Novel Molecular Variants of the Na-K-2Cl Cotransporter Gene Are Responsible for Antenatal Bartter Syndrome

Vargas‐Poussou, Rosa; Feldmann, Delphine; Vollmer, Martin; Konrad, Martin; Kelly, Lisa E.; Heuvel, L.P.W.J. van den; Tebourbi, L.; Brandis, M.; Károlyi, Lothar; Hebert, Steven C.; Lemmink, Henny H.; Deschenes, Georges; Hildebrandt, Friedhelm; Seyberth, H. W.; Guay‐Woodford, Lisa M.; Knoers, Nine V A M; Antignac, Corinne

doi:10.1086/301872

Cited by 146 publications

(102 citation statements)

References 27 publications

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“…The antenatal variant of Bartter syndrome, characterized by marked fetal polyuria, polyhydramnios, premature delivery, severe salt wasting, and marked hypercalciuria, is genetically heterogeneous. Mutations in the genes encoding either the luminal bumetanide-sensitive Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC2) or the luminal potassium channel, ROMK (KCJN1) have been described (14,(22)(23)(24). Finally, mutations in the CLCNKB gene, which codes for the basolateral renal chloride channel CLC-kb, are responsible for most of the cases of the classical variant, which is characterized by a milder phenotype beginning in infancy or childhood, hypomagnesemia in 40% of cases, and normo-or hypercalciuria (25,26).…”

Section: Discussionmentioning

confidence: 99%

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Functional Characterization of a Calcium-Sensing Receptor Mutation in Severe Autosomal Dominant Hypocalcemia with a Bartter-Like Syndrome

Vargas‐Poussou¹,

Huang²,

Hulin³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. The extracellular Ca 2ϩ -sensing receptor (CaSR) plays an essential role in extracellular Ca 2ϩ homeostasis by regulating the rate of parathyroid hormone (PTH) secretion and the rate of calcium reabsorption by the kidney. Activation of the renal CaSR is thought to inhibit paracellular divalent cation reabsorption in the cortical ascending limb (cTAL) both directly and indirectly via a decrease in NaCl transport. However, in patients with autosomal dominant hypocalcemia (ADH), caused by CaSR gain-of-function mutations, a defect in tubular NaCl reabsorption with renal loss of NaCl has not been described so far. This article describes a patient with ADH due to a gain-of-function mutation in the CaSR, L125P, associated with a Bartter-like syndrome that is characterized by a decrease in distal tubular fractional chloride reabsorption rate and negative NaCl balance with secondary hyperaldosteronism and hypokalemia. The kinetics of activation of the L125P mutant receptor expressed in HEK-293 cells, assessed by measuring CaSR-stimulated changes in intracellular Ca 2ϩ and ERK activity, showed a dramatic reduction in the EC 50 for extracellular Ca 2ϩ compared with the wild-type and a loss-offunction mutant CaSR (I40F). This study describes the first case of ADH associated with a Bartter-like syndrome. It is herein proposed that the L125P mutation of the CaSR, which represents the most potent gain-of-function mutation reported so far, may reduce NaCl reabsorption in the cTAL sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia.

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Section: Discussionmentioning

confidence: 99%

“…The DNA of the parents of proband 2 was not available. The absence of these mutations in 50 normal controls was verified by SSCP analysis as described (14).…”

Section: Mutation Analysismentioning

confidence: 99%

Functional Characterization of a Calcium-Sensing Receptor Mutation in Severe Autosomal Dominant Hypocalcemia with a Bartter-Like Syndrome

Vargas‐Poussou¹,

Huang²,

Hulin³

et al. 2002

Journal of the American Society of Nephrology

Self Cite

312

195

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“…A genetic analysis of families affected by Bartter syndrome has recently identified a patient with a mild Bartter phenotype bearing a single mutation in exon 4 of NKCC2 that results in a G243D (G224D human) substitution only in the B variant (20). We analyzed the functional consequence of this mutation by expression of a G243D rabbit NKCC2 construct in oocytes.…”

