Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia

Baaij, Jeroen H. F. de; Dorresteijn, Eiske M.; Hennekam, Eric A.M.; Kamsteeg, Erik‐Jan; Meijer, Rowdy; Dahan, Karin; Müller, Michelle; Dorpel, Marinus A. van den; Bindels, René J. M.; Hoenderop, Joost G. J.; Devuyst, Olivier; Knoers, Nine V A M

doi:10.1093/ndt/gfv014

Cited by 51 publications

(39 citation statements)

References 21 publications

(28 reference statements)

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“…4, 20 Indeed, heterozygous mutations in FXYD2 are known to cause autosomal dominant hypomagnesemia with hypocalciuria (OMIM: 154020). 21, 22 Whether the regulation of FXYD2 by HNF1β is sufficient to explain the symptoms in ADTKD-HNF1β is being questioned. 23 Current studies on HNF1β binding sites depend mainly on bioinformatical identification of the HNF1β recognition sequence in gene promoters.…”

Section: Introductionmentioning

confidence: 99%

Loss of transcriptional activation of the potassium channel Kir5.1 by HNF1β drives autosomal dominant tubulointerstitial kidney disease

Kompatscher

Baaij

Aboudehen

et al. 2017

Kidney International

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HNF1β is an essential transcription factor for the development and functioning of the kidney. Mutations in HNF1β cause autosomal dominant tubulointerstitial kidney disease (ADTKD-HNF1β), which is characterized by renal cysts and maturity-onset diabetes of the young (MODY). Moreover, patients suffer from a severe electrolyte phenotype consisting of hypomagnesemia and hypokalemia. Until now, genes that are regulated by HNF1β are only partially known and do not fully explain the phenotype of the patients. Therefore, we conducted chIP-seq in immortalized mouse kidney cells (mpkDCT) to identify HNF1β binding sites at a genome-wide scale. In total 7,421 HNF1β binding sites were identified, including several genes involved in electrolyte transport and diabetes. A highly specific and conserved HNF1β site was identified in the promoter of Kcnj16, encoding the potassium channel Kir5.1. Luciferase-promoter assays showed a 2.2 fold increase in Kcnj16 expression when HNF1β was present. Expression of the Hnf1β p.Lys156Glu mutant that was previously identified in a ADTKD-HNF1β patient, did not activate Kcnj16 expression. Knock down of Hnf1β in mpkDCT cells significantly reduced the expression of Kcnj16 (Kir5.1) and Kcnj10 (Kir4.1) by 38% and 37%, respectively. These results were confirmed in a HNF1β renal knockout mouse, exhibiting downregulation of Kcnj16, Kcnj10 and Slc12a3 transcripts in the kidney by 78%, 83% and 76%, respectively, compared to HNF1β wild-type mice. In conclusion, HNF1β has been identified as a transcriptional activator of Kcnj16. Consequently patients with HNF1β mutations may have a reduced Kir5.1 activity in the kidney, resulting in hypokalemia and hypomagnesemia.

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Section: Introductionmentioning

confidence: 99%

Loss of transcriptional activation of the potassium channel Kir5.1 by HNF1β drives autosomal dominant tubulointerstitial kidney disease

Kompatscher

Baaij

Aboudehen

et al. 2017

Kidney International

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“…In the distal convoluted tubule, Mg 2+ reabsorption is achieved via transient receptor potential melastatin type 6 (TRPM6) Mg 2+ channels and is dependent upon the voltage gradient set by the Na + -K + -ATPase. Indeed, patients with mutations in FXYD2 , which encodes the γ-subunit of the Na + -K + -ATPase, suffer from hypomagnesemia and renal Mg 2+ wasting [6] . In addition, it has been shown that HNF1B, together with its dimerization factor PCBD1, regulates the transcription of FXYD2 , which explains why HNF1B and PCBD1 mutations result in renal Mg 2+ wasting [3,7] .…”

