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The dual effect of the lupus-associated polymorphism rs10516487 on BANK1 gene expression and protein localization

Genes & Immunity volume 13, pages 129–138 (2012)Cite this article

Abstract

Numerous loci have been found genetically associated with complex diseases, but only in a few cases has the functional variant and the molecular mechanism behind it been identified. Recently, the association of the BANK1 gene with systemic lupus erythematosus (SLE) was described. Here, we investigated the role of the associated polymorphisms on gene function and found that SNP rs17266594 located in the branch point consensus sequence has negligible effect on splicing or gene expression. The non-synonymous SNP rs10516487 located in exon 2 influenced splicing efficiency by creating an exonic splicing enhancer site for the SRp40 factor. Further, this same SNP generates protein isoforms with differential and measurable self-association properties. The full-length protein isoform containing the R61 variant forms larger protein scaffold complexes in the cell cytoplasm compared with the protective BANK1-61H variant. We also observed that, contrary to the full-length isoforms, the short Δ2 isoform of BANK1 displays a homogeneous cytoplasmic distribution, underscoring the potential role of the exon 2-coded protein domain in the scaffolding function of BANK1. We provide evidence that the non-synonymous SNP rs10516487 (G>A; R61H) shows a dual nature by first, influencing mRNA splicing and consequently the quantity of protein, and, second, by producing a risk variant-containing protein isoform with increased potential for multimerization.

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Acknowledgements

This work has been supported by the Swedish research council to MEAR, the King Gustaf Vth–80th jubilee fund to MEAR and SVK, Clas Groschinskys fund and Olle Engkvist Byggmästare fund and Marcus Borgström fund to SVK and the Swedish association against rheumatism to CCL, MEAR and SVK. We also acknowledge the NIH COBRE grant RR020143, the OCAST grant HR09-106/7569 and the alliance for lupus research and the Instituto de Salud Carlos III (PS09/00129) partially co-financed with FEDER funds from the European union to MEAR. We are grateful to Ammar Zaghlool for cloning of the ΔT minigene and SRp40 expression construct and help with initial transfection data analysis.

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  1. M E Alarcón-Riquelme and C Castillejo-López: Author position shared.

Authors and Affiliations

  1. Department of Medical Biochemistry and Microbiology, BMC, Uppsala University, Uppsala, Sweden

    S V Kozyrev

  2. Area of Human DNA variability, Centro de Genómica e Investigacion Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, Spain

    M Bernal-Quirós, M E Alarcón-Riquelme & C Castillejo-López

  3. Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    M E Alarcón-Riquelme

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Correspondence to M E Alarcón-Riquelme or C Castillejo-López.

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Kozyrev, S., Bernal-Quirós, M., Alarcón-Riquelme, M. et al. The dual effect of the lupus-associated polymorphism rs10516487 on BANK1 gene expression and protein localization. Genes Immun 13, 129–138 (2012). https://doi.org/10.1038/gene.2011.62

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