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https://www.readbyqxmd.com/read/28511177/familial-hyperkalemia-and-hypertension-fhht-and-klhl3-description-of-a-family-with-a-new-recessive-mutation-s553l-compared-to-a-family-with-a-dominant-mutation-q309r-with-analysis-of-urinary-sodium-chloride-cotransporter
#1
Orit Kliuk-Ben Bassat, Vered Carmon, Aaron Hanukoglu, Liat Ganon, Eias Massalha, Eliezer J Holtzman, Zvi Farfel, Haim Mayan
BACKGROUND: Familial hyperkalemia and hypertension (FHHt) is an inherited disorder manifested by hyperkalemia and hypertension. The following four causative genes were identified: WNK1, WNK4, CUL3, and KLHL3. For the first 3 genes, inheritance is autosomal dominant. For KLHL3, inheritance is mostly dominant. A few cases with autosomal recessive disease were described. The mechanism of these 2 modes of inheritance is not clear. In the recessive form, the phenotype of heterozygotes is not well described...
May 17, 2017: Nephron
https://www.readbyqxmd.com/read/28414128/impaired-degradation-of-medullary-wnk4-in-the-kidneys-of-klhl2-knockout-mice
#2
Yuri Kasagi, Daiei Takahashi, Tomomi Aida, Hidenori Nishida, Naohiro Nomura, Moko Zeniya, Takayasu Mori, Emi Sasaki, Fumiaki Ando, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara
Mutations in the with-no-lysine kinase 1 (WNK1), WNK4, Kelch-like 3 (KLHL3), and Cullin3 (CUL3) genes were identified as being responsible for hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII). Normally, the KLHL3/CUL3 ubiquitin ligase complex degrades WNKs. In PHAII, the loss of interaction between KLHL3 and WNK4 increases levels of WNKs because of impaired ubiquitination, leading to abnormal over-activation of the WNK-OSR1/SPAK-NCC cascade in the kidney's distal convoluted tubules (DCT)...
May 27, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28315668/cmybp-c-was-decreased-via-klhl3-mediated-proteasomal-degradation-in-congenital-heart-diseases
#3
Leitong Wang, Guangrui Lai, Guoming Chu, Xiaoyan Liang, Yanyan Zhao
Cardiac myosin binding protein C (cMyBP-C) is a cardiac structural and regulatory protein; mutations of cMyBP-C are frequently associated with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Cardiac special transcription factors may regulate the expression of cMyBP-C. However, the role of cMyBP-C in congenital heart diseases (CHD) remains poorly understood. In the current study, western blotting and the MRM approach showed that cMyBP-C expression was significantly reduced in fetuses with CHD compared to those without...
March 16, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28222034/three-cases-of-gordon-syndrome-with-dominant-klhl3-mutations
#4
Ji Soo Park, Eujin Park, Hye Sun Hyun, Yo Han Ahn, Hee Gyung Kang, Il-Soo Ha, Hae Il Cheong
BACKGROUND: Gordon syndrome (GS) is a rare form of monogenic hypertension characterized by low renin hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular filtration rate. To date, four genes causing GS have been identified as: WNK1, WNK4, CUL3, and KLHL3. CASE PRESENTATION: We report three cases of GS in two families. All patients presented with typical clinical features of GS and had a known dominant KLHL3 mutation. Oral thiazide treatment with low salt diet resulted in normalization of blood pressure and serum electrolytes in all three cases...
March 1, 2017: Journal of Pediatric Endocrinology & Metabolism: JPEM
https://www.readbyqxmd.com/read/28178566/wnk-kinase-signaling-in-ion-homeostasis-and-human-disease
#5
REVIEW
Masoud Shekarabi, Jinwei Zhang, Arjun R Khanna, David H Ellison, Eric Delpire, Kristopher T Kahle
WNK kinases, along with their upstream regulators (CUL3/KLHL3) and downstream targets (the SPAK/OSR1 kinases and the cation-Cl(-) cotransporters [CCCs]), comprise a signaling cascade essential for ion homeostasis in the kidney and nervous system. Recent work has furthered our understanding of the WNKs in epithelial transport, cell volume homeostasis, and GABA signaling, and uncovered novel roles for this pathway in immune cell function and cell proliferation.