Section: Introductionmentioning

confidence: 99%

Hypomagnesemia as First Clinical Manifestation of ADTKD-HNF1B: A Case Series and Literature Review

et al. 2015

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Background: Autosomal dominant tubulointerstitial kidney disease subtype HNF1B (ADTKD-HNF1B) is caused by a mutation in hepatocyte nuclear factor 1 homeobox beta (HNF1B). Although 50-60% of ADTKD-HNF1B patients develop hypomagnesemia, HNF1B mutations are mainly identified in patients with structural kidney defects or diabetes. Cases: The current case series describes 3 patients in whom hypomagnesemia proved to be the first clinical manifestation of ADTKD-HNF1B. All patients presented with hypomagnesemia with a high fractional excretion of Mg²⁺ and hypocalciuria. Exome sequencing performed for analysis of known and candidate hypomagnesaemia genes and subsequent multiplex ligation-dependent probe amplification analysis revealed a large deletion at the chromosome 17q12. Follow-up analysis showed increased blood glucose concentrations in all 3 patients and high hemoglobin A1c levels in 2 out of 3 patients, indicating diabetes mellitus. Although all patients suffered from mild renal insufficiency, only 1 of the 3 patients was shown to have renal cysts on CT. Conclusion: The prevalence of HNF1B mutations and the relative contribution of hypomagnesemia to its symptoms are underestimated. Therefore, patients with primary renal magnesium wasting should be tested for HNF1B mutations to ensure early detection and optimal management of ADTKD-HNF1B.

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“…The phenotype produced is reminiscent of the rare genetic disorder, isolated dominant hypomagnesemia, which is associated with urinary Mg wasting [9]. In this condition, linkage analysis identified the genetic defect as a G41R mutation in the FXYD2 gene, which encodes the γ subunit of the Na,K-ATPase [6, 10, 11]. This is clearly a loss of function mutation, which causes a dominant negative effect, and misrouting of the γ subunit to the plasma membrane [6].…”

Section: Discussionmentioning

confidence: 99%

Hypermagnesuria in Humans Following Acute Intravenous Administration of Digoxin

Abu-Amer

Priel

Karlish

et al. 2017

Nephron

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Background: Hypomagnesemia is a known predisposing condition for the appearance of digitalis toxicity. The detection of a genetic form of Mg urinary wasting with hypomagnesemia being caused by a mutation in the γ subunit (FXYD2) of the Na,K-ATPase, the pharmacological target of Digoxin, prompted us to investigate whether Digoxin administration increases urinary Mg excretion. Methods: Two groups of subjects, with rapid atrial fibrillation, received intravenous Digoxin (n = 9) or verapamil (n = 8), for heart rate control. During the following 4 h, blood and urinary creatinine, sodium, potassium, calcium, and magnesium levels were determined, and fractional excretion (Fex) values for Na, K, Ca, and Mg were calculated. Results: In the Digoxin group, at 60 min Fex Mg rose from 3.07 ± 1.21 to 7.58 ± 2.51% (an increase of 269 ± 107% of baseline, p < 0.001), and at 240 min to 6.05 ± 2.30% (204 ± 56% of baseline, p < 0.01). No significant change was observed for Fex Na, Fex K, and Fex Ca. A striking correlation was found between individual values of Fex Mg and serum Digoxin concentration (r = 0.678, p < 0.0001). No significant correlation was found between Fex Na or Fex K and serum Digoxin. A correlation of borderline significance was found between Fex Ca and serum Digoxin (r = 0.349, p = 0.073). Conclusions: The hypermagnesuric effect of acute Digoxin treatment is reminiscent of the effect of the missense mutation in FXYD2, which assumes that FXYD2 is a positive regulator of Na,K-ATPase in the distal convoluted tubule (DCT). The borderline calciuric effect of Digoxin may point to an additional site of action, more proximal to the DCT, that is, the thick ascending limb.

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Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia

Abstract: The recurrent p.Gly41Arg FXYD2 mutation in two new families with IDH confirms that FXYD2 mutation causes hypomagnesaemia. Until now, no other FXYD2 mutations have been reported which could indicate that other FXYD2 mutations will not cause hypomagnesaemia or are embryonically lethal.

Cited by 51 publications

References 21 publications

Loss of transcriptional activation of the potassium channel Kir5.1 by HNF1β drives autosomal dominant tubulointerstitial kidney disease

Loss of transcriptional activation of the potassium channel Kir5.1 by HNF1β drives autosomal dominant tubulointerstitial kidney disease

Hypomagnesemia as First Clinical Manifestation of ADTKD-HNF1B: A Case Series and Literature Review

Hypermagnesuria in Humans Following Acute Intravenous Administration of Digoxin

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