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Familial cases of pseudohypoaldosteronism type II harboring a novel mutation in the Cullin 3 gene
Author(s) -
Nakano Kiyoshi,
Kubota Yasuo,
Mori Takayuki,
Chiga Motoko,
Mori Takayasu,
Sonoda Shyunya,
Ueda Daisuke,
Asakura Isao,
Ikegaya Takeshi,
Kagawa Jiro,
Uchida Shinichi,
Kubota Akira
Publication year - 2020
Publication title -
nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 61
eISSN - 1440-1797
pISSN - 1320-5358
DOI - 10.1111/nep.13752
Subject(s) - exon , rna splicing , intron , genetics , biology , gene , mutation , silent mutation , microbiology and biotechnology , missense mutation , rna
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.