RT Journal Article
SR Electronic
T1 Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes <em>BANK1</em> and <em>BLK</em>
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 136
OP 142
DO 10.1136/annrheumdis-2011-200085
VO 71
IS 1
A1 Casimiro Castillejo-López
A1 Angélica M Delgado-Vega
A1 Jerome Wojcik
A1 Sergey V Kozyrev
A1 Elangovan Thavathiru
A1 Ying-Yu Wu
A1 Elena Sánchez
A1 David Pöllmann
A1 Juan R López-Egido
A1 Serena Fineschi
A1 Nicolás Domínguez
A1 Rufei Lu
A1 Judith A James
A1 Joan T Merrill
A1 Jennifer A Kelly
A1 Kenneth M Kaufman
A1 Kathy L Moser
A1 Gary Gilkeson
A1 Johan Frostegård
A1 Bernardo A Pons-Estel
A1 Sandra D'Alfonso
A1 Torsten Witte
A1 José Luis Callejas
A1 John B Harley
A1 Patrick M Gaffney
A1 Javier Martin
A1 Joel M Guthridge
A1 Marta E Alarcón-Riquelme
YR 2012
UL http://ard.bmj.com/content/71/1/136.abstract
AB Objectives Altered signalling in B cells is a predominant feature of systemic lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein involved in B-cell receptor signalling and BLK codes for an Src tyrosine kinase with important roles in B-cell development. To characterise the role of BANK1 and BLK in SLE, a genetic interaction analysis was performed hypothesising that genetic interactions could reveal functional pathways relevant to disease pathogenesis. Methods The GPAT16 method was used to analyse the gene–gene interactions of BANK1 and BLK. Confocal microscopy was used to investigate co-localisation, and immunoprecipitation was used to verify the physical interaction of BANK1 and BLK. Results Epistatic interactions between BANK1 and BLK polymorphisms associated with SLE were observed in a discovery set of 279 patients and 515 controls from northern Europe. A meta-analysis with 4399 European individuals confirmed the genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding partner of the Src tyrosine kinase LYN, the possibility that BANK1 and BLK could also show a protein–protein interaction was tested. The co-immunoprecipitation and co-localisation of BLK and BANK1 were demonstrated. In a Daudi cell line and primary naive B cells endogenous binding was enhanced upon B-cell receptor stimulation using anti-IgM antibodies. Conclusion This study shows a genetic interaction between BANK1 and BLK, and demonstrates that these molecules interact physically. The results have important consequences for the understanding of SLE and other autoimmune diseases and identify a potential new signalling pathway.