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Titolo:
Functional heterogeneity of ROMK mutations linked to hyperprostaglandin E syndrome
Autore:
Jeck, N; Derst, C; Wischmeyer, E; Ott, H; Weber, S; Rudin, C; Seyberth, HW; Daut, J; Karschin, A; Konrad, M;
Indirizzi:
Univ Marburg, Dept Pediat, D-35037 Marburg, Germany Univ Marburg MarburgGermany D-35037 pt Pediat, D-35037 Marburg, Germany Univ Marburg, Inst Physiol, D-35037 Marburg, Germany Univ Marburg Marburg Germany D-35037 t Physiol, D-35037 Marburg, Germany Max Planck Inst Biophys Chem, D-3400 Gottingen, Germany Max Planck Inst Biophys Chem Gottingen Germany D-3400 Gottingen, Germany Univ Basel, Childrens Hosp, Basel, Switzerland Univ Basel Basel Switzerland Basel, Childrens Hosp, Basel, Switzerland
Titolo Testata:
KIDNEY INTERNATIONAL
fascicolo: 5, volume: 59, anno: 2001,
pagine: 1803 - 1811
SICI:
0085-2538(200105)59:5<1803:FHORML>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
ANTENATAL BARTTER-SYNDROME; RECTIFIER K+ CHANNEL; POTASSIUM CHANNEL; CLONING; GENE; HYPERCALCIURIA; EXPRESSION; FAMILY; LOOP;
Keywords:
K+ channel; channelopathy; antenatal Bartter syndrome; KCNJl gene; renal fluid wasting; salt reabsorption;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
30
Recensione:
Indirizzi per estratti:
Indirizzo: Konrad, M Univ Marburg, Dept Pediat, Deutschhausstr 12, D-35037 Marburg, Germany Univ Marburg Deutschhausstr 12 Marburg Germany D-35037 Germany
Citazione:
N. Jeck et al., "Functional heterogeneity of ROMK mutations linked to hyperprostaglandin E syndrome", KIDNEY INT, 59(5), 2001, pp. 1803-1811

Abstract

Background. The renal K+ channel ROMK (Kir1.1) controls salt reabsorption in the kidney. Loss-of-function mutations in this channel cause hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), which is characterized by severe renal salt and fluid wasting. Methods. We investigated 10 HPS/aBS patients for mutations in the ROMK gene by single-strand conformation polymorphism analysis (SSCA) and direct sequencing. To assess the functional consequences, Ba2+-sensitive K+ currents were measured in five mutants of the tore region as well as one mutant withtruncated C-terminus, using the two-electrode voltage-clamp technique after an injection of mutant cRNA into Xenopus oocytes. Results. Three novel ROMK mutations were identified together with six mutations described previously. The mutations were categorized into three groups: (1) amino acid exchanges in the core region (M1-H5-M2), (2) truncation at the cytosolic C-terminus, and (3) deletions of putative promoter elements. While the core mutations W99C, N124K, and I142T led to significantly reduced macroscopic K+ currents (1 to 8% of wildtype currents), the A103V and P110L variants retained substantial K+ conductivity (23 and 35% of wild-typecurrents respectively). Coexpression of A103V and P110L, resembling the compound heterozygous state of the affected individual, further reduced macroscopic currents to 9% of the wild-type currents. All mutants in the core region exerted a dominant-negative effect on wild-type ROMK1, The C-terminal frame shift (fs) mutation (H354fs) did not change current amplitudes compared with ROMK1 wild type, suggesting that a mechanism other than alteration of the electrophysiological properties may responsible fur loss of channel activity. Conclusions. Analysis of ROMK mutants linked to HPS/aBS revealed a spectrum of mechanisms accounting for loss of channel function. Further characterization of the molecular defects might be helpful for the development of newtherapeutic approaches.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 21/10/20 alle ore 04:42:32