Molecular Mechanisms of Renal Magnesium Reabsorption

Ellison, David H.; Maeoka, Yujiro; McCormick, James A.

doi:10.1681/asn.2021010042

Cited by 29 publications

(26 citation statements)

References 114 publications

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“…The distal convoluted tubule (DCT) is important in determining the urine excretion of Mg 2+ and Ca 2+ by modulating transcellular reabsorption via TRPM6/7 Mg 2+ channels and TRPV5 Ca 2+ channels 25 , 26 . To study whether there are differences in the length of the distal convoluted tubule (DCT) between Fam111a + / + and Fam111a −/− mice, immunohistochemical staining was performed on kidney sections (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Regulation of Ca 2+ and Mg 2+ homeostasis mainly occurs by absorption from the intestine, storage in bone and reabsorption by the kidneys. The thick ascending limb (TAL) and the distal convoluted tubule (DCT) segments of the nephron are important for the renal handling of these ions by expressing specific channels and transporters, thereby regulating ion excretion into the urine according to the requirements of the body 25 , 26 . Disturbed electrolyte homeostasis is an essential feature of KCS2, but the primary cause of the electrolyte disturbances has not been established.…”

Section: Introductionmentioning

confidence: 99%

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FAM111A is dispensable for electrolyte homeostasis in mice

Ilenwabor

Schigt

Kompatscher

et al. 2022

Sci Rep

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Autosomal dominant mutations in FAM111A are causative for Kenny-Caffey syndrome type 2. Patients with Kenny-Caffey syndrome suffer from severe growth retardation, skeletal dysplasia, hypoparathyroidism, hypocalcaemia, hyperphosphataemia and hypomagnesaemia. While recent studies have reported FAM111A to function in antiviral response and DNA replication, its role in regulating electrolyte homeostasis remains unknown. In this study, we assessed the role of FAM111A in the regulation of serum electrolyte balance using a Fam111a knockout (Fam111a−/−) C57BL/6 N mouse model. Fam111a−/− mice displayed normal weight and serum parathyroid hormone (PTH) concentration and exhibited unaltered magnesium, calcium and phosphate levels in serum and 24-hour urine. Expression of calciotropic (including Cabp28k, Trpv5, Klotho and Cyp24a1), magnesiotropic (including Trpm6, Trpm7, Cnnm2 and Cnnm4) and phosphotropic (Slc20a1, Slc20a2, Slc34a1 and Slc34a3) genes in the kidneys, duodenum and colon were not affected by Fam111a depletion. Only Slc34a2 expression was significantly upregulated in the duodenum, but not in the colon. Analysis of femurs showed unaffected bone morphology and density in Fam111a−/− mice. Kidney and parathyroid histology were also normal in Fam111a−/− mice. In conclusion, our study is the first to characterise the function of FAM111A in vivo and we report that mice lacking FAM111A exhibit normal electrolyte homeostasis on a standard diet.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FAM111A is dispensable for electrolyte homeostasis in mice

Ilenwabor

Schigt

Kompatscher

et al. 2022

Sci Rep

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“…At the apical membrane, TRPM6 (transient receptor potential melastatin, subtype 6) channels, supported by TRPM7 in its surface expression, allow Mg 2+ influx into the DCT cell ( Schlingmann et al, 2002 ; Chubanov et al, 2004 ; Voets et al, 2004 ). As basolateral extrusion mechanisms, Na + /Mg 2+ exchangers and an Mg 2+ -ATPase have been proposed ( Dai et al, 2001 ; Ellison et al, 2021 ). How does decreased Mg 2+ reabsorption occur in EAST/SeSAME syndrome?…”

Section: East/sesame Syndrome: a Pleiotropic Monogenetic Disease Caus...mentioning

confidence: 99%

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies

Forst

Warth

et al. 2022

Front. Physiol.