February 7, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28052936/klhl3-knockout-mice-reveal-the-physiological-role-of-klhl3-and-the-pathophysiology-of-pseudohypoaldosteronism-type-ii-caused-by-mutant-klhl3
#6
Emi Sasaki, Koichiro Susa, Takayasu Mori, Kiyoshi Isobe, Yuya Araki, Yuichi Inoue, Yuki Yoshizaki, Fumiaki Ando, Yutaro Mori, Shintaro Mandai, Moko Zeniya, Daiei Takahashi, Naohiro Nomura, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara
Mutations in the with-no-lysine kinase 1 (WNK1), WNK4, kelch-like 3 (KLHL3), and cullin3 (CUL3) genes are known to cause the hereditary disease pseudohypoaldosteronism type II (PHAII). It was recently demonstrated that this results from the defective degradation of WNK1 and WNK4 by the KLHL3/CUL3 ubiquitin ligase complex. However, the other physiological in vivo roles of KLHL3 remain unclear. Therefore, here we generated KLHL3(-/-) mice that expressed β-galactosidase (β-Gal) under the control of the endogenous KLHL3 promoter...
April 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27983989/potassium-depletion-stimulates-na-cl-cotransporter-via-phosphorylation-and-inactivation-of-the-ubiquitin-ligase-kelch-like-3
#7
Kenichi Ishizawa, Ning Xu, Johannes Loffing, Richard P Lifton, Toshiro Fujita, Shunya Uchida, Shigeru Shibata
Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase complex that regulates blood pressure by targeting With-No-Lysine (WNK) kinases for degradation. Mutations in KLHL3 cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia. Although clinical studies have shown that dietary K(+) intake affects blood pressure, the mechanisms have been obscure. In this study, we demonstrate that the KLHL3 ubiquitin ligase complex is involved in the low-K(+)-mediated activation of Na-Cl cotransporter (NCC) in the kidney...
October 28, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27942049/potassium-depletion-stimulates-na-cl-cotransporter-via-phosphorylation-and-inactivation-of-the-ubiquitin-ligase-kelch-like-3
#8
Kenichi Ishizawa, Ning Xu, Johannes Loffing, Richard P Lifton, Toshiro Fujita, Shunya Uchida, Shigeru Shibata
Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase complex that regulates blood pressure by targeting With-No-Lysine (WNK) kinases for degradation. Mutations in KLHL3 cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia. Although clinical studies have shown that dietary K(+) intake affects blood pressure, the mechanisms have been obscure. In this study, we demonstrate that the KLHL3 ubiquitin ligase complex is involved in the low-K(+)-mediated activation of Na-Cl cotransporter (NCC) in the kidney...
November 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27878608/claudins-in-barrier-and-transport-function-the-kidney
#9
REVIEW
Yongfeng Gong, Jianghui Hou
Claudins are discovered to be key players in renal epithelial physiology. They are involved in developmental, physiological, and pathophysiological differentiation. In the glomerular podocytes, claudin-1 is an important determinant of cell junction fate. In the proximal tubule, claudin-2 plays important roles in paracellular salt reabsorption. In the thick ascending limb, claudin-14, -16, and -19 regulate the paracellular reabsorption of calcium and magnesium. Recessive mutations in claudin-16 or -19 cause an inherited calcium and magnesium losing disease...
January 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/27780982/a-patient-with-pseudohypoaldosteronism-type-ii-complicated-by-congenital-hypopituitarism-carrying-a-klhl3-mutation
#10
Marie Mitani, Munehiro Furuichi, Satoshi Narumi, Tomonobu Hasegawa, Motoko Chiga, Shinichi Uchida, Seiji Sato
Pseudohypoaldosteronism type II (PHA II) is a renal tubular disease that causes hyperkalemia, hypertension, and metabolic acidosis. Mutations in four genes (WNK4, WNK1, KLHL3, and CUL3) are known to cause PHA II. We report a patient with PHA II carrying a KLHL3 mutation, who also had congenital hypopituitarism. The patient, a 3-yr-old boy, experienced loss of consciousness at age 10 mo. He exhibited growth failure, hypertension, hyperkalemia, and metabolic acidosis. We diagnosed him as having PHA II because he had low plasma renin activity with normal plasma aldosterone level and a low transtubular potassium gradient...
