A novel mutation in exon 9 of Cullin 3 gene contributes to aberrant splicing in pseudohypoaldosteronism type II

Pseudohypoaldosteronism type II ( PHAII ) is a rare renal tubular disease that is inherited in an autosomal dominant manner. Mutations in four genes ( WNK 1 , WNK 4 , CUL 3, and KLHL 3 ) have been identified to be responsible for this disease. Cullin 3 ( CUL 3) and KLHL 3 are subunits of Cullin– RING E3 ubiquitin ligase complexes, and the serine–threonine kinases WNK 1 and WNK 4 are substrates of this ubiquitin ligase. For CUL 3 , all mutations associated with PHAII exclusively lead to exon 9 skipping. In this study, we identified a Chinese PHAII kindred caused by a novel synonymous mutation (c.1221A > G p.Glu407Glu) in CUL 3 , and explored its effects on exon 9 abnormal splicing through an in vitro splicing assay and study of the patients’ RNA . We obtained evidence that this synonymous mutation leads to complete exon 9 skipping, and in silico bioinformatics analysis demonstrated that the CUL 3 c.1221A > G mutation might decrease the ratio of exonic splicing enhancers and silencers. This is the first report of PHAII in Chinese patients with a novel CUL 3 mutation. Our findings add a novel pathogenic splicing variant to the CUL 3 mutational spectrum and provide reference for further research on mechanisms of splicing modulation and development of potential therapeutic reagents for PHAII .