Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. International Collaborative Study Group for Bartter-like Syndromes [published erratum appears in Hum Mol Genet 1997 Apr;6(4):650]

Károlyi, Lothar; Konrad, Martin; Köckerling, Arnold; Ziegler, Andreas; Zimmermann, Dorthe K.; Roth, B.; Wieg, Christian; Grzeschik, Karl‐Heinz; Koch, Manuela C.; Seyberth, Hannsjörg W.; Vargas, Rosa; Forestier, Lionel; Jean, G; Deschaux, Michele; Rizzoni, G; Niaudet, Patrick; Antignac, Corinne; Feldmann, Delphine; Lorridon, Frederique; Cougoureux, Emmanuel; Alessandri, Jean‐Luc; David, L; Saunier, P; Deschênes, Georges; Hildebrandt, Friedhelm; Vollmer, Martin; Proesmans, Willem; Brandis, M.; Heuvel, L.P.W.J. van den; Lemmink, Henny H.; Nillesen, Willy M.; Monnens, L.A.H.; Knoers, Nine V A M; Guay‐Woodford, Lisa M.; Wright, Christopher J.; Madrigal, Gilbert; Hebert, Steven C.

doi:10.1093/hmg/6.1.17

Cited by 145 publications

(7 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to NKCC2 mutations, ROMK defects are responsible for a typical loop disorder [20, 21]. The difference between these two disorders is a transient hyperkalemia within the first days of life of patients with this mixed type of loop disorder.…”

Section: Distal Nephron Disordersmentioning

confidence: 99%

Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects

2011

View full text Add to dashboard Cite

Salt-losing tubulopathies with secondary hyperaldosteronism (SLT) comprise a set of well-defined inherited tubular disorders. Two segments along the distal nephron are primarily involved in the pathogenesis of SLTs: the thick ascending limb of Henle’s loop, and the distal convoluted tubule (DCT). The functions of these pre- and postmacula densa segments are quite distinct, and this has a major impact on the clinical presentation of loop and DCT disorders – the Bartter- and Gitelman-like syndromes. Defects in the water-impermeable thick ascending limb, with its greater salt reabsorption capacity, lead to major salt and water losses similar to the effect of loop diuretics. In contrast, defects in the DCT, with its minor capacity of salt reabsorption and its crucial role in fine-tuning of urinary calcium and magnesium excretion, provoke more chronic solute imbalances similar to the effects of chronic treatment with thiazides. The most severe disorder is a combination of a loop and DCT disorder similar to the enhanced diuretic effect of a co-medication of loop diuretics with thiazides. Besides salt and water supplementation, prostaglandin E2-synthase inhibition is the most effective therapeutic option in polyuric loop disorders (e.g., pure furosemide and mixed furosemide–amiloride type), especially in preterm infants with severe volume depletion. In DCT disorders (e.g., pure thiazide and mixed thiazide–furosemide type), renin–angiotensin–aldosterone system (RAAS) blockers might be indicated after salt, potassium, and magnesium supplementation are deemed insufficient. It appears that in most patients with SLT, a combination of solute supplementation with some drug treatment (e.g., indomethacin) is needed for a lifetime.

show abstract

Section: Distal Nephron Disordersmentioning

confidence: 99%

Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects

2011

View full text Add to dashboard Cite

show abstract

“…ROMK (renal outer medullary potassium) channels are believed to constitute the major K + secretory pathway in the distal nephron [3, 4]. The major role of ROMK channels in the TAL transport functions and thus in the renal regulation of sodium and water balance is demonstrated by the fact that mutations in the ROMK gene cause Bartter’s syndrome, which is characterized by severe salt wasting and impaired urinary concentrating ability [5,6,7]. Furthermore, data obtained in ROMK null mutant mice have shown the role of ROMK in both the 30 pS and 70 pS apical channels in the TAL [8, 9].…”

Section: Introductionmentioning

confidence: 99%

Regulation of ROMK (Kir 1.1) Channel Expression in Kidney Thick Ascending Limb by Hypertonicity: Role of TonEBP and MAPK Pathways

