KLHL-perheestä: KLHL3 (5q31.2) , PHA2D, Sekundääri hypertensio

https://www.ncbi.nlm.nih.gov/gene/26249 

Official Full Name kelch like family member 3

Also known as PHA2D

Summary. This gene is ubiquitously expressed and encodes a full-length protein which has an N-terminal BTB domain followed by a BACK domain and six kelch-like repeats in the C-terminus. These kelch-like repeats promote substrate ubiquitination of bound proteins via interaction of the BTB domain with the CUL3 (cullin 3) component of a cullin-RING E3 ubiquitin ligase (CRL) complex. Muatations in this gene cause pseudohypoaldosteronism type IID (PHA2D); a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Mar 2012]

Expressio: Broad expression in thyroid (RPKM 5.9), heart (RPKM 4.0) and 23 other tissues See more

1. KLHL3 single-nucleotide polymorphism is associated with essential hypertension in Chinese Han population. Li J, et al. Medicine (Baltimore), 2019 May. PMID 31096542, Free PMC Article Hypertension, including secondary and essential hypertension (EH) variants, is a multifactorial disease, affecting more than one billion people worldwide. Secondary hypertension results from mutations in the putative gene KLHL3 (Kelch-like protein 3); however, it has not been reported whether the KLHL3 gene polymorphisms are associated with EH. Here, we investigated the association between KLHL3 (rs2301708 and rs7444370) polymorphisms and EH in the Chinese Han population.This case-control study included 522 subjects-260 patients with EH and 262 normotensive controls matched for age, gender, body mass index (BMI), hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG), and levels of Na, K, and Cl. The distribution of functional rs2301708 and rs7444370 polymorphisms within the KLHL3 gene was assessed through polymerase chain reaction (PCR) and restriction-fragment length polymorphism (RFLP).There was no significant difference in allelic and genotypic frequencies of KLHL3 rs2301708 between the EH and normotensive groups; however, the rs7444370 T allele and CT genotype in females was significantly associated with a protective effect against EH (P = .001, P = .002; P = .019, P = .052), and the haplotype CT of rs2301708 and rs7444370 among females in the EH group was less than in the normotensive group (P = .000; P = .007).The KLHL3 rs7444370 variant could be a protective factor in the pathogenesis of females' EH.
2. Three cases of Gordon syndrome with dominant KLHL3 mutations. Park JS, et al. J Pediatr Endocrinol Metab, 2017 Mar 1. PMID 28222034
   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,
   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.
   GS should be considered in patients with low renin hypertension and hyperkalemia. Although it is a rare disease, the correct diagnosis of GS is clinically important, as it can easily be treated with a low sodium diet or thiazides. In addition, family studies can identify individuals with undiagnosed GS as all mutations causing this disease, except for some recessive KLHL3 mutations, are dominant mutations.
3. Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations. Mayan H, et al. Nephron, 2015. PMID 25925082 F amilial hyperkalemia and hypertension (FHHt) is a rare genetic disorder manifested by hyperkalemia and early hypertension. Hypercalciuria is another accompanying feature. Mutations in WNK4 and WNK1 were found initially, and recently additional mutations were found in two genes, KLHL3 and CUL3, which are components of the Ubiquitin system. It was not reported whether these latter mutations are accompanied by hypercalciuria. We compared urinary calcium excretion (UCa) in affected subjects with FHHt and KLHL3 mutations, and in their unaffected family members, and in affected subjects with FHHt and WNK4 Q565E mutation.
   Two new families with FHHt including a total number of 23 subjects, 10 of them affected, in whom previously described mutations in KLHL3 (Q309R and R528H) were identified. Presenting features were short stature in the first family, and transient tachypnea of the newborn (TTN) in the second. Affected subjects had hypercalciuria. UCa levels in affected subjects in the two families were significantly higher than in unaffected subjects (0.608 ± 0.196 vs. 0.236 ± 0.053 mmol Ca per mmol creatinine, respectively (p < 0.0001)). Hypercalciuria in FHHt with KLHL3 mutations is less severe than that observed in FHHt with the Q565E WNK4 mutation (0.608 ± 0.196 (n = 10) mmol Ca per mmol creatinine versus 0.860 ± 0.295 (n = 29), respectively (p = 0.0168)).
   FHHt caused by KLHL3 mutations is accompanied by hypercalciuria as well as hyperkalemia and hypertension. The similar phenomena observed for FHHt caused by WNK4 mutations fits the other evidence that WNK4 mutations are activating, and the aberrant mechanism of calcium handling by the kidney in FHHt.
   
