Familial cases of pseudohypoaldosteronism type II harboring a novel mutation in the Cullin 3 gene. Issue 11 (10th August 2020)

• Record Type: Journal Article
• Authors: Nakano, Kiyoshi; Kubota, Yasuo; Mori, Takayuki; Chiga, Motoko; Mori, Takayasu; Sonoda, Shyunya; Ueda, Daisuke; Asakura, Isao; Ikegaya, Takeshi; Kagawa, Jiro; Uchida, Shinichi; Kubota, Akira
• Is Part Of: Nephrology. Volume 25:Issue 11(2020)
• Page Start: 818
• Page End: 821
• Publication Date: 2020-08-10
• Subjects: children -- CUL3 -- familial -- PHA II -- splicing; Nephrology -- Periodicals; Kidneys -- Diseases -- Periodicals; Nephrologists -- Periodicals; 616.61; 616.61
• DOI: 10.1111/nep.13752
• Languages: English
• ISSNs: 1320-5358

Abstract

Abstract: Pseudohypoaldosteronism type II (PHA II) is inherited in an autosomal dominant manner and is characterized by hypertension, hyperkalemia, and hyperchloremic metabolic acidosis. The enhancement of with‐no‐lysine kinase (WNK) functions is correlated to the pathogenesis of the condition. Cullin 3 (CUL3) forms an E3 ubiquitin ligase complex, and it can ubiquitinate WNK. Most CUL3 gene mutations are distributed in sites, such as intron 8 splice acceptor, intron 9 splice donor, and putative intron 8 splice branch sites, which are involved in the splicing of exon 9. These mutations result in the deletion of exon 9, which reduces the activity of ubiquitination against WNK and inhibits the degradation of WNK. In this report, we identified a novel CUL3 c.1312A>G mutation in familial cases. A mutation prediction software showed that the significance of these mutations was not clear. However, using the Human Splicing Finder 3.1 software, in silico analyses revealed that these mutations induced splicing alterations, which affected the sites of exon 9, altered the balance between predicted exonic splicing enhancers and silencers, and led to the deletions of exon 9. This study presented a novel pathogenic splicing variant to the CUL3 mutation and provided a reference for further research about the mechanisms of splicing. Moreover, it showed that not only amino acid substitution caused by nonsynonymous mutations but also splicing motif changes due to base substitutions have important roles in the pathogenesis of PHA II. SUMMARY AT A GLANCE: This study reported familial cases of pseudohypoaldosteronism type 2 (PHA 2) harbouring a novel mutation (c.1312A<G) in the Cullin 3 gene, and indicated that splicing motif changes due to base substitutions have important roles in the pathogenesis of PHA 2.