<i>KLHL3</i>et<i>CULLIN-3</i>

Louis-Dit-Picard, Hélène; Hadchouel, Juliette; Jeunemaı̂tre, Xavier

doi:10.1051/medsci/2012288010

Cited by 5 publications

(4 citation statements)

References 12 publications

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“…Mutations causing FHHt were first identified in the WNK1 and WNK4 genes that encode 2 members of the with no lysine (K) (WNK) serine-threonine kinase family (2). More recently, we and others have identified disease-causing mutations in the Kelch-like 3 (KLHL3) and Cullin 3 (CUL3) proteins belonging to a ubiquitin-protein ligase complex (3,4). This complex has been shown in vitro to interact with WNK1 and WNK4, induce their ubiquitination, and regulate their protein levels through proteasomal degradation (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis

Louis-Dit-Picard¹,

Kouranti²,

Rafael³

et al. 2020

Journal of Clinical Investigation

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Using a SNP-based linkage approach, 7 suggestive linkage regions (maximum logarithm of odds [LOD] score = 1.8 in all linked regions) were identified in this panel (Supplemental Table 1B). In total, linked regions spanned 69 Mb and included 829 protein-coding genes. After filtering, WES performed in 1 unaffected and 2 affected individuals identified 71 possible disease-causing coding variants (Supplemental Table 1C). Four missense variants mapped to the linkage regions and were predicted in silico to be damaging. These variants were located in solute carrier family 30 member 7, a zinc transporter (SLC30A7), kinesin family member 11 (KIF11), tectonic family member 3 (TCTN3), and WNK1. The WNK1 variant (c.1905T>A; P.Asp635Glu) (Figure 1B) was located in exon 7 (ex7), which encodes the conserved acidic motif, previously shown to mediate the interaction with the substrate adaptor KLHL3 ( 14).Additional variants in the WNK1 acidic motif in other cases and kindreds. FHHt-causing WNK4 mutations are located in ex7 and ex17, encoding highly conserved acid and base motifs, respectively. Thus, we screened the homologous motifs of WNK1 encoded by ex7 and ex25, respectively, in 26 unrelated affected cases previously found as negative for the classical mutations in WNK4, KLHL3, CUL3, or the intron 1 deletion in WNK1. Direct sequencing identified 5 additional nonsynonymous heterozygous variants in ex7 in 8 unrelated subjects (Figure 2, A-C). The in silico pathogenicity of these variants is described in Supplemental Table 2. All were located within the acidic motif, between positions 631 and 636 of the L-WNK1 protein, and were predicted to be pathogenic. Four of the 6 missense variants were charge changing (E631K, D635N, Q636R, Q636E); 2 affected residues (D635, Q636) were also found mutated in the homologous acidic motif of WNK4 (D564 and Q565, Figure 2, C and D)Clinical and biochemical characteristics: hydrochlorothiazide-sensitive hyperkalemic acidosis without hypertension. Detailed clinical and biological characteristics of index cases are given in Table 1. The circumstances of discovery and the clinical symptoms of these index patients are detailed in Supplemental Table 3. In most of the cases, patients were asymptomatic and showed with no signs of hyperkalemia on an electrocardiogram. All displayed the electrolyte anomalies typical of FHHt, including marked hyperkalemia (median, 5.9 mmol/L; IQR, 5.3-6.3), hyperchloremia (median, 108 mmol/L; IQR, 106-110), and metabolic acidosis (total CO 2 , 20 mmol/L; IQR, 19-21) despite a normal glomerular filtration rate (GFR) (median creatinine, 58 μmol/L; IQR, 47-74). For the 7 index cases with prospective reliable clinical data, hyperkalemia and hyperchloremia were rapidly corrected with low doses of hydrochlorothiazide (HCTZ) (6.25 to 25 mg/d; Supplemental Figure 1). In comparison, an average drop in potassium of only 0.7 mmol/L was observed in normal, healthy subjects administered a much higher dose of HCTZ (50 mg for 3 weeks) (15). Compared with reference values (16), we also obser...

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Section: Introductionmentioning

confidence: 99%

Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis

Louis-Dit-Picard¹,

Kouranti²,

Rafael³

et al. 2020

Journal of Clinical Investigation

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“…21 Specific deletion of CSN/Jab1 along the mouse nephron regulates the substrate abundance of CUL3. 22 Individuals with pathogenic variants in WNK1, 9 WNK4, 9 and KLHL3 23,24 typically produce FHHt symptoms in adulthood with rare cases demonstrating pediatric onset. 25 In contrast, CUL3 variants are commonly presented in infants and children and induce FHHt symptoms and growth failure.…”

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confidence: 99%

Novel CUL3 Variant Causing Familial Hyperkalemic Hypertension Impairs Regulation and Function of Ubiquitin Ligase Activity

et al. 2022

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Familial hyperkalemic hypertension is caused by pathogenic variants in genes of the CUL3 (cullin-3)-KLHL3 (kelch-like-family-member-3)-WNK (with no-lysine [K] kinase) pathway, manifesting clinically as hyperkalemia, metabolic acidosis, and high systolic blood pressure. The ubiquitin E3 ligase CUL3-KLHL3 targets WNK kinases for degradation to limit activation of the thiazide-sensitive NCC (Na-Cl cotransporter). All known variants in CUL3 lead to exon 9 skipping (CUL3Δ9) and typically result in severe familial hyperkalemic hypertension and growth disturbances in patients. Whether other variants in CUL3 cause familial hyperkalemic hypertension is unknown. Here, we identify a novel de novo heterozygous CUL3 variant (CUL3Δ474–477) in a pediatric familial hyperkalemic hypertension patient with multiple congenital anomalies and reveal molecular mechanisms by which CUL3Δ474–477 leads to dysregulation of the CUL3-KLHL3-WNK signaling axis. Using patient-derived urinary extracellular vesicles and dermal fibroblasts, in vitro assays, and cultured kidney cells, we demonstrate that CUL3Δ474–477 causes reduced total CUL3 levels due to increased autoubiquitination. The CUL3Δ474–477 that escapes autodegradation shows enhanced modification with NEDD8 (neural precursor cell expressed developmentally down-regulated protein 8) and increased formation of CUL3-KLHL3 complexes that are impaired in ubiquitinating WNK4. Proteomic analysis of CUL3 complexes revealed that, in addition to increased KLHL3 binding, the CUL3Δ474–477 variant also exhibits increased interactions with other BTB (Bric-a-brac, Tramtrack, and Broad complex) substrate adaptors, providing a rationale for the patient’s diverse phenotypes. We conclude that the pathophysiological effects of CUL3Δ474–477 are caused by reduced CUL3 levels and formation of catalytically impaired CUL3 ligase complexes.

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“…Ces mutations pourraient donc modifier l'interaction de WNK4 avec ses partenaires. Cette hypothèse a été confirmée grâce à l'identification de deux nouveaux gènes dont des mutations sont responsables de la FHHt [19,20], KLHL3 (Kelch-like 3) et Cullin3 [35] ( §).…”

Section: Wnk1-wnk4 Et Hypertension Hyperkaliémique Familialeunclassified