4. Molecular characterization of KLHL3, a human homologue of the Drosophila kelch gene. Lai F, et al. Genomics, 2000 May 15. PMID 10843806
5. Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling. Ishizawa K, et al. Proc Natl Acad Sci U S A, 2019 Feb 19. PMID 30718414, Free PMC Article   Calcineurin is a calcium/calmodulin-regulated phosphatase known for its role in activation of T cells following engagement of the T cell receptor. Calcineurin inhibitors (CNIs) are widely used as immunosuppressive agents; common adverse effects of CNIs are hypertension and hyperkalemia. While previous studies have implicated activation of the Na-Cl cotransporter (NCC) in the renal distal convoluted tubule (DCT) in this toxicity, the molecular mechanism of this effect is unknown. The renal effects of CNIs mimic the hypertension and hyperkalemia that result from germ-line mutations in with-no-lysine (WNK) kinases and the Kelch-like 3 (KLHL3)-CUL3 ubiquitin ligase complex. WNK4 is an activator of NCC and is degraded by binding to KLHL3 followed by WNK4's ubiquitylation and proteasomal degradation. This binding is prevented by phosphorylation of KLHL3 at serine 433 (KLHL3^S433-P) via protein kinase C, resulting in increased WNK4 levels and increased NCC activity. Mechanisms mediating KLHL3^S433-P dephosphorylation have heretofore been unknown. We now demonstrate that calcineurin expressed in DCT is a potent KLHL3^S433-P phosphatase. In mammalian cells, the calcium ionophore ionomycin, a calcineurin activator, reduces KLHL3^S433-P levels, and this effect is reversed by the calcineurin inhibitor tacrolimus and by siRNA-mediated knockdown of calcineurin. In vivo, tacrolimus increases levels of KLHL3^S433-P, resulting in increased levels of WNK4, phosphorylated SPAK, and NCC. Moreover, tacrolimus attenuates KLHL3-mediated WNK4 ubiquitylation and degradation, while this effect is absent in KLHL3 with S433A substitution. Additionally, increased extracellular K⁺ induced calcineurin-dependent dephosphorylation of KLHL3^S433-P These findings demonstrate that KLHL3^S433-P is a calcineurin substrate and implicate increased KLHL3 phosphorylation in tacrolimus-induced pathologies.

See all (43) citations in PubMed

 Huom. Insuliini ja vasopressiini ovat WNK-signaloinnin aktivoijia. WNK on KLHL3 adaptorin substraatti ja  johdetaan degradaatioon  CLR3 ubikitiiniligaasi-proteosomi-tietä.
Jos KLHL3 fosforyloituu seriiniin 433, sen sitoutuminen  substraattiin WNK4  on vajaata Akt ja PJA fosforylaatiomotiivien komponentti on  juuri S433. Akt ja PKA voivat fosforyloida  KLHL3  seriiniin 433. Myös PKC voi suorittaa sen fosforylaation. Myös insuliini vaikuttaa S433 fosforylaatiota KLHL3:ssa joten  se ei voi  johtaa WNK4:ää silppuriin. Tässä lienee  taustaa sille,että insuliini ja vasopressiini aktivoivat WNK-signalointia ( Na-reabsorptiota munuaisessa).

 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. Mass spectrometry analysis revealed that KLHL3 phosphorylation at S433. Phospho-specific antibody demonstrated defective binding between phosphorylated KLHL3 and WNK4. Consistent with the fact that S433 is a component of Akt and PKA phosphorylation motifs, in vitro kinase assay demonstrated that Akt and PKA can phosphorylate KLHL3 at S433, that was previously reported to be phosphorylated by PKC. Further, forskolin, a representative PKA stimulator, increased phosphorylation of KLHL3 at S433 and WNK4 protein expression in HEK293 cells by inhibiting the KLHL3 effect that leads to WNK4 degradation. Insulin also increased phosphorylation of KLHL3 at S433 in cultured cells. In conclusion, we found that Akt and PKA phosphorylated KLHL3 at S433, and phosphorylation of KLHL3 by PKA inhibited WNK4 degradation. This could be a novel mechanism on how insulin and vasopressin physiologically activate the WNK signal.

https://www.ncbi.nlm.nih.gov/pubmed/24641320/