Dataset Information

A familial case of pseudohypoaldosteronism type II (PHA2) with a novel mutation (D564N) in the acidic motif in WNK4.

ABSTRACT: BACKGROUND:There have been still few case reports of pseudohypoaldosteronism type II (PHA2), also known as Gordon's syndrome, genetically diagnosed, and this is the first report of familial PHA2 case in Japan with a novel D564N mutation in WNK4. METHODS:A 29-year-old woman was admitted to our hospital due to hyperkalemia (serum potassium: 6.4 mmol/L). She had mild hypertension (135/91 mm Hg), a bicarbonate level at the lower limit of the normal range (HCO3 : 22 mmol/L) with a normal anion gap, low plasma renin activity (0.2 ng ml-1 hr-1 ), and high urinary calcium excretion (505.4 mg/g Cre). A hereditary condition was suspected because her mother also had the same symptoms. We performed a comprehensive genetic analysis for major inherited kidney diseases with next-generation sequencing including the genes responsible for PHA2 (WNK1, WNK4, KLHL3, and CUL3). RESULTS:Genetic analysis revealed that the patient and her mother had a novel missense mutation (D564N) in the acidic motif in WNK4, which leads to the diagnosis of PHA2. Administration of trichlormethiazide (1 mg/day) effectively ameliorated her blood pressure (114/69 mm Hg), plasma bicarbonate (25 mmol/L), serum potassium (4.3 mmol/L), and urinary calcium excretion (27.2 mg/g Cre). CONCLUSION:We report the first Japanese familial case of PHA2 with WNK4 mutation. D564N mutation in WNK4 is a novel genetic cause of PHA2 with a relatively mild phenotype.

SUBMITTER: Sakoh T

PROVIDER: S-EPMC6565545 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A familial case of pseudohypoaldosteronism type II (PHA2) with a novel mutation (D564N) in the acidic motif in WNK4.

Sakoh Takashi T Sekine Akinari A Mori Takayasu T Mizuno Hiroki H Kawada Masahiro M Hiramatsu Rikako R Hasegawa Eiko E Hayami Noriko N Yamanouchi Masayuki M Suwabe Tatsuya T Sawa Naoki N Ubara Yoshifumi Y Fujimaru Takuya T Sohara Eisei E Shinichi Uchida U Hoshino Junichi J Takaichi Kenmei K

Molecular genetics & genomic medicine 20190501 6

<h4>Background</h4>There have been still few case reports of pseudohypoaldosteronism type II (PHA2), also known as Gordon's syndrome, genetically diagnosed, and this is the first report of familial PHA2 case in Japan with a novel D564N mutation in WNK4.<h4>Methods</h4>A 29-year-old woman was admitted to our hospital due to hyperkalemia (serum potassium: 6.4 mmol/L). She had mild hypertension (135/91 mm Hg), a bicarbonate level at the lower limit of the normal range (HCO<sub>3</sub> : 22 mmol/L) ...[more]

PMID: 31044551

Similar Datasets

Project description: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. In this study, we approached this problem using molecular dynamics simulation with structural, dynamical and energetic analyses. Results from independent simulations indicate that when S433 was phosphorylated, the electrostatic potential became more negative in the AM binding site of KLHL3 and therefore was unfavorable for binding with the negatively charged AM. In addition, the intermolecular hydrogen bond network that kept the AM stable in the binding site of KLHL3 was disrupted, and the forces for the hydrophobic interactions between the AM of WNK4 and KLHL3 were also reduced. As a result, the weakened interactions were no longer capable of holding the AM of WNK4 at its binding site in KLHL3. In conclusion, phosphorylation of KLHL3 at S433 disrupts the hydrogen bonds, hydrophobic and electrostatic interactions between the Kelch domain of KLHL3 and the AM of WNK4. This study provides a key molecular understanding of the KLHL3-mediated regulation of WNK4, which is an integrative regulator of electrolyte homeostasis and blood pressure regulation in the kidney. Significances Statement: WNK4 is an integrative regulator of electrolyte homeostasis, which is important in the blood pressure regulation by the kidney. Interaction between WNK4 and KLHL3 is a key physiological process that is impaired in a hereditary form of hypertension. This study provides substantial new insights into the role of phosphorylation of KLHL3 in regulating the interaction with WNK4, and therefore advances our understanding of molecular pathogenesis of hypertension and the mechanism of blood pressure regulation.

Project description:UnlabelledAutosomal recessive pseudohypoaldosteronism type 1 (PHA1) is a rare disorder characterized by sodium wasting, failure to thrive, hyperkalemia, hypovolemia and metabolic acidosis. It is due to mutations in the amiloride-sensitive epithelial sodium channel (ENaC) and is characterized by diminished response to aldosterone. Patients may present with life-threatening hyperkalemia, which must be recognized and appropriately treated. A 32-year-old female was referred to the National Institutes of Health (NIH) for evaluation of hyperkalemia and muscle pain. Her condition started in the second week of life, when she was brought to an outside hospital lethargic and unresponsive. At that time, she was hypovolemic, hyperkalemic and acidotic, and was eventually treated with sodium bicarbonate and potassium chelation. At the time of the presentation to the NIH, her laboratory evaluation revealed serum potassium 5.1 mmol/l (reference range: 3.4-5.1 mmol/l), aldosterone 2800 ng/dl (reference range: ≤21 ng/dl) and plasma renin activity 90 ng/ml/h (reference range: 0.6-4.3 ng/ml per h). Diagnosis of PHA1 was suspected. Sequencing of the SCNN1B gene, which codes for ENaC, revealed that the patient is a compound heterozygote for two novel variants (c.1288delC and c.1466+1 G>A), confirming the suspected diagnosis of PHA1. In conclusion, we report a patient with novel variants of the SCNN1B gene causing PHA1 with persistent, symptomatic hyperkalemia.Learning pointsPHA1 is a rare genetic condition, causing functional abnormalities of the amiloride-sensitive ENaC.PHA1 was caused by previously unreported SCNN1B gene mutations (c.1288delC and c.1466+1 G>A).Early recognition of this condition and adherence to symptomatic therapy is important, as the electrolyte abnormalities found may lead to severe dehydration, cardiac arrhythmias and even death.High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment.

Dataset Information

A familial case of pseudohypoaldosteronism type II (PHA2) with a novel mutation (D564N) in the acidic motif in WNK4.

Publications

A familial case of pseudohypoaldosteronism type II (PHA2) with a novel mutation (D564N) in the acidic motif in WNK4.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets