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Variants Affecting the C-Terminal Tail of UNC93B1 Are Not a Common Risk Factor for Systemic Lupus Erythematosus

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Variants Affecting the C-Terminal Tail of UNC93B1 Are Not a Common Risk Factor for Systemic Lupus Erythematosus G C A T T A C G G C A T genes Article Variants Affecting the C-Terminal Tail of UNC93B1 Are Not a Common Risk Factor for Systemic Lupus Erythematosus Sarah Kiener 1,2 , Camillo Ribi 3 , Irene Keller 4, Carlo Chizzolini 5 , Marten Trendelenburg 6, Uyen Huynh-Do 7 , Johannes von Kempis 8, on behalf of Swiss SLE Cohort Study (SSCS) † and Tosso Leeb 1,2,* 1 Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; [email protected] 2 Dermfocus, University of Bern, 3001 Bern, Switzerland 3 Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), 1011 Lausanne, Switzerland; [email protected] 4 Interfaculty Bioinformatics Unit, University of Bern, 3012 Bern, Switzerland; [email protected] 5 Department of Pathology and Immunology, School of Medicine, Geneva University, 1211 Geneva, Switzerland; [email protected] 6 Laboratory for Clinical Immunology, Department of Biomedicine and Division of Internal Medicine, University Hospital of Basel, 4031 Basel, Switzerland; [email protected] 7 Division of Nephrology and Hypertension, Inselspital, Bern University Hospital, 3010 Bern, Switzerland; [email protected] 8 Division of Rheumatology, Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland; [email protected] * Correspondence: [email protected]; Tel.: +41-31-684-2326 † Association of the Swiss SLE Cohort Study (ASSCS), 4031 Basel, Switzerland. Citation: Kiener, S.; Ribi, C.; Keller, I.; Abstract: Systemic lupus erythematosus (SLE) is a heterogeneous multifactorial disease. Upregulated Chizzolini, C.; Trendelenburg, M.; TLR7 signaling is a known risk factor for SLE. Recently, it was shown that specific genetic variants in Huynh-Do, U.; von Kempis, J.; on UNC93B1 affect the physiological regulation of TLR7 signaling and cause characteristic autoimmune behalf of Swiss SLE Cohort Study (SSCS); Leeb, T. Variants Affecting the phenotypes with monogenic autosomal recessive inheritance in mutant mice and dogs. We therefore C-Terminal Tail of UNC93B1 Are Not hypothesized that homologous variants in the human UNC93B1 gene might be responsible for a a Common Risk Factor for Systemic fraction of human SLE patients. We analyzed 536 patients of the Swiss SLE Cohort Study for the pres- Lupus Erythematosus. Genes 2021, 12, ence of genetic variants affecting the C-terminal tail of UNC93B1. None of the investigated patients 1268. https://doi.org/10.3390/ carried bi-allelic UNC93B1 variants that were likely to explain their SLE phenotypes. We conclude genes12081268 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. Academic Editor: Katsushi Tokunaga Keywords: Homo sapiens; immunology; autoimmunity; candidate gene; TLR7 signaling Received: 5 July 2021 Accepted: 8 August 2021 Published: 19 August 2021 1. Introduction Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in SLE (Systemic Lupus Erythematosus) is a highly complex and heterogenous autoim- published maps and institutional affil- mune disease with incompletely understood etiopathology [1,2]. Age of onset, specific iations. organs affected, and the severity of the disease are highly variable between patients. SLE is characterized by a breakdown in immune tolerance, which promotes the formation of autoreactive B and T cells, abnormal cytokine production, and the subsequent generation of autoantibodies against DNA- and RNA-based self-antigens [2]. Women are nine times more frequently affected than men, and the incidence of the disease is highest in women of Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. childbearing age [3]. This article is an open access article SLE is thought to be caused by interactions between susceptibility genes and environ- distributed under the terms and mental factors resulting in an irreversible loss of immunologic self-tolerance. Several GWAS conditions of the Creative Commons identified more than 100 risk loci for SLE, including associations to the HLA locus and Attribution (CC BY) license (https:// many non-coding and presumably regulatory genome regions [4,5]. The X-chromosomal creativecommons.org/licenses/by/ TLR7 gene encoding toll-like receptor 7 is one of the confirmed risk loci for SLE [5]. In- 4.0/). creased TLR7 activity promotes autoimmunity [6–8], and there are indications that partial Genes 2021, 12, 1268. https://doi.org/10.3390/genes12081268 https://www.mdpi.com/journal/genes Genes 2021, 12, x FOR PEER REVIEW 2 of 6 Genes 2021, 12, 1268 and many non-coding and presumably regulatory genome regions [4,5]. The X-chromo-2 of 6 somal TLR7 gene encoding toll-like receptor 7 is one of the confirmed risk loci for SLE [5]. Increased TLR7 activity promotes autoimmunity [6–8], and there are indications that par- tialescape escape of TLR7 of TLR7from from X-chromosome X-chromosome inactivation inactivation may contributemay contribute to the to extreme the extreme sex-bias sex- in biasSLE in incidence SLE incidence [9]. A single[9]. A nucleotidesingle nucleotide variant variant in the 3in0-UTR, the 3′-UTR, rs3853839, rs3853839, modulates modulates TLR7 TLR7expression expression and has and been has repeatedlybeen repeat associatededly associated with SLE with [10 SLE,11 ].