title: Genetic causes of hypomagnesemia, a clinical overview.
abstract: 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.
authors.affiliation: Centre for Nephrology, University College London, London, UK.|Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Daan H H M
authors.initials: DHHM
authors.lastname: Viering
authors.affiliation: Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jeroen H F
authors.initials: JHF
authors.lastname: de Baaij
authors.affiliation: Centre for Nephrology, University College London, London, UK.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Walsh
authors.affiliation: Centre for Nephrology, University College London, London, UK. r.kleta@ucl.ac.uk.|Paediatric Nephrology, Great Ormond Street Hospital, London, UK. r.kleta@ucl.ac.uk.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Centre for Nephrology, University College London, London, UK.|Paediatric Nephrology, Great Ormond Street Hospital, London, UK.
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
mesh_terms: D001145:Arrhythmias, Cardiac / Q000097:blood* / Q000209:etiology; D002648:Child; D062686:Epithelial Sodium Channel Blockers / Q000627:therapeutic use; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D053565:Hypercalciuria / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D007008:Hypokalemia / Q000097:blood / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D007686:Kidney Tubules, Distal / Q000502:physiology; D008138:Loop of Henle / Q000502:physiology; D008274:Magnesium / Q000097:blood* / Q000502:physiology / Q000627:therapeutic use; D008275:Magnesium Deficiency / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009397:Nephrocalcinosis / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D010641:Phenotype; D064167:Recommended Dietary Allowances; D065667:Renal Elimination / Q000235:genetics*; D065608:Renal Reabsorption / Q000187:drug effects / Q000235:genetics*; D015499:Renal Tubular Transport, Inborn Errors / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D012640:Seizures / Q000097:blood* / Q000209:etiology
chemical_list: D062686:Epithelial Sodium Channel Blockers; D008565:Membrane Proteins; D000451:Mineralocorticoid Receptor Antagonists; D008274:Magnesium
keywords: Distal convoluted tubule; Hereditary; Homeostasis; Kidney; Magnesium; Thick ascending limb of Henle’s loop