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Kevin M Oshaughnessy - One of the best experts on this subject based on the ideXlab platform.
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molecular insights from dysregulation of the thiazide sensitive wnk spak ncc pathway in the kidney Gordon Syndrome and thiazide induced hyponatraemia
Clinical and Experimental Pharmacology and Physiology, 2013Co-Authors: Mark Glover, Kevin M OshaughnessyAbstract:Summary Human blood pressure is dependent on balancing dietary salt intake with its excretion by the kidney. Mendelian Syndromes of altered blood pressure demonstrate the importance of the distal nephron in this process and of the thiazide-sensitive pathway in particular. Gordon Syndrome (GS), the phenotypic inverse of the salt-wasting Gitelman Syndrome, is a condition of hyperkalaemic hypertension that is reversed by low-dose thiazide diuretics or a low-salt diet. Variants within at least four genes [i.e. with-no-lysine(K) kinase 1 (WNK1), WNK4, kelch-like family member 3 (KLHL3) and cullin 3 (CUL3)] can cause the phenotype of GS. Details are still emerging for some of these genes, but it is likely that they all cause a gain-of-function in the thiazide-sensitive Na+–Cl− cotransporter (NCC) and hence salt retention. Herein, we discuss the key role of STE20/sporulation-specific protein 1 (SPS1)-related proline/alanine-rich kinase (SPAK), which functions as an intermediary between the WNKs and NCC and for which a loss-of-function mutation produces a Gitelman-type phenotype in a mouse model. In addition to Mendelian blood pressure Syndromes, the study of patients who develop thiazide-induced-hyponatraemia (TIH) may give further molecular insights into the role of the thiazide-sensitive pathway for salt reabsorption. In the present paper we discuss the key features of TIH, including its high degree of reproducibility on rechallenge, possible genetic predisposition and mechanisms involving excessive saliuresis and water retention. Together, studies of Gordon Syndrome and TIH may increase our understanding of the molecular regulation of sodium trafficking via the thiazide-sensitive pathway and have important implications for hypertensive patients, both in the identification of new antihypertensive drug targets and avoidance of hyponatraemic side-effects.
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regulation of the expression of the na cl cotransporter by wnk4 and wnk1 evidence that accelerated dynamin dependent endocytosis is not involved
American Journal of Physiology-renal Physiology, 2006Co-Authors: Amir P Golbang, Abbas Hamad, Meena Murthy, Alan W. Cuthbert, Georgina Cope, Kevin M OshaughnessyAbstract:The novel serine/threonine kinases (with no lysine kinases or WNKs), WNK1 and WNK4, are encoded by the disease genes for Gordon Syndrome (PRKWNK1 and PRKWNK4), a rare monogenic Syndrome of hyperten...
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wnk1 affects surface expression of the romk potassium channel independent of wnk4
Journal of The American Society of Nephrology, 2006Co-Authors: Georgina Cope, Amir P Golbang, Abbas Hamad, Meena Murthy, Alan W. Cuthbert, Kevin M OshaughnessyAbstract:The WNK (with no lysine kinase) kinases are a novel class of serine/threonine kinases that lack a characteristic lysine residue for ATP docking. Both WNK1 and WNK4 are expressed in the mammalian kidney, and mutations in either can cause the rare familial Syndrome of hypertension and hyperkalemia (Gordon Syndrome, or pseudohypoaldosteronism type 2). The molecular basis for the action of WNK4 is through alteration in the membrane expression of the NaCl co-transporter (NCCT) and the renal outer-medullary K channel KCNJ1 (ROMK). The actions of WNK1 are less well defined, and evidence to date suggests that it can affect NCCT expression but only in the presence of WNK4. The results of co-expressing WNK1 with ROMK in Xenopus oocytes are reported for the first time. These studies show that WNK1 is able to suppress total current directly through ROMK by causing a marked reduction in its surface expression. The effect is mimicked by a kinase-dead mutant of WNK1 (368D>A), suggesting that it is not dependent on its catalytic activity. Study of the time course of ROMK expression further suggests that WNK1 accelerates trafficking of ROMK from the membrane, and this effect seems to be dynamin dependent. Using fragments of full-length WNK1, it also is shown that the effect depends on residues in the middle section of the protein (502 to 1100 WNK1) that contains the acidic motif. Together, these findings emphasize that the molecular mechanisms that underpin WNK1 regulation of ROMK expression are distinct from those that affect NCCT expression.
Neeme Tonisson - One of the best experts on this subject based on the ideXlab platform.
