This report describes susceptibility to spondyloarthropathy 1 (SPDA1), which shows multifactorial inheritance. The human gene implicated in this disease is the class I major histocompatibility complex gene HLA-B (human leukocyte antigen B), specifically the HLA-B27 allele. There are no orthologs of HLA-B in Drosophila.
The human gene Hsap\HLA-B has been introduced into flies, both as alleles associated (Hsap\HLA-B27:04.UAS, Hsap\HLA-B27:05.UAS) and not associated (Hsap\HLA-B07:02.UAS) with spondyloarthropathy.
Expressing SPDA1-implicated Hsap\HLA-B alleles along with the β2-microglobulin chain (Hsap\B2M) that HLA-B physically associates with in Drosophila causes a loss of specific wing veins and a reduction in eye size. No phenotype is not seen when any of these genes are expressed alone, nor when the non-implicated Hsap\HLA-B07:02.UAS allele is expressed with Hsap\B2M. Epistasis analysis with sax and other core BMP signaling pathway members (FBgg0001085) shows that co-expression of Hsap\HLA-B27:05.UAS and Hsap\HLA-B represses BMP signaling, providing a potential mechanism for SPDA1.
[updated Feb 2020 by FlyBase; FBrf0222196]
The spondyloarthropathies (SpA) now better termed spondyloarthritides (SpAs) are a group of diverse interrelated inflammatory arthritides which share multiple clinical features as well as common genetic predisposing factors. The group includes the prototypical disease ankylosing spondylitis (AS), reactive arthritis (ReA) or spondyloarthritis, psoriatic arthritis (PsA) or spondyloarthritis, SpA associated with inflammatory bowel disease (IBD) (Crohn's disease or ulcerative colitis), undifferentiated SpA (uSpA) and juvenile-onset spondyloarthritis. (From Ehrenfeld 2012 and references therein, pubmed:22424199.)
Spondyloarthritides are characterised by sacroiliitis with inflammatory back pain, peripheral arthropathy (joint disease), absence of rheumatoid factor and subcutaneous nodules, enthesitis (inflammation of entheses, sites where tendons or ligaments insert into bone), and extra-articular or extra-spinal involvement, including of the eye, heart, lung and skin. (Adapted from Taurog et al. 2016, pubmed:27355535.)
Spondyloarthropathy (SpA), one of the commonest chronic rheumatic diseases, includes a spectrum of related disorders comprising the prototype ankylosing spondylitis (AS), a subset of psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy (Miceli-Richard et al. 2004, pubmed:15234954). [from MIM:106300, 2020.02.25]
[SPONDYLOARTHROPATHY, SUSCEPTIBILITY TO, 1; SPDA1](https://omim.org/entry/106300)
[MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS I, B; HLA-B](https://omim.org/entry/142830)
HLA-B27, a class I surface antigen encoded by the B locus in the major histocompatibility complex (MHC), is found in 74 to 89% of patients with either nonradiographic axial spondyloarthritis or ankylosing spondylitis (odds ratio for the allele, >50). The absolute risk of spondyloarthritis in persons with HLA-B27 positivity is estimated to be 2 to 10% but is higher if a first-degree relative is affected. More than 140 variant alleles (subtypes) of HLA-B27 have been described at the level of protein sequence (www.ebi.ac.uk/ipd/imgt/hla/). (From Taurog et al. 2016, pubmed:27355535.)
De Blecourt et al. 1961 (pubmed:13869952) found spondylitis 22.6 times more frequently in the relatives of spondylitic patients than in the relatives of controls. They suggested autosomal dominant inheritance with greater penetrance in males than in females. O'Connell 1959 (pubmed:13650428) arrived at the same conclusion. The familial incidence was higher when the proband was female. Kornstad and Kornstad 1960 (pubmed:14411096) described 2 families in which only females were affected. Emery and Lawrence 1967 (pubmed:6082899) presented data that they interpreted as indicating multifactorial inheritance, however. Linkage data were published by Kornstad and Kornstad 1960 (pubmed:14411096) and earlier by Riecker et al. 1950 (pubmed:14783304). Schlosstein et al. 1973 (pubmed:4688372) found HLA specificity w27 in 35 of 40 cases (87.5%) of ankylosing spondylitis and in only 8% of normal controls. The HLA findings brought thinking about the genetics full-circle. Autosomal dominant inheritance with reduced penetrance seemed to be established.