October 2016: Clinical Pediatric Endocrinology: Case Reports and Clinical Investigations: Official Journal of the Japanese Society for Pediatric Endocrinology
https://www.readbyqxmd.com/read/27727489/phosphorylation-of-klhl3-at-serine-433-impairs-its-interaction-with-the-acidic-motif-of-wnk4-a-molecular-dynamics-study
#11
Lingyun Wang, Ji-Bin Peng
Interaction between the acidic motif (AM) of protein kinase WNK4 and the Kelch domain of KLHL3 are involved in the pathogenesis of pseudohypoaldosteronism type II, a hereditary form of hypertension. This interaction is disrupted by some disease-causing mutations in either WNK4 or KLHL3, or by angiotensin II- and insulin-induced phosphorylation of KLHL3 at serine 433, which is also a site frequently mutated in patients. However, the mechanism by which this phosphorylation disrupts the interaction is unclear...
February 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/27639857/hyperkalemia-in-young-children-blood-pressure-checked
#12
Richard Hollander, Geert Mortier, Koen van Hoeck
Hyperkalemia in young children is a rare phenomenon and in many cases caused by hemolysis in the specimen due to difficulties in obtaining a sample. However, hyperkalemia can also be a sign of a rare Mendelian syndrome known as familial hyperkalemic hypertension or pseudohypoaldosteronism type II. This disease is characterized by hyperkalemia, hypertension, and mild hyperchloremic metabolic acidosis (with normal anion gap) despite normal glomerular filtration. Full recovery of these abnormalities with thiazide diuretics is essential not to miss the diagnosis of this syndrome...
December 2016: European Journal of Pediatrics
https://www.readbyqxmd.com/read/27508683/-op-lb01-10-the-skipping-of-exon-9-in-cullin-3-causes-a-severe-form-of-familial-hyperkalemic-hypertension-in-mice
#13
C Rafael, W Abdel Khalek, I Kouranti, E Clauser, X Jeunemaitre, J Hadchouel
OBJECTIVE: Familial Hyperkalemic Hypertension (FHHt) is caused by mutations in WNK1, WNK4, KLHL3 or CUL3 (cullin-3). Patients with CUL3 mutation display a more severe phenotype. The mechanisms associated with this severity remain unclear. DESIGN AND METHOD: All CUL3 mutations result in the skipping of exon 9. We have generated a mouse model of "Cul3-FHHt" by deleting Cul3 exon 9. RESULTS: RT-PCR proved that the exon skipping occurred as expected in the kidney of Cul3+/d9 mice...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27378813/romk-expression-remains-unaltered-in-a-mouse-model-of-familial-hyperkalemic-hypertension-caused-by-the-cul3%C3%AE-403-459-mutation
#14
Meena Murthy, Thimo Kurz, Kevin M O'Shaughnessy
Familial hyperkalemic hypertension (FHHt) is a rare inherited form of salt-dependent hypertension caused by mutations in proteins that regulate the renal Na(+)-Cl(-) cotransporter NCC Mutations in four genes have been reported to cause FHHt including CUL3 (Cullin3) that encodes a component of a RING E3 ligase. Cullin-3 binds to WNK kinase-bound KLHL3 (the substrate recognition subunit of the ubiquitin ligase complex) to promote ubiquitination and proteasomal degradation of WNK kinases. Deletion of exon 9 from CUL3 (affecting residues 403-459, CUL3(Δ403-459)) causes a severe form of FHHt (PHA2E) that is recapitulated closely in a knock-in mouse model...
July 2016: Physiological Reports
https://www.readbyqxmd.com/read/27076645/the-cul3-klhl3-wnk-spak-osr1-pathway-as-a-target-for-antihypertensive-therapy
#15
Mohammed Z Ferdaus, James A McCormick
Chronic high blood pressure (hypertension) is the most common disease in the Unites States. While several classes of drugs exist to treat it, many patients (up to 10 million Americans) respond poorly to therapy, even when multiple classes are used. Recent evidence suggests that a significant portion of patients will always remain hypertensive despite maximum therapy with the drugs currently available. Therefore, there is a pressing need to develop novel antihypertensive agents. One limitation has been the identification of new targets, a limitation that has been overcome by recent insights into the mechanisms underlying monogenic forms of hypertension...
June 1, 2016: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/27026694/a-novel-mutation-in-klhl3-gene-causes-familial-hyperkalemic-hypertension
#16
D Kelly, M R Rodzlan, X Jeunemaitre, C Wall
No abstract text is available yet for this article.
