibitors. We now want to see if we can use them in children who have this mutation. These inhibitors are heavy drugs with considerable side effects. But if you can prevent a heart transplant with them, then we should definitely investigate that." 

Suspicious energy factories

The second article is about mutations that are inherited through the mother. These mutations cause Gitelman syndrome, in which not only magnesium but also potassium deficiency plays a role. PhD student Daan Viering explains: "The discovery of these mutations has important implications for the diagnosis of unexplained magnesium deficiencies. We did not find the errors in the DNA in the cell nucleus, which is what doctors normally investigate, but in the DNA of the mitochondria. These are the energy factories of the cell and are located outside the nucleus. They have their own DNA that is rarely looked at in standard diagnostics. Our advice for additional diagnostics in unexplained Gitelman syndrome is therefore: also look at the DNA in the mitochondria."

About the publications

The article on mutations in RRAGD appeared in JASN: mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy. Karl P. Schlingmann, Francois Jouret, Kuang Shen, Anukrati Nigam, Francisco J. Arjona, Claudia Dafinger, Pascal Houillier, Deborah P. Jones, Felix Kleineruschkamp, Jun Oh, Nathalie Godefroid, Mehmet Eltan, Tulay Guran, Stephane Burtey, Marie-Christine Parotte, Jens Konig, Alina Braun, Caro Bos, Maria Ibars Serra, Holger Rehmann, Fried J.T. Zwartkruis, Kirsten Y. Renkema, Karin Klingel, Eric Schulze-Bahr, Bernhard Schermer, Carsten Bergmann, Janine Altmuller, Holger Thiele, Bodo B. Beck, Karin Dahan, David Sabatini, Max C. Liebau, Rosa Vargas-Poussou, Nine V.A.M. Knoers, Martin Konrad, Jeroen H.F. de Baaij.

The article on mutations in mitochondrial DNA also appeared in JASN: Gitelman-like syndrome caused by pathogenic variants in mtDNA. Daan Viering, Karl-Peter Schlingmann, Marguerite Hureaux, Tom Nijenhuis, Andrew Mallett, Melanie MY Chan, André van Beek, Albertien M van Eerde, Jean-Marie Coulibaly, Marion Vallet, Stéphane Decramer, Solenne Pelletier, Günter Klaus, Martin Kömhoff, Rolf Beetz, Chirag Patel, Mohan Shenoy, Eric J. Steenbergen, Glenn Anderson, Genomics England Research Consortium, Ernie MHF Bongers, Carsten Bergmann, Daan Panneman, Richard J. Rodenburg, Robert Kleta, Pascal Houillier, Martin Konrad, Rosa Vargas-Poussou, Nine Knoers, Detlef Bockenhauer, Jeroen HF de Baaij.

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