title: Sarcoidosis is associated with a truncating splice site mutation in BTNL2.
abstract: Sarcoidosis is a polygenic immune disorder with predominant manifestation in the lung. Genome-wide linkage analysis previously indicated that the extended major histocompatibility locus on chromosome 6p was linked to susceptibility to sarcoidosis. Here, we carried out a systematic three-stage SNP scan of 16.4 Mb on chromosome 6p21 in as many as 947 independent cases of familial and sporadic sarcoidosis and found that a 15-kb segment of the gene butyrophilin-like 2 (BTNL2) was associated with the disease. The primary disease-associated variant (rs2076530; P(TDT) = 3 x 10(-6), P(case-control) = 1.1 x 10(-8); replication P(TDT) = 0.0018, P(case-control) = 1.8 x 10(-6)) represents a risk factor that is independent of variation in HLA-DRB1. BTNL2 is a member of the immunoglobulin superfamily and has been implicated as a costimulatory molecule involved in T-cell activation on the basis of its homology to B7-1. The G --> A transition constituting rs2076530 leads to the use of a cryptic splice site located 4 bp upstream of the affected wild-type donor site. Transcripts of the risk-associated allele have a premature stop in the spliced mRNA. The resulting protein lacks the C-terminal IgC domain and transmembrane helix, thereby disrupting the membrane localization of the protein, as shown in experiments using green fluorescent protein and V5 fusion proteins.
authors.affiliation: Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany.
authors.forename: Ruta
authors.initials: R
authors.lastname: Valentonyte
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Klaus
authors.initials: K
authors.lastname: Huse
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Mario
authors.initials: M
authors.lastname: Albrecht
authors.forename: Annette
authors.initials: A
authors.lastname: Stenzel
authors.forename: Marion
authors.initials: M
authors.lastname: Nagy
authors.forename: Karoline I
authors.initials: KI
authors.lastname: Gaede
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Robert
authors.initials: R
authors.lastname: Haesler
authors.forename: Andreas
authors.initials: A
authors.lastname: Koch
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.forename: Dirk
authors.initials: D
authors.lastname: Seegert
authors.forename: Norbert
authors.initials: N
authors.lastname: Reiling
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehlers
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schwinger
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.forename: Joachim
authors.initials: J
authors.lastname: Müller-Quernheim
authors.forename: Manfred
authors.initials: M
authors.lastname: Schürmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
mesh_terms: D018893:Bronchoalveolar Lavage; D000071797:Butyrophilins; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D059811:HLA-DRB1 Chains; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D009000:Monocytes / Q000382:microbiology / Q000502:physiology; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D022821:RNA Splice Sites / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D011993:Recombinant Fusion Proteins; D012307:Risk Factors; D012507:Sarcoidosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C408263:BTNL2 protein, human; D000071797:Butyrophilins; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D008562:Membrane Glycoproteins; D022821:RNA Splice Sites; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins