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Nat Genet. 2005 Apr;37(4):357-64. Epub 2005 Feb 27.

Sarcoidosis is associated with a truncating splice site mutation in BTNL2.

Author information

1
Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany.

Erratum in

  • Nat Genet. 2005 Jun;37(6):652.

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.

PMID:
15735647
DOI:
10.1038/ng1519
[Indexed for MEDLINE]

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