Functional Analysis of the Kv1.1 N255D Mutation Associated with Autosomal Dominant Hypomagnesemia

Wijst, Jenny van der; Glaudemans, Bob; Venselaar, Hanka; Nair, Anil V.; Forst, A. W.; Hoenderop, Joost G. J.; Bindels, René J. M.

doi:10.1074/jbc.m109.041517

Cited by 43 publications

(23 citation statements)

References 36 publications

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“…A mutation in KCNA1, encoding Kv1.1, results in a non-functional channel, and has been identified in a family with autosomal dominant hypomagnesaemia. 85,86 Interestingly, other mutations in the same protein cause the neurological syndrome of Episodic Ataxia type 1 -these patients are not reported to be hypomagnesaemic. 87 …”

Section: Kv11 -Autosomal Dominant Hypomagnesaemiamentioning

confidence: 98%

The renal channelopathies

Loudon

Fry

2014

Ann Clin Biochem

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Specific channels permit movement of selected ions through cellular membranes, and are of vital importance in a number of physiological processes, particularly in excitable tissues such as nerve and muscle, but also in endocrine organs and in epithelial biology. Disorders of channel proteins are termed channelopathies, and their importance is increasingly recognised within medicine. In the kidney, ion channels have critical roles enabling sodium and potassium reuptake or excretion along the nephron, in magnesium homeostasis, in the control of water reabsorption in the collecting duct, and in determining glomerular permeability. In this review, we assess the channelopathies encountered in each nephron segment, and see how their molecular and genetic characterisation in the past 20-30 years has furthered our understanding of normal kidney physiology and disease processes, aids correct diagnosis and promises future therapeutic opportunities.

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Section: Kv11 -Autosomal Dominant Hypomagnesaemiamentioning

confidence: 98%

The renal channelopathies

Loudon

Fry

2014

Ann Clin Biochem

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“…It is believed that by secreting K 1 , Kv1.1 channels extrude positive charges into the lumen that provide a driving force for TRPM6-dependent Mg 21 transport (Figure 12). Mutation of Kv1.1 at a specific residue renders the channel nonfunctional, and one mutant allele is sufficient to cause the disease, presumably because of dominant negative inhibition of the remaining wild-type allele (117). A current theory is that the lack of functional Kv1.1 channels decreases the efflux of potassium cations into the lumen, which, in turn, would be expected to make the intracellular voltage on the luminal membrane more positive, decreasing the voltage gradient for luminal Mg 21 entry.…”

Section: Magnesiummentioning

confidence: 99%

Distal Convoluted Tubule

Subramanya

Ellison

2014

Clinical Journal of the American Society of Nephrology

218

185

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The distal convoluted tubule is the nephron segment that lies immediately downstream of the macula densa. Although short in length, the distal convoluted tubule plays a critical role in sodium, potassium, and divalent cation homeostasis. Recent genetic and physiologic studies have greatly expanded our understanding of how the distal convoluted tubule regulates these processes at the molecular level. This article provides an update on the distal convoluted tubule, highlighting concepts and pathophysiology relevant to clinical practice.

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“…1d). Previously, a homology model was developed (http://www.cmbi.ru.nl/∼hvensela/Kv1.1/, [4]) that was based on the resolved chimaeric Kv1.2-Kv2.1 structure (PDB 2R9R [12]). Figure 1e shows the Kv1.1 homology model and depicts the transmembrane helices surrounding Leu328.…”

Section: Resultsmentioning

confidence: 99%

“…In the DCT, intracellular Mg 2+ levels are comparable to the Mg 2+ concentration in the pro-urine and therefore a chemical gradient for Mg 2+ reabsorption is suggested to be virtually absent. It has therefore been hypothesized that K + secretion via Kv1.1 provides an electrical gradient that drives Mg 2+ reabsorption via TRPM6 [3, 4]. Indeed, our previous studies showed that Kv1.1 activity determined the membrane potential in HEK293 cells [3].…”

Section: Discussionmentioning

confidence: 99%

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A de novo <b><i>KCNA1</i></b> Mutation in a Patient with Tetany and Hypomagnesemia

Wijst

Konrad

Verkaart

et al. 2018

Nephron

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Mutations in the KCNA1 gene encoding the voltage-gated potassium (K⁺) channel Kv1.1 have been linked to rare neurological syndromes, episodic ataxia type 1 (EA1) and myokymia. In 2009, a KCNA1 mutation was identified in a large family with autosomal dominant hypomagnesemia. Despite efforts in establishing a genotype-phenotype correlation for the wide variety of symptoms in EA1, little is known on the serum magnesium (Mg²⁺) levels in these patients. In the present study, we describe a new de novo KCNA1 mutation in a Polish patient with tetany and hypomagnesemia. Electrophysiological and biochemical analyses were performed to determine the pathogenicity of the mutation. A female patient presented with low serum Mg²⁺ levels, renal Mg²⁺ wasting, muscle cramps, and tetanic episodes. Whole exome sequencing identified a p.Leu328Val mutation in KCNA1 encoding the Kv1.1 K⁺ channel. Electrophysiological examinations demonstrated that the p.Leu328Val mutation caused a dominant-negative loss of function of the encoded Kv1.1 channel. Cell surface biotinylation showed normal plasma membrane expression. Taken together, this is the second report linking KCNA1 with hypomagnesemia, thereby emphasizing the need for further evaluation of the clinical phenotypes observed in patients carrying KCNA1 mutations.

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Functional Analysis of the Kv1.1 N255D Mutation Associated with Autosomal Dominant Hypomagnesemia

Cited by 43 publications

References 36 publications

The renal channelopathies

The renal channelopathies

Distal Convoluted Tubule

A de novo <b><i>KCNA1</i></b> Mutation in a Patient with Tetany and Hypomagnesemia

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