A Young Female with Spitzer-Weinstein Syndrome Diagnosed by Thiazide Test

Weng, Cheng Hao; Cheng, Jen Wei; Hung, Chen Chieh; Wu, Mai Szu; Yang, Chih Wei; Chang, Chiz Tzung

doi:10.1080/08860220601100510

Cited by 2 publications

(1 citation statement)

References 9 publications

(11 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, given the information raised sic FHHt. Our cases are very similar to the 3 published cases of Spitzer-Weinstein syndrome, characterized by normotension and early onset hyperkalemic tubular acidosis and sensitive to HCTZ (34)(35)(36). The mutations are all located in the acidic motif, which is highly conserved across members of the WNK family and pivotal for their recruitment by KLHL proteins for ubiquitination by the CUL3-based E3 ligase ubiquitin complex (5,37).…”

Section: Discussionsupporting

confidence: 82%

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

Louis-Dit-Picard¹,

Kouranti²,

Rafael³

et al. 2020

Journal of Clinical Investigation

View full text Add to dashboard Cite

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...

show abstract