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Endocrine

, Volume 64, Issue 3, pp 708–718 | Cite as

Eleven novel SLC12A1 variants and an exonic mutation cause exon skipping in Bartter syndrome type I

  • Yue Han
  • Xiangzhong Zhao
  • Sai Wang
  • Cui Wang
  • Dongxu Tian
  • Yanhua Lang
  • Irene Bottillo
  • Xinsheng WangEmail author
  • Leping ShaoEmail author
Original Article
  • 112 Downloads

Abstract

Introduction

Bartter syndrome type I (BS1) has been rarely reported in large groups. On the other hand, the phenomenon of exon skipping, in which exonic mutations result in abnormal splicing, has been reported to be associated with various diseases. Specifically, mutations that result in the disruption of exonic splicing enhancers (ESEs) and/or the creation of exonic splicing silencers (ESSs) can promote exon skipping. However, the aberrant exon skipping caused by an exonic variant in such splicing regulatory elements (SREs) sequences has never been reported in the causal gene of SLC12A1 in BS1.

Methods

We analyze the variants in nine Chinese families with BS1, including eight with antenatal BS (aBS) and one presenting as classical BS (cBS), by next-generation sequencing. Then we used bioinformatics programs to analyze all these variants found in this study and identify candidate mutations that may induce exon skipping. Furthermore, the effects of identified variants were classified according to the 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines.

Results

Fifteen different variants of SLC12A1 gene were identified, including 11 novel ones. Two of the nine probands were homozygotes, the rest seven ones were compound heterozygotes. One candidate variant (c.1435C>G), not only significantly reduced ESEs scores but also markedly increased ESSs scores, were further investigated by mini-gene splicing assay, and found this single-nucleotide substitution causes abnormal splicing in vitro (exclusion of exon 11). Finally, among 15 variants, 9, 3, and 3 were classified as “pathogenic variants”, “likely pathogenic variants”, “variants with uncertain significance”, respectively.

Conclusion

These data would enrich the human gene mutation database (HGMD) and would provide valuable references to the genetic counseling and diagnosis of BS1 for Chinese population. Additionally, our results suggest that aberrant exon skipping is one previously unrecognized mechanism by which an exonic variant in SLC12A1 can lead to BS1.

Keywords

Bartter syndrome type I SLC12A1 gene Exonic splicing enhancer Exonic splicing silencers Exon skipping 

Notes

Acknowledgements

We thank all subjects for their participation.

Funding

This study was funded by the by grants from the National Natural Scientific Foundation (81873594).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

12020_2019_1856_MOESM1_ESM.docx (19 kb)
Supplementary Tables
12020_2019_1856_MOESM2_ESM.tif (1.4 mb)
Supplementary Figure

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yue Han
    • 1
    • 2
  • Xiangzhong Zhao
    • 2
  • Sai Wang
    • 1
    • 2
  • Cui Wang
    • 1
    • 2
  • Dongxu Tian
    • 3
  • Yanhua Lang
    • 4
  • Irene Bottillo
    • 5
  • Xinsheng Wang
    • 3
    Email author
  • Leping Shao
    • 1
    • 2
    Email author
  1. 1.Department of NephrologyThe Affiliated Qingdao Municipal Hospital of Qingdao UniversityQingdaoPeople’s Republic of China
  2. 2.Central LaboratoryThe Affiliated Hospital of Qingdao UniversityQingdaoPeople’s Republic of China
  3. 3.Department of UrologyThe Affiliated Hospital of Qingdao UniversityQingdaoPeople’s Republic of China
  4. 4.Department of NursingThe Affiliated Hospital of Qingdao UniversityQingdaoPeople’s Republic of China
  5. 5.Division of Medical Genetics, Department of Molecular MedicineSapienza University, San Camillo-Forlanini HospitalRomeItaly

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