SLC12A1 variant c.1684+1 G>A causes Bartter syndrome type 1 by promoting exon 13 skipping.

Autor: Yang W; Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, China.; National Health Commission Key Laboratory of Birth Defects Prevention, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Zhengzhou, China., Li Y; Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, China., Guo Z; Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, China.; National Health Commission Key Laboratory of Birth Defects Prevention, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Zhengzhou, China., Ren Y; Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, China.; National Health Commission Key Laboratory of Birth Defects Prevention, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Zhengzhou, China., Huang J; Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, China.; National Health Commission Key Laboratory of Birth Defects Prevention, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Zhengzhou, China., Zhao H; Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, China., Liao S; Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, China.; National Health Commission Key Laboratory of Birth Defects Prevention, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Zhengzhou, China.
Jazyk: angličtina
Zdroj: Nephrology (Carlton, Vic.) [Nephrology (Carlton)] 2024 Dec; Vol. 29 (12), pp. 801-805. Date of Electronic Publication: 2024 Sep 11.
DOI: 10.1111/nep.14390
Abstrakt: Background: Bartter syndrome type 1, an autosomal recessive genetic disorder, is caused by pathogenic loss-of-function variants in the SLC12A1 gene. It is characterized by metabolic alkalosis and prenatal-onset polyuria leading to polyhydramnios.
Methods: We identified pathogenic gene in a 12-day-old newborn boy with Bartter syndrome type 1 using whole-exome sequencing. Sanger sequencing validated the identified variants. A minigene assay was performed to investigate the effect of a novel splice site variant on pre-mRNA splicing.
Results: We found a compound heterozygous variants in the SLC12A1 gene, consisting of a known pathogenic missense mutation (NM_000338: c.769 G>A; p.Gly257Ser) and a novel splice site variant (c.1684+1 G>A). In silico predictions and an in vitro minigene splicing assay demonstrated that the splicing variant c.1684+1 G>A abolished a consensus splice donor site of SLC12A1 intron 13, resulting in complete exon 13 skipping, translational frameshift, and premature termination codon, ultimately leading to loss of SLC12A1 function.
Conclusion: Using a cell-based in vitro assay, we revealed the aberrant effect of the pathogenic splicing variant SLC12A1 c.1684+1 G>A on pre-mRNA splicing. Our findings expand the gene mutation spectrum of Bartter syndrome type 1, providing a basis for genetic diagnosis and the development of genetic medicines.
(© 2024 Asian Pacific Society of Nephrology.)
Databáze: MEDLINE
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