| A new kindred with pseudohypoaldosteronism type II and a novel mutation (564D>H) in the acidic motif of the WNK4 gene. | |
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MedLine Citation:
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PMID: 15998707 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We identified a new kindred with the familial syndrome of hypertension and hyperkalemia (pseudohypoaldosteronism type II or Gordon's syndrome) containing an affected father and son. Mutation analysis confirmed a single heterozygous G to C substitution within exon 7 (1690G>C) that causes a missense mutation within the acidic motif of WNK4 (564D>H). We confirmed the function of this novel mutation by coexpressing it in Xenopus oocytes with either the NaCl cotransporter (NCCT) or the inwardly rectifying K-channel (ROMK). Wild-type WNK4 inhibits 22Na+ flux in Xenopus oocytes expressing NCCT by approximately 90% (P<0.001), whereas the 564D>H mutant had no significantly inhibitory effect on flux through NCCT. In oocytes expressing ROMK, wild-type WNK4 produced >50% inhibition of steady-state current through ROMK at a +20-mV holding potential (P<0.001). The 564D>H mutant produced further inhibition with steady-state currents to some 60% to 70% of those seen with the wild-type WNK4. Using fluorescent-tagged NCCT (enhanced cyan fluorescent protein-NCCT) and ROMK (enhanced green fluorescent protein-ROMK) to quantify the expression of the proteins in the oocyte membrane, it appears that the functional effects of the 564D>H mutation can be explained by alteration in the surface expression of NCCT and ROMK. Compared with wild-type WNK4, WNK4 564D>H causes increased cell surface expression of NCCT but reduced expression of ROMK. This work confirms that the novel missense mutation in WNK4, 564D>H, is functionally active and highlights further how switching charge on a single residue in the acid motif of WNK4 affects its interaction with the thiazide-sensitive target NCCT and the potassium channel ROMK. |
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Authors:
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Amir P Golbang; Meena Murthy; Abbas Hamad; Che-Hsiung Liu; Georgina Cope; William Van't Hoff; Alan Cuthbert; Kevin M O'Shaughnessy |
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Publication Detail:
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Type: Case Reports; Journal Article; Research Support, Non-U.S. Gov't Date: 2005-07-05 |
Journal Detail:
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Title: Hypertension Volume: 46 ISSN: 1524-4563 ISO Abbreviation: Hypertension Publication Date: 2005 Aug |
Date Detail:
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Created Date: 2005-07-29 Completed Date: 2005-11-29 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 7906255 Medline TA: Hypertension Country: United States |
Other Details:
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Languages: eng Pagination: 295-300 Citation Subset: IM |
Affiliation:
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Clinical Pharmacology Unit, University of Cambridge, United Kingdom. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Amino Acid Motifs Animals Aspartic Acid Cell Membrane / metabolism Female Genetic Testing Histidine Humans Hyperkalemia / etiology Hypertension / etiology Male Mutation, Missense* Oocytes / metabolism Pedigree Potassium Channels, Inwardly Rectifying / metabolism Protein-Serine-Threonine Kinases / genetics* Pseudohypoaldosteronism / complications, genetics*, physiopathology Receptors, Drug / metabolism Sodium Chloride Symporters / metabolism Sodium Radioisotopes / pharmacokinetics Xenopus laevis |
| Chemical | |
Reg. No./Substance:
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0/KCNJ1 protein, human; 0/Potassium Channels, Inwardly Rectifying; 0/Receptors, Drug; 0/Sodium Chloride Symporters; 0/Sodium Radioisotopes; 0/thiazide receptor; 56-84-8/Aspartic Acid; 71-00-1/Histidine; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/WNK4 protein, human |
| Comments/Corrections | |
Comment In:
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Hypertension. 2005 Aug;46(2):263-4
[PMID:
15998705
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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