Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations.

Abstract

BACKGROUND:

Familial 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.

METHODS:

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.

RESULTS:

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)).

CONCLUSIONS:

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.

• Authors: Haim Mayan, Vered Carmon, Kira Oleinikov, Shira London, Raphael Halevy, Eliezer J Holtzman, Yardena Tenenbaum-Rakover, Zvi Farfel, Aaron Hanukoglu
• Journal: Nephron (Nephron) Vol. 130 Issue 1 Pg. 59-65 ( 2015) ISSN: 2235-3186 [Electronic] Switzerland
• PMID: 25925082 (Publication Type: Journal Article)
• Copyright: © 2015 S. Karger AG, Basel.

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• KLHL3 protein, human
• Microfilament Proteins
• Creatinine
• Calcium

Topics

• Adaptor Proteins, Signal Transducing
• Aged
• Arabs
• Blood Pressure (physiology)
• Body Height
• Calcium (urine)
• Carrier Proteins (genetics)
• Child
• Creatinine (blood)
• Female
• Humans
• Hypercalciuria (etiology, genetics)
• Kidney Function Tests
• Male
• Microfilament Proteins
• Middle Aged
• Mutation (genetics)
• Pedigree
• Pseudohypoaldosteronism (complications, genetics)
• Transient Tachypnea of the Newborn (genetics)
• Twins, Monozygotic