Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01889 (ankylosing spondylitis)
 5,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With the mapping of the human genome having been completed, our ability to investigate and ideally better understand the genetic basis of rheumatic diseases is advancing at a rapid pace. Substantial evidence strongly favors a direct role for HLA-B27 in genetic susceptibility to ankylosing spondylitis and related spondyloarthropathies, although the underlying molecular basis has yet to be identified. HLA-B27 contributes only 16 to 50% of the total genetic risk for the disease, clearly indicating that other genes must be involved. However, no other putative disease genes have yet been absolutely proven. Potential genes include MHC (HLA class II, low molecular weight proteasome [LMP], transporter associated with antigen processing (TAP), tumor necrosis factor [TNF]-alpha, and major histocompatibility complex class I chain-related gene A (MICA), as well as non-MHC genes (IL-1RA, IL-6, IL-10, and CYP2D6). Genome-wide screens have identified other chromosomal areas of interest: 1p, 2q, 6p, 9q, 10q, 16q, and 19q. However, different studies have given conflicting results. HLA-B27 itself is a serologic specificity, which encompasses 25 different alleles that encode 23 different products (proteins): HLA-B*2701 to B*2723. These alleles may have evolved from the most widespread subtype, B*2705, and two of them, B*2706 in Southeast Asia and B*2709 in Sardinia, seem not to be associated with ankylosing spondylitis. The distinction between the disease associated and nonassociated subtypes may provide clues to the actual role of B27 in disease pathogenesis.
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PMID:HLA-B27 and genetic predisposing factors in spondyloarthropathies. 1155 26

HLA-B27 confers susceptibility to ankylosing spondylitis (AS) but the mechanism linking this association remains unknown. Other properties unrelated to its natural role of antigen presenting function may be important in disease pathogenesis. We determined here the impact of N97D substitution on the folding and expression of HLA-B*2704 transfected in the 721.221 cell line. The mutation at position 97 abolishes the surface expression of non-conformational (HC10) and conformational (ME1) forms. The expression of ME1 forms was found to be absent in B*2704 N97D by immunoprecipitation and flow cytometry of fixed and permeabilized cell experiments with the conformation-sensitive ME1 antibody. However, immunoblotting cell lysates with HC10 revealed the presence of unfolded heavy chain (HC) and HC-dimer forms. The impact of the N97D mutation in the exit from the endoplasmic reticulum (ER) was analysed by western blot after endoglycosidase-H treatment, and it was found that B*2704 N97D was retained and accumulated as unfolded molecules. We tested for mutant association with transporter associated with antigen processing (TAP), calnexin (CNX), calreticulin (CLR) and beta2 microglobulin (beta2m). The wild-type B*2704 and N97D mutants were associated with TAP, CNX and CLR, although HC10 forms of mutant N97D interact more weakly with TAP. Only folded molecules of HLA-B*2704 were associated with beta2m. Surprisingly, the peptide-binding assay demonstrated the ability of unfolded N97D molecules to bind high-affinity peptides. It has been suggested that AS may arise because of aberrant folding of HLA-B27 molecules within the ER. Future work must therefore aim to clarify the functional connection between the unfolded protein response pathway in response to the accumulation of HLA-B27 in the ER. This mutant could be useful as a model for the misfolding of HLA-B27.
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PMID:The amino acid at position 97 is involved in folding and surface expression of HLA-B27. 1636 12

HLA-B27 confers susceptibility to ankylosing spondylitis but AS disease mechanisms remain unknown. We determined here the effect of polymorphism and tapasin dependence on the expression, intracellular maturation and homodimer formation among HLA-B27 subtypes. We found that B*2709 with a histidine at position 116 was strongly associated with the transporter associated with antigen processing complex, correlated with lower, non-conformational expression on the cell surface, delayed maturation rate and minimal conformational and non-conformational homodimer formation. In contrast, B*2705 showed a low dependence for transporter associated with antigen processing, faster intracellular maturation and increased levels of homodimeric forms. The absence of tapasin significantly influenced the rate of intracellular maturation of B*2709, showing faster transport out of the endoplasmic reticulum, but similar to that of B*2705. All B27 subtypes examined were unable to express conformational homodimeric forms in the absence of tapasin. This study suggests that HLA-B27 polymorphism drives the tapasin dependency, rates of intracellular maturation and expressions of homodimers.
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PMID:HLA-B27 polymorphism at position 116 critically influences the association with TAP/tapasin, intracellular trafficking and conformational homodimers formation. 1916 61

Human leukocyte antigen (HLA)-B27 is strongly associated with the autoimmune disease ankylosing spondylitis (AS). Other autoimmune disease-associated genes, such as transporter associated with antigen processing (TAP) genes, could also influence AS susceptibility. In this study, we investigated the association of TAP1 and TAP2 polymorphisms in genetically homogenous Chinese AS patients. Six TAP1 single nucleotide polymorphisms (SNPs) and three TAP2 SNPs sites were analyzed in B27-positive AS cases, healthy B27-negative controls, and healthy B27-positive controls. In the allele and genotype analysis, the results indicated that TAP1 site 1910 allele G, genotype AG and TAP2 site 1693 genotype AA were associated with increased AS risk in a case-B27 negative control (p < 0.05). In the haplotype analysis, TAP1 SNP haplotype (GGGGGG, TAP1*020101) and TAP1-TAP2 SNP haplotypes (GGGGGG-GGG, TAP1*020101-TAP2*0101, and GGAAGG-GAG, TAP1*0101-TAP2*0102) increased AS risk in case-B27 negative control (p < 0.05). In contrast, TAP1-TAP2 SNP haplotype GGGGGG-GAG (TAP1*020101-TAP2*0102) was less common in cases than in B27-negative controls (p < 0.05). Moreover, TAP1-TAP2 SNP haplotype GGGAGG-GGG (TAP1*0301-TAP2*0101) was less common in cases than in B27-positive controls. The two haplotypes appeared to confer protection in AS (p < 0.05). These results suggest a potential mechanism of altered antigen-peptide selection and transport in AS pathogenesis.
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PMID:TAP1 and TAP2 polymorphisms associated with ankylosing spondylitis in genetically homogenous Chinese Han population. 1948 Aug 48