July 2016: QJM: Monthly Journal of the Association of Physicians
https://www.readbyqxmd.com/read/26863326/regulation-of-renal-electrolyte-transport-by-wnk-and-spak-osr1-kinases
#17
REVIEW
Juliette Hadchouel, David H Ellison, Gerardo Gamba
The discovery of four genes responsible for pseudohypoaldosteronism type II, or familial hyperkalemic hypertension, which features arterial hypertension with hyperkalemia and metabolic acidosis, unmasked a complex multiprotein system that regulates electrolyte transport in the distal nephron. Two of these genes encode the serine-threonine kinases WNK1 and WNK4. The other two genes [kelch-like 3 (KLHL3) and cullin 3 (CUL3)] form a RING-type E3-ubiquitin ligase complex that modulates WNK1 and WNK4 abundance. WNKs regulate the activity of the Na(+):Cl(-) cotransporter (NCC), the epithelial sodium channel (ENaC), the renal outer medullary potassium channel (ROMK), and other transport pathways...
2016: Annual Review of Physiology
https://www.readbyqxmd.com/read/26607111/degradation-by-cullin-3-and-effect-on-wnk-kinases-suggest-a-role-of-klhl2-in-the-pathogenesis-of-familial-hyperkalemic-hypertension
#18
Chong Zhang, Nicholas P Meermeier, Andrew S Terker, Katharina I Blankenstein, Jeffrey D Singer, Juliette Hadchouel, David H Ellison, Chao-Ling Yang
Mutations in WNK1 and WNK4, and in components of the Cullin-Ring Ligase system, kelch-like 3 (KLHL3) and Cullin 3 (CUL3), can cause the rare hereditary disease, Familial Hyperkalemic Hypertension (FHHt). The disease is characterized by overactivity of the renal sodium chloride cotransporter (NCC), which is phosphorylated and activated by the WNK-stimulated Ste20-type kinases, SPAK and OSR1. WNK kinases themselves can be targeted for ubiquitination and degradataion by the CUL3-KLHL3 E3 ubiquitin ligase complex...
January 1, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26490675/generation-and-analysis-of-knock-in-mice-carrying-pseudohypoaldosteronism-type-ii-causing-mutations-in-the-cullin-3-gene
#19
Yuya Araki, Tatemitsu Rai, Eisei Sohara, Takayasu Mori, Yuichi Inoue, Kiyoshi Isobe, Eriko Kikuchi, Akihito Ohta, Sei Sasaki, Shinichi Uchida
Pseudohypoaldosteronism type II (PHAII) is a hereditary hypertensive disease caused by mutations in four different genes: with-no-lysine kinases (WNK) 1 and 4, Kelch-like family member 3 (KLHL3), and cullin 3 (Cul3). Cul3 and KLHL3 form an E3 ligase complex that ubiquitinates and reduces the expression level of WNK4. PHAII-causing mutations in WNK4 and KLHL3 impair WNK4 ubiquitination. However, the molecular pathogenesis of PHAII caused by Cul3 mutations is unclear. In cultured cells and human leukocytes, PHAII-causing Cul3 mutations result in the skipping of exon 9, producing mutant Cul3 protein lacking 57 amino acids...
2015: Biology Open
https://www.readbyqxmd.com/read/26435498/impaired-degradation-of-wnk-by-akt-and-pka-phosphorylation-of-klhl3
#20
Yuki Yoshizaki, Yutaro Mori, Yoshihito Tsuzaki, Takayasu Mori, Naohiro Nomura, Mai Wakabayashi, Daiei Takahashi, Moko Zeniya, Eriko Kikuchi, Yuya Araki, Fumiaki Ando, Kiyoshi Isobe, Hidenori Nishida, Akihito Ohta, Koichiro Susa, Yuichi Inoue, Motoko Chiga, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida, Eisei Sohara
Mutations in with-no-lysine kinase (WNK) 1, WNK4, Kelch-like 3 (KLHL3), and Cullin3 result in an inherited hypertensive disease, pseudohypoaldosteronism type II. WNK activates the Na-Cl cotransporter (NCC), increasing sodium reabsorption in the kidney. Further, KLHL3, an adapter protein of Cullin3-based E3 ubiquitin ligase, has been recently found to bind to WNK, thereby degrading them. Insulin and vasopressin have been identified as powerful activators of WNK signaling. In this study, we investigated effects of Akt and PKA, key downstream substrates of insulin and vasopressin signaling, respectively, on KLHL3...
November 13, 2015: Biochemical and Biophysical Research Communications
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