Section: Residues Responsible For the Difference In Chloride Affinitymentioning

confidence: 99%

“…We propose that the Gly-Gly of the GGAYYLIS sequence, conserved throughout the CCC family, forms a hinge that is important in the conformational transition involved in ion transport. The functional importance of these residues is underscored by the finding that mutation of the second of these glycines to glutamate has been identified as the genetic defect in an antenatal Bartter patient (20).…”

Section: Residues Responsible For the Difference In Chloride Affinitymentioning

confidence: 99%

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The Residues Determining Differences in Ion Affinities among the Alternative Splice Variants F, A, and B of the Mammalian Renal Na-K-Cl Cotransporter (NKCC2)

Gíménez

Forbush

2007

Journal of Biological Chemistry

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Three alternatively spliced variants of the renal Na-K-Cl cotransporter (NKCC2) are found in distinct regions of the thick ascending limb of the mammalian kidney; these variants mediate Na ؉ K ؉ 2Cl ؊ transport with different ion affinities. Here, we examine the specific residues involved in the variant-specific affinity differences, utilizing a mutagenic approach to change the NKCC2B variant into the A or F variant, with functional expression in Xenopus oocytes. The splice region contains the second transmembrane domain (TM2) and the putative intracellular loop (ICL1) connecting TM2 and TM3. It is found that the B variant is functionally changed to the F variant by replacement of six residues, half of the effect brought about by three TM2 residues and half by three ICL1 residues. The involvement of the ICL1 residues strongly suggests that this region of ICL1 may actually be part of a membrane-embedded domain. Changing six residues is also sufficient to bring about the smaller functional change from the B to the A variant; three residues in TM2 appear to be primarily responsible, two of which correspond to residues involved in the B-to-F changes. A B-variant mutation reported in a mild case of Bartter disease was found to render the cotransporter inactive. These results identify the combination of amino acid variations responsible for the differences among the three splice variants of NKCC2, and they support a model in which a reentrant loop following TM2 contributes to the chloride binding and translocation domains.

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In VivoandEx VivoAnalysis of Tubule Function

Stockand

Vallon²,

Ortíz

2012

Comprehensive Physiology

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Analysis of tubule function with in vivo and ex vivo approaches has been instrumental in revealing renal physiology. This work allows assignment of functional significance to known gene products expressed along the nephron, primary of which are proteins involved in electrolyte transport and regulation of these transporters. Not only we have learned much about the key roles played by these transport proteins and their proper regulation in normal physiology but also the combination of contemporary molecular biology and molecular genetics with in vivo and ex vivo analysis opened a new era of discovery informative about the root causes of many renal diseases. The power of in vivo and ex vivo analysis of tubule function is that it preserves the native setting and control of the tubule and proteins within tubule cells enabling them to be investigated in a "real-life" environment with a high degree of precision. In vivo and ex vivo analysis of tubule function continues to provide a powerful experimental outlet for testing, evaluating, and understanding physiology in the context of the novel information provided by sequencing of the human genome and contemporary genetic screening. These tools will continue to be a mainstay in renal laboratories as this discovery process continues and as we continue to identify new gene products functionally compromised in renal disease.

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Novel Molecular Variants of the Na-K-2Cl Cotransporter Gene Are Responsible for Antenatal Bartter Syndrome

Cited by 146 publications

References 27 publications

Functional Characterization of a Calcium-Sensing Receptor Mutation in Severe Autosomal Dominant Hypocalcemia with a Bartter-Like Syndrome

Functional Characterization of a Calcium-Sensing Receptor Mutation in Severe Autosomal Dominant Hypocalcemia with a Bartter-Like Syndrome

The Residues Determining Differences in Ion Affinities among the Alternative Splice Variants F, A, and B of the Mammalian Renal Na-K-Cl Cotransporter (NKCC2)

In VivoandEx VivoAnalysis of Tubule Function

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