Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous multifactorial disease. Upregulated TLR7 signaling is a known risk factor for SLE. Recently, it was shown that specific genetic variants in UNC93B1 affect the physiological regulation of TLR7 signaling and cause characteristic autoimmune phenotypes with monogenic autosomal recessive inheritance in mutant mice and dogs. We therefore hypothesized that homologous variants in the human UNC93B1 gene might be responsible for a fraction of human SLE patients. We analyzed 536 patients of the Swiss SLE Cohort Study for the presence of genetic variants affecting the C-terminal tail of UNC93B1. None of the investigated patients carried bi-allelic UNC93B1 variants that were likely to explain their SLE phenotypes. We conclude that genetic variants affecting the C-terminal tail of UNC93B1 are not a common risk factor for SLE. It cannot be excluded that such variants might contribute to other heritable autoimmune diseases.
Highlights
Systemic lupus erythematosus (SLE) (Systemic Lupus Erythematosus) is a highly complex and heterogenous autoimmune disease with incompletely understood etiopathology [1,2]
One patient carried one copy of the mutant Asn-allele, which was present once in the current gnomAD dataset of 128,930 alleles. This female patient developed the first SLE manifestations including polyarthritis, acute cutaneous lupus, antinuclear, and anti-dsDNA antibodies at 16 years of age
We tested the hypothesis that genetic variants affecting the SDCBP binding domain of UNC93B1 might cause SLE. This hypothesis was developed from the observation that mouse and dog mutants with such variants exhibit severe autoimmune phenotypes [18,22]
Summary
SLE (Systemic Lupus Erythematosus) is a highly complex and heterogenous autoimmune disease with incompletely understood etiopathology [1,2]. Specific organs affected, and the severity of the disease are highly variable between patients. Several GWAS identified more than 100 risk loci for SLE, including associations to the HLA locus and many non-coding and presumably regulatory genome regions [4,5]. The X-chromosomal TLR7 gene encoding toll-like receptor 7 is one of the confirmed risk loci for SLE [5]. Increased TLR7 activity promotes autoimmunity [6,7,8], and there are indications that partial. Somal TLR7 gene encoding toll-like receptor 7 is one of the confirmed risk loci for SLE [5]. Increased TLR7 activity promotes autoimmunity [6,7,8], and there are indications that parteisaclaepsecaopf eTLoRf 7TLfrRo7mfrXo-mchrXo-mchorsoommoesionmacetiivnaatcitoinvamtiaoyncmonatyricbountetrtiobuthtee teoxttrheemeextsreexm-beiasseixnbSiLaEs iinncSiLdEenicneci[d9e].nAces[i9n]g. This ssttuuddyyiinnccluluddeedd553366paptaietinetnstosfotfhethSewSiwssiSssLESLCEohCoorht oStrut dSytu(dSSyC(S)S.COSf)t.hOefptahteienptas-, t4i5e7nt(s8,54%57) w(8e5r%e)fwemeraelefeamndale41a4n(d7481%4)(o7f8%Eu)roofpEeuarnodpesacnednet.scInen4t9. 7In(9439%7 )(9o3f%p)aotifepnatsti,eSnLtsE, SwLaEs wdiaasgdnioasgendosaeftderafttheer tahgeeaogfe1o8f 1y8eayresa.rsD. eDtaetialsilasbaobuotuththisiscocohhoortrthhaavveebbeeeenn reported previously [[2277––2299]]..GGeneonmomiciDc NDANAwaws aissoliasoteldatferdomfroEmTDEATDblAoobdlosaomd pslaems wplietsh twhiethMtahxewMealxl wRSeCll RWShCoW le hBololeodBlKoiotdusKinitguasiMngaxawMeallxRwSeClliRnsStCruimnsetnrut m(Pernomt (ePgrao,mDeügbae, nDdüobref,nSdwoirtf-, zSewrliatznedr)la. nd)
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