Genetic causes of hypomagnesemia, a clinical overview

Pediatr Nephrol. 2017 Jul;32(7):1123-1135. doi: 10.1007/s00467-016-3416-3. Epub 2016 May 27.


Magnesium is essential to the proper functioning of numerous cellular processes. Magnesium ion (Mg2+) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias. With normal Mg2+ intake, homeostasis is maintained primarily through the regulated reabsorption of Mg2+ by the thick ascending limb of Henle's loop and distal convoluted tubule of the kidney. Inadequate reabsorption results in renal Mg2+ wasting, as evidenced by an inappropriately high fractional Mg2+ excretion. Familial renal Mg2+ wasting is suggestive of a genetic cause, and subsequent studies in these hypomagnesemic families have revealed over a dozen genes directly or indirectly involved in Mg2+ transport. Those can be classified into four groups: hypercalciuric hypomagnesemias (encompassing mutations in CLDN16, CLDN19, CASR, CLCNKB), Gitelman-like hypomagnesemias (CLCNKB, SLC12A3, BSND, KCNJ10, FYXD2, HNF1B, PCBD1), mitochondrial hypomagnesemias (SARS2, MT-TI, Kearns-Sayre syndrome) and other hypomagnesemias (TRPM6, CNMM2, EGF, EGFR, KCNA1, FAM111A). Although identification of these genes has not yet changed treatment, which remains Mg2+ supplementation, it has contributed enormously to our understanding of Mg2+ transport and renal function. In this review, we discuss general mechanisms and symptoms of genetic causes of hypomagnesemia as well as the specific molecular mechanisms and clinical phenotypes associated with each syndrome.

Keywords: Distal convoluted tubule; Hereditary; Homeostasis; Kidney; Magnesium; Thick ascending limb of Henle’s loop.

Publication types

  • Review

MeSH terms

  • Arrhythmias, Cardiac / blood*
  • Arrhythmias, Cardiac / etiology
  • Child
  • Epithelial Sodium Channel Blockers / therapeutic use
  • Homeostasis / genetics
  • Humans
  • Hypercalciuria / blood
  • Hypercalciuria / complications
  • Hypercalciuria / drug therapy
  • Hypercalciuria / genetics*
  • Hypokalemia / blood
  • Hypokalemia / drug therapy
  • Hypokalemia / etiology
  • Hypokalemia / genetics
  • Kidney Tubules, Distal / physiology
  • Loop of Henle / physiology
  • Magnesium / blood*
  • Magnesium / physiology
  • Magnesium / therapeutic use
  • Magnesium Deficiency / complications
  • Magnesium Deficiency / drug therapy
  • Magnesium Deficiency / genetics*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mineralocorticoid Receptor Antagonists / therapeutic use
  • Mitochondria / metabolism
  • Mutation
  • Nephrocalcinosis / blood
  • Nephrocalcinosis / complications
  • Nephrocalcinosis / drug therapy
  • Nephrocalcinosis / genetics*
  • Phenotype
  • Recommended Dietary Allowances
  • Renal Elimination / genetics*
  • Renal Reabsorption / drug effects
  • Renal Reabsorption / genetics*
  • Renal Tubular Transport, Inborn Errors / blood
  • Renal Tubular Transport, Inborn Errors / complications
  • Renal Tubular Transport, Inborn Errors / drug therapy
  • Renal Tubular Transport, Inborn Errors / genetics*
  • Seizures / blood*
  • Seizures / etiology


  • Epithelial Sodium Channel Blockers
  • Membrane Proteins
  • Mineralocorticoid Receptor Antagonists
  • Magnesium

Supplementary concepts

  • Hypomagnesemia primary