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novel polymorphic aluyb8 insertion in the wnk1 gene is associated with blood pressure variation in europeans
Human Mutation, 2011Co-Authors: Margus Putku, David Comas, Katrin Kepp, Siim Sober, Gudrun Veldre, Peeter Juhanson, Neeme Tonisson, Margus Viigimaa, Pille Hallast, Sue ShawhawkinsAbstract:Mutations in WNK1 and WNK4 cause familial hypertension, the Gordon Syndrome. WNK1 and WNK4 conserved noncoding regions were targeted to polymorphism screening using DHPLC and DGGE. The scan identified an undescribed polymorphic AluYb8 insertion in WNK1 intron 10. Screening in primates revealed that this Alu-insertion has probably occurred in human lineage. Genotyping in 18 populations from Europe, Asia, and Africa (n = 854) indicated an expansion of the WNK1 AluYb8 bearing chromosomes out of Africa. The allele frequency in Sub-Saharan Africa was ∼3.3 times lower than in other populations (4.8 vs. 15.8%; P = 9.7 × 10−9). Meta-analysis across three European sample sets (n = 3,494; HYPEST, Estonians; BRIGHT, the British; CADCZ, Czech) detected significant association of the WNK1 AluYb8 insertion with blood pressure (BP; systolic BP, P = 4.03 × 10−3, effect 1.12; diastolic BP, P = 1.21 × 10−2, effect 0.67). Gender-stratified analysis revealed that this effect might be female-specific (n = 2,088; SBP, P = 1.99 × 10−3, effect 1.59; DBP P = 3.64 × 10−4, effect 1.23; resistant to Bonferroni correction), whereas no statistical support was identified for the association with male BP (n = 1,406). In leucocytes, the expressional proportions of the full-length WNK1 transcript and the splice-form skipping exon 11 were significantly shifted in AluYb8 carriers compared to noncarriers. The WNK1 AluYb8 insertion might affect human BP via altering the profile of alternatively spliced transcripts. Hum Mutat 32:1–9, 2011. © 2011 Wiley-Liss, Inc.
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Novel polymorphic AluYb8 insertion in the WNK1 gene is associated with blood pressure variation in Europeans
Human Mutation, 2011Co-Authors: Margus Putku, David Comas, Katrin Kepp, Siim Sober, Gudrun Veldre, Peeter Juhanson, Margus Viigimaa, Pille Hallast, Elin Org, Neeme TonissonAbstract:Mutations in WNK1 and WNK4 cause familial hypertension, the Gordon Syndrome. WNK1 and WNK4 conserved non-coding regions were targeted to polymorphism screening using DHPLC and DGGE. The scan identified an undescribed polymorphic AluYb8 insertion in WNK1 intron 10. Screening in primates revealed that this Alu-insertion has probably occurred in human lineage. Genotyping in 18 populations from Europe, Asia and Africa (n=854) indicated an expansion of the WNK1 AluYb8 bearing chromosomes out-of-Africa. The allele frequency in Sub-Saharan Africa was ~3.3 times lower than in other populations (4.8% versus 15.8%; P=9.7x10-9). Meta-analysis across three European sample-sets (n=3494; HYPEST, Estonians; BRIGHT, the British; CADCZ, Czech) detected significant association of the WNK1 AluYb8 insertion with blood pressure (BP; systolic BP, P=4.03x10-3, effect 1.12; diastolic BP, P=1.21x10-2, effect 0.67). Gender-stratified analysis revealed that this effect might be female-specific (n=2088; SBP, P=1.99x10-3, effect 1.59; DBP P=3.64x10-4, effect 1.23; resistant to Bonferroni correction), while no statistical support was identified for the association with male BP (n=1406). In leucocytes, the expressional proportions of the full-length WNK1 transcript and the splice-form skipping exon 11 were significantly shifted in AluYb8 carriers compared to non-carriers. The WNK1 AluYb8 insertion might affect human BP via altering the profile of alternatively spliced transcripts.
Margus Putku - One of the best experts on this subject based on the ideXlab platform.
