title: Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Correspondence to Marta E Alarcón-Riquelme, Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73102, USA. alarconm@omrf.org.
authors: Casimiro
authors: C
authors: Castillejo-López
authors: Angélica M
authors: AM
authors: Delgado-Vega
authors: Jerome
authors: J
authors: Wojcik
authors: Sergey V
authors: SV
authors: Kozyrev
authors: Elangovan
authors: E
authors: Thavathiru
authors: Ying-Yu
authors: YY
authors: Wu
authors: Elena
authors: E
authors: Sánchez
authors: David
authors: D
authors: Pöllmann
authors: Juan R
authors: JR
authors: López-Egido
authors: Serena
authors: S
authors: Fineschi
authors: Nicolás
authors: N
authors: Domínguez
authors: Rufei
authors: R
authors: Lu
authors: Judith A
authors: JA
authors: James
authors: Joan T
authors: JT
authors: Merrill
authors: Jennifer A
authors: JA
authors: Kelly
authors: Kenneth M
authors: KM
authors: Kaufman
authors: Kathy L
authors: KL
authors: Moser
authors: Gary
authors: G
authors: Gilkeson
authors: Johan
authors: J
authors: Frostegård
authors: Bernardo A
authors: BA
authors: Pons-Estel
authors: Sandra
authors: S
authors: D'Alfonso
authors: Torsten
authors: T
authors: Witte
authors: José Luis
authors: JL
authors: Callejas
authors: John B
authors: JB
authors: Harley
authors: Patrick M
authors: PM
authors: Gaffney
authors: Javier
authors: J
authors: Martin
authors: Joel M
authors: JM
authors: Guthridge
authors: Marta E
authors: ME
authors: Alarcón-Riquelme
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D004843:Epistasis, Genetic / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019061:src-Family Kinases / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C447641:BANK1 protein, human; D008565:Membrane Proteins; C082599:protein-tyrosine kinase p55(blk); D019061:src-Family Kinases