Sarcoidosis is associated with a truncating splice site mutation in BTNL2.
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.
Valentonyte
Ruta
R
Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany.
Hampe
Jochen
J
Huse
Klaus
K
Rosenstiel
Philip
P
Albrecht
Mario
M
Stenzel
Annette
A
Nagy
Marion
M
Gaede
Karoline I
KI
Franke
Andre
A
Haesler
Robert
R
Koch
Andreas
A
Lengauer
Thomas
T
Seegert
Dirk
D
Reiling
Norbert
N
Ehlers
Stefan
S
Schwinger
Eberhard
E
Platzer
Matthias
M
Krawczak
Michael
M
Müller-Quernheim
Joachim
J
Schürmann
Manfred
M
Schreiber
Stefan
S
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
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