Gallazzini

Karim²,

Bichara³

2006

Nephron Physiol

View full text Add to dashboard Cite

The present study assessed the mechanisms by which hypertonicity caused by NaCl enhances the renal outer medullary potassium channel (ROMK) mRNA abundance in rat kidney medullary thick ascending limb (MTAL) and in cultured mouse TAL cells. Using the run-off technique, we observed that the ROMK gene transcription rate in nuclei isolated from MTAL fragments was enhanced ∼40% by a high NaCl medium. In MTAL fragments, hypertonicity (450 mosm) caused by NaCl, not by mannitol or urea, enhanced both ROMK mRNA abundance and tonicity-responsive enhancer binding protein (TonEBP) total abundance and nuclear localization. In an immortalized mouse TAL cell culture in which ROMK is apically expressed, hypertonicity caused by both NaCl and mannitol, not urea, enhanced both ROMK mRNA abundance and TonEBP total abundance and nuclear localization. Confocal microscopy confirmed an increased nuclear translocation of TonEBP in response to NaCl-induced hypertonicity. Finally, inhibition of the p38 MAPK pathway by SB203580 and of the ERK pathway by PD98059 abolished the NaCl-induced stimulation of TonEBP and ROMK. These results establish that mRNA expression of ROMK is augmented in the MTAL by NaCl-induced hypertonicity through stimulation of ROMK gene transcription, and that TonEBP and the p38 MAPK and ERK pathways are involved in this effect.

show abstract

“…At same time, mutations were found in its target molecule, the furosemide-sensitive Na-K-2Cl symporter (NKCC2) [5]. Within the next 5 years, genetic heterogeneity of the loop disorder was clarified by the demonstration that mutations in five distinct genes may be responsible for the disease [6,7,8,9,10]. Definition of the genetic pathogenesis together with thorough clinical examination illuminated the nature of transepithelial Na-Cl reabsorption in human TAL.…”

Section: Discussionmentioning

confidence: 99%

“…Nearly 35 missense mutations have been reported to be equally distributed throughout the channel molecule [6,7,17]. Their functional consequences have been extensively studied.…”

Section: Romk Mutationsmentioning

confidence: 99%

Loop Disorders: Insights Derived from Defined Genotypes

Jeck

Seyberth²

2010

Nephron Physiol

View full text Add to dashboard Cite

Great progress has been made in the last 15 years in the characterization and the pathophysiological understanding of renal salt and water wasting associated with inherited disorders of the thick ascending limb (TAL) of Henle’s loop, the loop disorders. Besides careful clinical observations and innovative physiological concepts, molecular genetics have made this progress possible. So far, mutations in five different genes may be responsible for the loop disorders. These gene products are as follows: NKCC2 symporter, ROMK, ClC-Ka, ClC-Kb, and barttin, a β-subunit to both chloride channels. The key symptoms, such as polyhydramnios secondary to fetal polyuria, postnatal volume depletion with hypotension, iso- or hyposthenuria, hyperprostaglandinuria and hypercalciuria followed by hypokalemic alkalosis secondary to hyperaldosteronism, are typical features of loop disorders that are restricted to TAL, such as in disorders with NKCC2 and ROMK mutations. However, transient perinatal hyperkalemia in infants with ROMK mutations suggests an additional function of ROMK for K secretion in the cortical collecting duct. The extremely rare human ClC-Kamutation has only been described in combination with ClC-Kb mutations. Similar to barttin mutations, this double knockout of transepithelial salt transport in TAL and in distal convoluted tubule (DCT) leads to a severe loop disorder with deafness. In contrast, the isolated ClC-Kb mutation predominantly appears as an incomplete loop disorder with features similar to an isolated DCT defect, because ClC-Kb function in TAL can in part be compensated by ClC-Ka. This compensation does not exist in DCT. Besides these defined genotypes, the type and the severity of mutation as well as the onset and quality of medical care are important determinants for the patients’ outcome. Considering a few variables, such as transient hyperkalemia, disease onset beyond neonatal period, profound hypochloremia and hypokalemia, or congenital hearing loss, might be helpful to guide genetic testing efficiently.

show abstract

Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. International Collaborative Study Group for Bartter-like Syndromes [published erratum appears in Hum Mol Genet 1997 Apr;6(4):650]

Cited by 145 publications

References 48 publications

Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects

Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects

Regulation of ROMK (Kir 1.1) Channel Expression in Kidney Thick Ascending Limb by Hypertonicity: Role of TonEBP and MAPK Pathways

Loop Disorders: Insights Derived from Defined Genotypes

Contact Info

Product

Resources

About