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In 2009, two groups independently linked human mutations in the inwardly rectifying K+ channel Kir4.1 (gene name KCNJ10) to a syndrome affecting the central nervous system (CNS), hearing, and renal tubular salt reabsorption. The autosomal recessive syndrome has been named EAST (epilepsy, ataxia, sensorineural deafness, and renal tubulopathy) or SeSAME syndrome (seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance), accordingly. Renal dysfunction in EAST/SeSAME patients results in loss of Na+, K+, and Mg2+ with urine, activation of the renin–angiotensin–aldosterone system, and hypokalemic metabolic alkalosis. Kir4.1 is highly expressed in affected organs: the CNS, inner ear, and kidney. In the kidney, it mostly forms heteromeric channels with Kir5.1 (KCNJ16). Biallelic loss-of-function mutations of Kir5.1 can also have disease significance, but the clinical symptoms differ substantially from those of EAST/SeSAME syndrome: although sensorineural hearing loss and hypokalemia are replicated, there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected. This review provides a framework for understanding some of these differences and will guide the reader through the growing literature on Kir4.1 and Kir5.1, discussing the complex disease mechanisms and the variable expression of disease symptoms from a molecular and systems physiology perspective. Knowledge of the pathophysiology of these diseases and their multifaceted clinical spectrum is an important prerequisite for making the correct diagnosis and forms the basis for personalized therapies.

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“…In the gastrointestinal system, it is reabsorbed in the intestine and in the colon by fine-tuned control of an active transcellular Mg 2+ channel, followed by extrusion to the blood via the CNNM4 Na + /Mg 2+ exchanger. In the kidney, most of the filtered Mg 2+ is reabsorbed paracellularly in the proximal tubule (PT) and thick-ascending loop of Henle (TALH) via different claudins (claudins 1 and 2 in the PT, and claudins 10, 14, 16, and 19 in TALH) ( Stuiver et al, 2011 ; de Baaij et al, 2012 ; Curry and Yu, 2018 ; Ellison et al, 2021 ). Like the colon, the distal convoluted tubule (DCT) fine-tunes the reabsorption of tubular Mg 2+ via the transcellular TRPM6 channel along with basolateral Mg 2+ extrusion of Na + /Mg 2+ exchanger.…”

Section: Introductionmentioning

confidence: 99%

Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure

et al. 2022

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CNNM2 is primarily expressed in the brain and distal convoluted tubule (DCT) of the kidney. Mutations in CNNM2 have been reported to cause hypomagnesemia, seizure, and intellectual disability (HSMR) syndrome. However, the clinical and functional effect of CNNM2 mutations remains incompletely understood. We report our clinical encounter with a 1-year-old infant with HSMR features. Mutation screening for this trio family was performed using next-generation sequencing (NGS)-based whole exome sequencing (WES) with the identified mutation verified by Sanger sequencing. We identified a de novo heterozygous mutation c.G1439T (R480L) in the essential cystathionine β-synthase (CBS) domain of CNNM2 encoding CNNM2 (cyclin M2) without any other gene mutations related to hypomagnesemia. The amino acid involved in this missense mutation was conserved in different species. It was also found to be pathogenic based on the different software prediction models and ACGME criteria. In vitro studies revealed a higher expression of the CNNM2-R480L mutant protein compared to that of the wild-type CNNM2. Like the CNNM2-wild type, proper localization of CNNM2-R480L was shown on immunocytochemistry images. The Mg2+ efflux assay in murine DCT (mDCT) cells revealed a significant increase in intracellular Mg2+ green in CNNM2-R480L compared to that in CNNM2-WT. By using a simulation model, we illustrate that the R480L mutation impaired the interaction between CNNM2 and ATP-Mg2+. We propose that this novel R480L mutation in the CNNM2 gene led to impaired binding between Mg2+-ATP and CNNM2 and diminished Mg2+ efflux, manifesting clinically as refractory hypomagnesemia.

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Molecular Mechanisms of Renal Magnesium Reabsorption

Cited by 29 publications

References 114 publications

FAM111A is dispensable for electrolyte homeostasis in mice

FAM111A is dispensable for electrolyte homeostasis in mice

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies

Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure

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