A novel mutation in exon 9 of Cullin 3 gene contributes to aberrant splicing in pseudohypoaldosteronism type II. Issue 3 (10th February 2018)

• Record Type: Journal Article
• Authors: Shao, Leping; Cui, Li; Lu, Jingru; Lang, Yanhua; Bottillo, Irene; Zhao, Xiangzhong
• Is Part Of: FEBS open bio. Volume 8:Issue 3(2018)
• Page Start: 461
• Page End: 469
• Publication Date: 2018-02-10
• Subjects: CUL3 -- exonic splicing enhancers -- exonic splicing silencers -- pseudohypoaldosteronism type II -- splicing modulation; Molecular biology -- Periodicals; Cytology -- Periodicals; Life sciences -- Periodicals; Biological Science Disciplines -- Periodicals; Molecular Biology -- Periodicals; Cell Biology -- Periodicals; Cytology; Life sciences; Molecular biology; Periodicals; 572.805
• DOI: 10.1002/2211-5463.12389
• Languages: English
• ISSNs: 2211-5463

Abstract

Abstract : Pseudohypoaldosteronism type II (PHAII) is a rare renal tubular disease that is inherited in an autosomal dominant manner. Mutations in four genes ( WNK1, WNK4, CUL3, and KLHL3 ) have been identified to be responsible for this disease. Cullin 3 (CUL3) and KLHL3 are subunits of Cullin–RING E3 ubiquitin ligase complexes, and the serine–threonine kinases WNK1 and WNK4 are substrates of this ubiquitin ligase. For CUL3, 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 CUL3, 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 CUL3 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 CUL3 mutation. Our findings add a novel pathogenic splicing variant to the CUL3 mutational spectrum and provide reference for further research on mechanisms of splicing modulation and development of potential therapeutic reagents for PHAII. Abstract : Pseudohypoaldosteronism type II (PHAII) is a rare renal tubular disease that is inherited in an autosomal dominant manner. CUL3 mutations are associated with PHAII. Here, we report a novel synonymous mutation (c.1221A > G p.Glu407Glu) in CUL3 from a Chinese PHAII kindred. This synonymous mutation, which causes exon 9 skipping by decreasing the ratio of exonic splicing enhancers and silencers, contributes to PHAII.