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novel polymorphic aluyb8 insertion in the wnk1 gene is associated with blood pressure variation in europeans
Human Mutation, 2011Co-Authors: Margus Putku, David Comas, Katrin Kepp, Siim Sober, Gudrun Veldre, Peeter Juhanson, Neeme Tonisson, Margus Viigimaa, Pille Hallast, Sue ShawhawkinsAbstract:Mutations in WNK1 and WNK4 cause familial hypertension, the Gordon Syndrome. WNK1 and WNK4 conserved noncoding regions were targeted to polymorphism screening using DHPLC and DGGE. The scan identified an undescribed polymorphic AluYb8 insertion in WNK1 intron 10. Screening in primates revealed that this Alu-insertion has probably occurred in human lineage. Genotyping in 18 populations from Europe, Asia, and Africa (n = 854) indicated an expansion of the WNK1 AluYb8 bearing chromosomes out of Africa. The allele frequency in Sub-Saharan Africa was ∼3.3 times lower than in other populations (4.8 vs. 15.8%; P = 9.7 × 10−9). Meta-analysis across three European sample sets (n = 3,494; HYPEST, Estonians; BRIGHT, the British; CADCZ, Czech) detected significant association of the WNK1 AluYb8 insertion with blood pressure (BP; systolic BP, P = 4.03 × 10−3, effect 1.12; diastolic BP, P = 1.21 × 10−2, effect 0.67). Gender-stratified analysis revealed that this effect might be female-specific (n = 2,088; SBP, P = 1.99 × 10−3, effect 1.59; DBP P = 3.64 × 10−4, effect 1.23; resistant to Bonferroni correction), whereas no statistical support was identified for the association with male BP (n = 1,406). In leucocytes, the expressional proportions of the full-length WNK1 transcript and the splice-form skipping exon 11 were significantly shifted in AluYb8 carriers compared to noncarriers. The WNK1 AluYb8 insertion might affect human BP via altering the profile of alternatively spliced transcripts. Hum Mutat 32:1–9, 2011. © 2011 Wiley-Liss, Inc.
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Novel polymorphic AluYb8 insertion in the WNK1 gene is associated with blood pressure variation in Europeans
Human Mutation, 2011Co-Authors: Margus Putku, David Comas, Katrin Kepp, Siim Sober, Gudrun Veldre, Peeter Juhanson, Margus Viigimaa, Pille Hallast, Elin Org, Neeme TonissonAbstract:Mutations in WNK1 and WNK4 cause familial hypertension, the Gordon Syndrome. WNK1 and WNK4 conserved non-coding regions were targeted to polymorphism screening using DHPLC and DGGE. The scan identified an undescribed polymorphic AluYb8 insertion in WNK1 intron 10. Screening in primates revealed that this Alu-insertion has probably occurred in human lineage. Genotyping in 18 populations from Europe, Asia and Africa (n=854) indicated an expansion of the WNK1 AluYb8 bearing chromosomes out-of-Africa. The allele frequency in Sub-Saharan Africa was ~3.3 times lower than in other populations (4.8% versus 15.8%; P=9.7x10-9). Meta-analysis across three European sample-sets (n=3494; HYPEST, Estonians; BRIGHT, the British; CADCZ, Czech) detected significant association of the WNK1 AluYb8 insertion with blood pressure (BP; systolic BP, P=4.03x10-3, effect 1.12; diastolic BP, P=1.21x10-2, effect 0.67). Gender-stratified analysis revealed that this effect might be female-specific (n=2088; SBP, P=1.99x10-3, effect 1.59; DBP P=3.64x10-4, effect 1.23; resistant to Bonferroni correction), while no statistical support was identified for the association with male BP (n=1406). In leucocytes, the expressional proportions of the full-length WNK1 transcript and the splice-form skipping exon 11 were significantly shifted in AluYb8 carriers compared to non-carriers. The WNK1 AluYb8 insertion might affect human BP via altering the profile of alternatively spliced transcripts.
Sue Shawhawkins - One of the best experts on this subject based on the ideXlab platform.
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novel polymorphic aluyb8 insertion in the wnk1 gene is associated with blood pressure variation in europeans
Human Mutation, 2011Co-Authors: Margus Putku, David Comas, Katrin Kepp, Siim Sober, Gudrun Veldre, Peeter Juhanson, Neeme Tonisson, Margus Viigimaa, Pille Hallast, Sue ShawhawkinsAbstract:Mutations in WNK1 and WNK4 cause familial hypertension, the Gordon Syndrome. WNK1 and WNK4 conserved noncoding regions were targeted to polymorphism screening using DHPLC and DGGE. The scan identified an undescribed polymorphic AluYb8 insertion in WNK1 intron 10. Screening in primates revealed that this Alu-insertion has probably occurred in human lineage. Genotyping in 18 populations from Europe, Asia, and Africa (n = 854) indicated an expansion of the WNK1 AluYb8 bearing chromosomes out of Africa. The allele frequency in Sub-Saharan Africa was ∼3.3 times lower than in other populations (4.8 vs. 15.8%; P = 9.7 × 10−9). Meta-analysis across three European sample sets (n = 3,494; HYPEST, Estonians; BRIGHT, the British; CADCZ, Czech) detected significant association of the WNK1 AluYb8 insertion with blood pressure (BP; systolic BP, P = 4.03 × 10−3, effect 1.12; diastolic BP, P = 1.21 × 10−2, effect 0.67). Gender-stratified analysis revealed that this effect might be female-specific (n = 2,088; SBP, P = 1.99 × 10−3, effect 1.59; DBP P = 3.64 × 10−4, effect 1.23; resistant to Bonferroni correction), whereas no statistical support was identified for the association with male BP (n = 1,406). In leucocytes, the expressional proportions of the full-length WNK1 transcript and the splice-form skipping exon 11 were significantly shifted in AluYb8 carriers compared to noncarriers. The WNK1 AluYb8 insertion might affect human BP via altering the profile of alternatively spliced transcripts. Hum Mutat 32:1–9, 2011. © 2011 Wiley-Liss, Inc.