[10,11]. While SLE isis aa geneticallygenetically highlyhighly complex complex disease, disease, rare rare patients patients exist exist in in which which SLE SLE or orrelated related autoimmune autoimmune disorders disorders are are caused caused by by single-gene single-gene defects. defects. Genes Genes affectedaffected inin such patients include DNASE1 [[12]12] and TREX1 [[13].13]. TLR7 is activated by single-stranded RNA and represents a component of the innate immune defensedefense againstagainst RNA RNA viruses. viruses. The The trafficking trafficking chaperone chaperone UNC93B1 UNC93B1 is requiredis required for forthe correctthe correct localization localization of TLR7 of TLR7 to endosomal to endosomal membranes, membranes, and its loss-of-functionand its loss-of-function leads to leadsan immune to an immune deficiency deficiency [14–16]. [14–16]. TLR7 and TLR7 UNC93B1 and UNC93B1 form a heterotetrameric form a heterotetrameric complex com- in a plex2:2 stoichiometry in a 2:2 stoichiometry in endosomal in endosomal membranes memb [17].ranes Subsequent [17]. Subsequent to TLR7 activation, to TLR7 activation, syndecan syndecanbinding protein binding (SDCBP) protein binds(SDCBP) to thebinds C-terminal to the C-terminal tail of UNC93B1, tail of UNC93B1, which induces which thein- ducestermination the termination of TLR7 signaling of TLR7 signaling [18]. Genetic [18]. variantsGenetic variants in UNC93B1 in UNC93B1that prevent that prevent SDCBP SDCBPbinding binding without without affecting affecting other functionsother function of UNC93B1s of UNC93B1 result result in the in disruption the disruption of this of thisnegative negative feedback feedback loop loop and and consequently consequently overactive overactive TLR7 TLR7 signaling signaling that that will will eventually eventu- PKP/PKP allybe triggered be triggered by endogenous by endogenous RNA RNA molecules molecules [18–21 [18–21].]. Unc93b1 Unc93b1PKP/PKPmice mice with with a targeted a tar- geteddisruption disruption of the of SDCBP the SDCBP binding binding motif motif develop develop a fatal a fatal systemic systemic inflammation inflammation and and au- autoimmunetoimmune disease disease [18 [18].]. In In dogs, dogs, a spontaneousa spontaneous missense missense variant variant affecting affecting the the C-terminal C-termi- naltail tail of UNC93B1of UNC93B1 causes causes exfoliative exfoliative cutaneous cutaneous lupus lupus erythematosus erythematosus (ECLE) (ECLE) [ 22[22].]. ECLE starts with skin lesions but typically develops into a systemic form of lupus in the affected dogs [22–26] [22–26] (Figure 1 1).). Figure 1. Topology of the human UNC93B1 protein. ( A) UNC93B1 comprises 597 amino ac acidsids and and contains contains 12 12 transmem- transmem- brane domains.domains. AA segmentsegment of of the the C-terminal C-terminal tail tail indicated indicated in in red red is requiredis required for for the the interaction interaction with with SDCBP SDCBP and subsequentand subse- dampeningquent dampening of TLR7 of signalingTLR7 signaling [18]. (B [18].) Amino (B) Amino acid sequence acid sequence from position from position 521 to 521 553. to Substitution 553. Substitution of a highly of a highly conserved con- prolineserved proline with threonine with threonine causes causes exfoliative exfoliative cutaneous cutaneous lupus lupus erythematosus erythematosus in dogs in [dogs22]. Targeted[22]. Targeted mutagenesis mutagenesis of the of four the four underlined motifs disrupted SDCBP binding in mouse macrophages [18]. A targeted mouse mutant, Unc93b1PKP/PKP, underlined motifs disrupted SDCBP binding in mouse macrophages [18]. A targeted mouse mutant, Unc93b1PKP/PKP, in which the residues corresponding to the human positions 530-532 were replaced by alanines, developed systemic in- in which the residues corresponding to the human positions 530–532 were replaced by alanines, developed systemic flammation and autoimmunity [18]. inflammation and autoimmunity [18]. Based on the recent insights about UNC93B1 function and the phenotypes in Based on the recent insights about UNC93B1
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