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.
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.
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Authors: G Texido; I H Su; I Mecklenbräuker; K Saijo; S N Malek; S Desiderio; K Rajewsky; A Tarakhovsky Journal: Mol Cell Biol Date: 2000-02 Impact factor: 4.272
Authors: John B Harley; Marta E Alarcón-Riquelme; Lindsey A Criswell; Chaim O Jacob; Robert P Kimberly; Kathy L Moser; Betty P Tsao; Timothy J Vyse; Carl D Langefeld; Swapan K Nath; Joel M Guthridge; Beth L Cobb; Daniel B Mirel; Miranda C Marion; Adrienne H Williams; Jasmin Divers; Wei Wang; Summer G Frank; Bahram Namjou; Stacey B Gabriel; Annette T Lee; Peter K Gregersen; Timothy W Behrens; Kimberly E Taylor; Michelle Fernando; Raphael Zidovetzki; Patrick M Gaffney; Jeffrey C Edberg; John D Rioux; Joshua O Ojwang; Judith A James; Joan T Merrill; Gary S Gilkeson; Michael F Seldin; Hong Yin; Emily C Baechler; Quan-Zhen Li; Edward K Wakeland; Gail R Bruner; Kenneth M Kaufman; Jennifer A Kelly Journal: Nat Genet Date: 2008-01-20 Impact factor: 38.330
Authors: E M Tan; A S Cohen; J F Fries; A T Masi; D J McShane; N F Rothfield; J G Schaller; N Talal; R J Winchester Journal: Arthritis Rheum Date: 1982-11
Authors: Amr H Sawalha; Lu Wang; Ajay Nadig; Emily C Somers; W Joseph McCune; Travis Hughes; Joan T Merrill; R Hal Scofield; Faith M Strickland; Bruce Richardson Journal: J Autoimmun Date: 2012-02-03 Impact factor: 7.094