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Potential dysfunctional effects of synonymous variants: Insights from an exhaustive in silico analysis of the ABCB4 gene
Univ Sfax, Tunisia.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Univ Sfax, Tunisia.
Univ Sfax, Tunisia.
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2018 (English)In: Annals of Human Genetics, ISSN 0003-4800, E-ISSN 1469-1809, Vol. 82, no 6, p. 457-468Article in journal (Refereed) Published
Abstract [en]

The multiple drug resistance 3 (MDR3) protein is a canalicular phospholipid translocator involved in the bile secretion and encoded by the ABCB4 gene. Its deficiency is related to a large spectrum of liver diseases. Taking into account the increased evidence about the involvement of synonymous variants in inherited diseases, this study aims to explore the putative effects of silent genetic variants on the ABCB4 expression. We performed an exhaustive computational approach using ESE finder, RegRNA 2.0, MFOLD, SNPfold, and %MinMax software added to the measurement of the Relative Synonymous Codon Usage. This analysis included 216 synonymous variants distributed throughout the ABCB4 gene. Results have shown that 11 synonymous coding SNPs decrease the ESE activity, while 8 of them change the codon frequency. Besides, the c.24Camp;gt;T variation, located 21 nucleotides downstream the start A (Adenine) U (Uracil) G (Glutamine) AUG causes an increase in the local stability. Moreover, the computational analysis of the 3UTR region showed that six of the eight variants located in this region affected the Wild Type (WT) pattern of the miRNA targets sites and/or their proper display. The 26 sSNPs retained as putatively functional possessed a very low allele frequency, supporting their pathogenicity. In conclusion, the obtained results suggest that some synonymous SNPs in the ABCB4 gene, considered up to now as neutral, may be involved in the MDR3 deficiency.

Place, publisher, year, edition, pages
WILEY , 2018. Vol. 82, no 6, p. 457-468
Keywords [en]
ABCB4 gene; efficiency of translation; miRNAs; speed of translation; splicing accuracy; Synonymous SNPs
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:liu:diva-152814DOI: 10.1111/ahg.12276ISI: 000448261200012PubMedID: 30079523OAI: oai:DiVA.org:liu-152814DiVA, id: diva2:1265264
Note

Funding Agencies|Ministry of Higher Education and Scientific Research in Tunisia

Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2018-11-22

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CiteExportLink to record
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