Pille Hallast - One of the best experts on this subject based on the ideXlab platform.
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novel polymorphic aluyb8 insertion in the wnk1 gene is associated with blood pressure variation in europeans
Human Mutation, 2011Co-Authors: Margus Putku, David Comas, Katrin Kepp, Siim Sober, Gudrun Veldre, Peeter Juhanson, Neeme Tonisson, Margus Viigimaa, Pille Hallast, Sue ShawhawkinsAbstract:Mutations in WNK1 and WNK4 cause familial hypertension, the Gordon Syndrome. WNK1 and WNK4 conserved noncoding regions were targeted to polymorphism screening using DHPLC and DGGE. The scan identified an undescribed polymorphic AluYb8 insertion in WNK1 intron 10. Screening in primates revealed that this Alu-insertion has probably occurred in human lineage. Genotyping in 18 populations from Europe, Asia, and Africa (n = 854) indicated an expansion of the WNK1 AluYb8 bearing chromosomes out of Africa. The allele frequency in Sub-Saharan Africa was ∼3.3 times lower than in other populations (4.8 vs. 15.8%; P = 9.7 × 10−9). Meta-analysis across three European sample sets (n = 3,494; HYPEST, Estonians; BRIGHT, the British; CADCZ, Czech) detected significant association of the WNK1 AluYb8 insertion with blood pressure (BP; systolic BP, P = 4.03 × 10−3, effect 1.12; diastolic BP, P = 1.21 × 10−2, effect 0.67). Gender-stratified analysis revealed that this effect might be female-specific (n = 2,088; SBP, P = 1.99 × 10−3, effect 1.59; DBP P = 3.64 × 10−4, effect 1.23; resistant to Bonferroni correction), whereas no statistical support was identified for the association with male BP (n = 1,406). In leucocytes, the expressional proportions of the full-length WNK1 transcript and the splice-form skipping exon 11 were significantly shifted in AluYb8 carriers compared to noncarriers. The WNK1 AluYb8 insertion might affect human BP via altering the profile of alternatively spliced transcripts. Hum Mutat 32:1–9, 2011. © 2011 Wiley-Liss, Inc.
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Novel polymorphic AluYb8 insertion in the WNK1 gene is associated with blood pressure variation in Europeans
Human Mutation, 2011Co-Authors: Margus Putku, David Comas, Katrin Kepp, Siim Sober, Gudrun Veldre, Peeter Juhanson, Margus Viigimaa, Pille Hallast, Elin Org, Neeme TonissonAbstract:Mutations in WNK1 and WNK4 cause familial hypertension, the Gordon Syndrome. WNK1 and WNK4 conserved non-coding regions were targeted to polymorphism screening using DHPLC and DGGE. The scan identified an undescribed polymorphic AluYb8 insertion in WNK1 intron 10. Screening in primates revealed that this Alu-insertion has probably occurred in human lineage. Genotyping in 18 populations from Europe, Asia and Africa (n=854) indicated an expansion of the WNK1 AluYb8 bearing chromosomes out-of-Africa. The allele frequency in Sub-Saharan Africa was ~3.3 times lower than in other populations (4.8% versus 15.8%; P=9.7x10-9). Meta-analysis across three European sample-sets (n=3494; HYPEST, Estonians; BRIGHT, the British; CADCZ, Czech) detected significant association of the WNK1 AluYb8 insertion with blood pressure (BP; systolic BP, P=4.03x10-3, effect 1.12; diastolic BP, P=1.21x10-2, effect 0.67). Gender-stratified analysis revealed that this effect might be female-specific (n=2088; SBP, P=1.99x10-3, effect 1.59; DBP P=3.64x10-4, effect 1.23; resistant to Bonferroni correction), while no statistical support was identified for the association with male BP (n=1406). In leucocytes, the expressional proportions of the full-length WNK1 transcript and the splice-form skipping exon 11 were significantly shifted in AluYb8 carriers compared to non-carriers. The WNK1 AluYb8 insertion might affect human BP via altering the profile of alternatively spliced transcripts.
